Sustainability of tsetse control by subsequent treatment of 10% of a previously treated Ugandan cattle population with 1% w/v deltamethrin.
This study was conducted in Masaba and Masafu Sub-counties, Busia District, Uganda to assess the effect on the tsetse fly population of first treating all cattle with 1% w/v deltamethrin pour-on for a few months, followed by treating 10% of the cattle population. Treatment of all cattle for 6 months resulted in a significant reduction in the density of tsetse flies from 6.3 to 0.1 flies/trap/day (FTD), a 98.4% reduction. During the same period, the point prevalence of bovine trypanosomosis dropped from 37.7% to 2.9% (a 92.3% reduction). Treatment was resumed six months later, but this time only 10% of the cattle population received the pour-on treatment at three week intervals for a period of one year. This treatment maintained the tsetse fly density between 0 and 0.5 FTD and the prevalence of bovine trypanosomosis generally remained below 10%. In conclusion, under the local prevailing conditions, treatment of all communally grazed cattle with deltamethrin pour-on effectively suppressed the Glossina fuscipes fuscipes population. However, subsequent treatment of 10% of the cattle probably failed to control the tsetse fly population at a level sufficient to reduce trypanosomosis to acceptable levels.


Impact of BRAFV600E Mutation on Event-Free Survival in Patients with Papillary Thyroid Carcinoma: A Retrospective Study in a Romanian Population.
We aimed to evaluate the prognostic value of BRAFV600E mutation in a series of 127 papillary thyroid carcinoma (PTC) cases as a single factor, and in synergic interaction with other standard risk factors. BRAFV600E mutation was assessed by real-time PCR. Event-free survival (EFS) was calculated between the date of the first evaluation and the date of occurrence of an adverse event or the date of the last known status. The prevalence of BRAFV600E mutation was 57.2%. The Kaplan-Meier analysis showed a significant reduction of EFS among cases harboring BRAFV600E mutation compared to non-mutated cases (p = 0.010). In addition, BRAFV600E mutation was found to better predict adverse outcomes when associated with the following risk factors: age ≥ 55 years old (p < 0.001), male gender (p < 0.001), conventional (p = 0.005) and tall cell (p = 0.014) histology, tumor size > 40 mm (p = 0.001), extrathyroidal extension (p = 0.001), multifocality (p = 0.001) and lymph node metastasis (p < 0.001). In univariate analysis, a 3.74-fold increased risk for a reduced EFS (p = 0.018) was found for BRAFV600E-mutated cases, but no increased risk was further confirmed by multivariate analysis. Our results highlight that BRAFV600E mutation cannot be used alone as an independent predictive factor in PTC patients, but is prognostically valuable if integrated in the context of other clinicopathological risk factors.


Exfoliation and immobilization of anionic iron porphyrin in layered double hydroxides.
Mg-Al layered double hydroxide (LDH) intercalated with glycinate anions was synthesized through co-precipitation and exfoliated in formamide and the single-layer suspension was reacted with an aqueous iron porphyrin (FeTDFSPP) solution. The new composite was characterized by powder X-ray diffraction, UV-vis, FTIR, and electron paramagnetic spectroscopies and thermal analyses (simultaneous TG/DSC). The analyses demonstrated that glycinate anions continue to be intercalated and the anionic iron porphyrin is adsorbed at the surface of the layered double hydroxide crystals.


Currents activated by GABA and their modulation by Zn2+ in cerebellar granule cells in culture.
Whole-cell and single-channel currents evoked by gamma-aminobutyric acid (GABA) were recorded from rat cerebellar granule cells in culture. The electrophysiological properties of these currents were studied in control condition and in the presence of external Zn2+ (10-30 microM). GABA (10 microM) induced bicuculline-sensitive whole-cell currents which desensitized. The desensitization was more rapid for higher concentrations of GABA (30-300 microM). The current-voltage relation of GABA currents was linear from -70 to +50 mV. Two different types of cells were found with respect to the stoichiometry for agonist binding, one with Hill coefficient 1.5 and another one with coefficient 1. The half-maximum concentration displayed more variability, with values varying from 10 to 50 microM. The time constant of recovery from desensitization (tau r) was estimated to be 36 s. Zn2+ (30 microM) blocked GABA-activated whole-cell currents in a non-competitive and voltage-independent way without a significant change in the current kinetics. In excised outside-out patches, GABA (0.5 microM) activated single-channel events of 19 and 31 pS. Kinetic analysis yielded two mean shut times (tau c1 = 2.70 ms, tau c2 = 205 ms) and one mean open time (tau o = 3.64 ms). Zn2+ (10 microM) did not affect single-channel conductances and mean open and shut times, but significantly reduced the probability of opening from 0.17 to 0.06. It is probable that Zn2+ binds to a site located on the extracellular part of the GABAA receptor channel complex.


Photochemical mechanisms of light-triggered release from nanocarriers.
Over the last three decades, a handful of photochemical mechanisms have been applied to a large number of nanoscale assemblies that encapsulate a payload to afford spatio-temporal and remote control over activity of the encapsulated payload. Many of these systems are designed with an eye towards biomedical applications, as spatio-temporal and remote control of bioactivity would advance research and clinical practice. This review covers five underlying photochemical mechanisms that govern the activity of the majority of photoresponsive nanocarriers: 1. photo driven isomerization and oxidation, 2. surface plasmon absorption and photothermal effects, 3. photo driven hydrophobicity changes, 4. photo driven polymer backbone fragmentation and 5. photo driven de-crosslinking. The ways in which these mechanisms have been incorporated into nanocarriers and how they affect release are detailed, as well as the advantages and disadvantages of each system.


BAG3: a new player in the heart failure paradigm.
BAG3 is a cellular protein that is expressed predominantly in skeletal and cardiac muscle but can also be found in the brain and in the peripheral nervous system. BAG3 functions in the cell include: serving as a co-chaperone with members of the heat-shock protein family of proteins to facilitate the removal of misfolded and degraded proteins, inhibiting apoptosis by interacting with Bcl2 and maintaining the structural integrity of the Z-disk in muscle by binding with CapZ. The importance of BAG3 in the homeostasis of myocytes and its role in the development of heart failure was evidenced by the finding that single allelic mutations in BAG3 were associated with familial dilated cardiomyopathy. Furthermore, significant decreases in the level of BAG3 have been found in end-stage failing human heart and in animal models of heart failure including mice with heart failure secondary to trans-aortic banding and in pigs after myocardial infarction. Thus, it becomes relevant to understand the cellular biology and molecular regulation of BAG3 expression in order to design new therapies for the treatment of patients with both hereditary and non-hereditary forms of dilated cardiomyopathy.


Working From Home and Job Loss Due to the COVID-19 Pandemic Are Associated With Greater Time in Sedentary Behaviors.
Objectives: Due to the COVID-19 pandemic, major changes to how, or even whether, we work have occurred. This study examines associations of changing COVID-19-related employment conditions with physical activity and sedentary behavior. Methods: Data from 2,303 US adults in employment prior to COVID-19 were collected April 3rd-7th, 2020. Participants reported whether their employment remained unchanged, they were working from home (WFH) when they had not been before, or they lost their job due to the pandemic. Validated questionnaires assessed physical activity, sitting time, and screen time. Linear regression quantified associations of COVID-19-related employment changes with physical activity, sitting time, and screen time, controlling for age, sex, race, BMI, smoking status, marital status, chronic conditions, household location, public health restrictions, and recalled physical activity, sitting time, and screen time prior to the COVID-19 pandemic. Results: Compared to those whose employment remained unchanged, participants whose employment changed (either WFH or lost their job) due to COVID-19 reported higher sitting time (WFH: g = 0.153, 95% CI = 0.095-0.210; lost job: g = 0.212, 0.113-0.311) and screen time (WFH: g = 0.158, 0.104-0.212; lost job: g = 0.193, 0.102-0.285). There were no significant group differences for physical activity (WFH: g = -0.030, -0.101 to 0.042; lost job: g=-0.070, -0.178 to 0.037). Conclusion: COVID-19 related employment changes were associated with greater sitting and screen time. As sedentary time is consistently negatively associated with current and future health and wellbeing, increased sedentary time due to employment changes is a public health concern.


Initiation of translation makes attenuation of ampC in E. coli dependent on growth rate.
The chromosomal beta-lactamase gene of E. coli, ampC, shows increased expression with increased growth rate of the bacteria. We have previously shown that transcription of ampC is attenuated, and that a mutation in the terminator stem of this attenuator abolishes the growth rate-dependency of ampC expression. We now present studies using mutations, made in vitro, located such that the 5'-end of ampC mRNA carries a possible recognition sequence for initiation of translation close to the attenuator stem. Alteration of the supposed initiation codon AUG to UUG resulted in a reduced and growth rate-independent expression of ampC beta-lactamase. AmpC mRNA starts with the sequence AUC, which might be a non-typical ribosome binding site, situated four bases before the AUG. Deletion of the C in this sequence caused a partial reduction of ampC expression and also a partial loss of the growth rate-dependent regulation. The phenotypes of these mutants support a model in which formation of a ribosome initiation complex at a level increasing with the growth rate inhibits termination of transcription at the ampC attenuator.


Regulation of human erythropoietin gene induction by upstream flanking sequences in transgenic mice.
Human erythropoietin (Epo) gene expression is inducible by hypoxia or anaemia in the kidney and liver. Previous transgenic mouse experiments have demonstrated that sequences required for Epo gene induction in the kidney reside in a 7 8 kb Barn HI fragment located 6 kb upstream of the gene. To sublocalize these sequences, we performed Desoxyribonuclease I (DNAse I) mapping studies using transgenic mice which carried this DNA fragment. These studies revealed a DNAse I hypersensitive site (DNAse I HS) located 4 6 kb from the upstream end of the 7.8 kb fragment in anaemic kidney and liver samples. Sequence analysis of the region encompassing the DNAse I HS revealed an element with remarkable homology to the 3' Epo gene hypoxia-inducible enhancer. This suggested the presence of an additional regulatory element that contributes to the control of hypoxia-inducible Epo gene expression in kidney and liver. We constructed transgenic mice containing the human Epo gene linked to either the 5 kb upstream or 2.5 kb downstream portion of the 7.8kb fragment. Inducible expression was limited to the liver. Thus, neither fragment was alone sufficient to confer kidney inducible expression. These findings indicate that sequences more than 8.5 kb upstream of the Epo gene are required for kidney-specific induction. They suggest that either those sequences reside in an 0.3 kb Hind III fragment located between the 5 kb and the 2.5 kb fragments or that sequences in the 5 kb or 0.3 kb fragments must interact with sequences in the 2.5 kb fragment to allow Epo gene induction in the kidney.


Pediatric urodynamics: a clinical comparison of surface versus needle pelvic floor/external sphincter electromyography.
Urodynamic evaluations were done on 37 children to diagnose voiding pattern abnormalities and/or recurrent urinary infections. Each of 25 children had 2 sets of testing to judge a practical method of urodynamic evaluation. Bipolar anal skin electrodes were compared to bipolar perianal muscle needle electrodes as a means of monitoring the urethral sphincter/pelvic floow electromyographic activity. In addition, the urethral catheter was compared to the suprapubic catheter as a means of monitoring intravesical pressure. The results were similar and statistically significant (p less than 0.001). The remaining 12 children were evaluated based only on the results of bipolar anal skin electrodes and uroflowmetry. The results of both groups clearly demonstrated that surface perianal electrodes are practical, accurate and reliable for the diagnosis and treatment of children with voiding pattern abnormalities. We recommend the use of surface electrodes and a urethral catheter as techniques for the urodynamic evaluation of voiding pattern abnormalities of children without overt neuropathology or extensive urethral operation. Preoperative surface electromyography of the urinary sphincters may prove to be a useful screening test to detect occult dyssynergia in patients who have had failed ureteral reimplants.


Upgraded bidirectional approach video-assisted neck surgery (BAVANS) using a rigid endoscope with variable viewing direction for advanced endoscopic lymph node dissection in thyroid cancer patients.
In 2011, we developed bidirectional approach video-assisted neck surgery (BAVANS) for endoscopic thyroid cancer surgery. BAVANS combines two different approach pathways at 180 degrees to the cervical lesion for endoscopic thyroidectomy and complete cervical lymphadenectomy. We reported previously that the cranio-caudal approach is extremely useful for endoscopic complete lymph node dissection around the trachea. In 2014, we upgraded the initial BAVANS for better maneuverability and quality of lymph node dissection. A new high-tech rigid endoscope with a variable viewing direction (EndoCAMeleon™), has enabled us to reduce the camera port in the anterior neck while keeping the easy maneuverability and the same quality of central lymph node dissection (LND) as with the initial BAVANS. Endoscopic thyroid cancer surgery is now evolving concurrently with new visual technology.


Excess cardiac mortality on Monday: the importance of gender, age and hospitalisation.
Available evidence suggests a peak in the incidence of cardiovascular events on Mondays compared to other days of the week. The underlying mechanism may be summarised as naturally occurring rhythmic fluctuations in human physiology, and socially determined rhythms in human behaviour. Change in these rhythms may lead to attenuation of the peak on Mondays. To quantify the excess risk associated with the Monday peak in cardiovascular mortality and to explore the role of age, gender and hospitalisation. Details on time and cause of all deaths which occurred in the city of Rotterdam between November 21, 1988 and November 21, 1990 were obtained by sending a questionnaire to the physician who signed the death certificate. We studied the weekly distribution of 1828 confirmed cases of sudden cardiac death, for the group as a whole and in subgroups according to gender, age (< 65 years/65 years) and hospitalisation. The odds ratio (OR) of sudden cardiac death on Monday compared to other days of the week was 1.20 (95% CI: 1.06-1.36). The excess mortality due to the Monday peak amounted to 4.9 per 1000 deaths. The Monday peak was more pronounced in non-hospitalised (OR: 1.25; 95% CI: 1.08-1.44) than in hospitalised patients (OR: 1.06; 95% CI: 0.83-1.37), in men (OR: 1.25; 95% CI: 1.06-1.48) than in women (OR: 1.14; 95% CI: 0.95-1.36), and in those younger than 65 (OR: 1.29; 95% CI: 0.95-1.74) compared to those aged 65 years or over (OR: 1.18; 95% CI: 1.03-1.35). Yet, the confidence limits overlap. The incidence of sudden cardiac death is markedly increased on Monday, more pronounced in non-hospitalised patients. Our results may point to the relevance of naturally occurring rhythmic fluctuations in human physiology, and socially determined rhythms in human behaviour as underlying mechanism.


Evidence of prehistoric human activity in the Falkland Islands.
When Darwin visited the Falkland Islands in 1833, he noted the puzzling occurrence of the islands' sole terrestrial mammal, Dusicyon australis (or "warrah"). The warrah's origins have been debated, and prehistoric human transport was previously rejected because of a lack of evidence of pre-European human activity in the Falkland Islands. We report several lines of evidence indicating that humans were present in the Falkland Islands centuries before Europeans, including (i) an abrupt increase in fire activity, (ii) deposits of mixed marine vertebrates that predate European exploration by centuries, and (iii) a surface-find projectile point made of local quartzite. Dietary evidence from D. australis remains further supports a potential mutualism with humans. The findings from our study are consistent with the culture of the Yaghan (Yámana) people from Tierra del Fuego. If people reached the Falkland Islands centuries before European colonization, this reopens the possibility of human introduction of the warrah.


Coupling in vitro assays with sequential extraction to investigate cadmium bioaccessibility in contaminated soils.
To understand how Cd in different fractions contributes to Cd bioaccessibility by in vitro assays, Cd bioaccessibility in 12 contaminated soils was determined by four assays (UBM, SBRC, IVG, and PBET) and correlated with different Cd fractions based on a sequential extraction scheme. The Cd bioaccessibility in the gastric phase (GP) was high (35-107%, averaging at 77%), implicating high risk to human health, while it decreased to 19-88% averaging at 47% in the intestinal phased (IP). From the GP to IP, the reduction of extractable Cd (0.45-48 mg kg-1) and Fe (118-3884 mg kg-1) showed significant correlation (R = 0.54-0.74) via UBM, SBRC, and IVG, suggesting co-precipitation with Fe and/or sorption onto Fe oxides maybe responsible for decrease in Cd bioaccessibility. Although Cd bioaccessibility varied among assays, their results show some consistency based on their correlation in the GP (R = 0.56-0.90) and IP (0.34-0.73, excluding UBM-IP and PBET-IP). Sequential extraction data show that Cd was primarily associated with the exchangeable fraction (E1; 7.05-72.9%, averaging 39.4%). The carbonate (C2; 6.86-44.8%, 21.9%) and Fe/Mn oxides fraction (F3; 12.5-53.6%, 28.2%) were similar, while organic (O4; 0.62-25.0%, 7.91%) and residual fraction (R5; 0.22-8.54%, 2.62%) were the lowest. Significant correlation (R = 0.59-0.88) between the first two fractions (E1+C2) and bioaccessible Cd suggest they were the main sources of bioaccessible Cd in those contaminated soils.


Tumour microenvironment changes after osimertinib treatment resistance in non-small cell lung cancer.
Growing evidence suggests that acquired resistance to targeted therapy in non-small cell lung cancer patients is linked to the mutual domestication between the tumour and its surrounding microenvironment. Our study aims to explore the remodelling of tumour microenvironment after osimertinib treatment resistance. We took RNA-seq-based tumour immune infiltration analysis using the TIMER 2.0. We carried out flow cytometry assay and real-time cell analysis to explore the interaction between tumour cells and immune cells. In addition, we analysed exosomes via miRNA-seq and label-free proteomics. Immune infiltration estimation showed a significant decrease in the immune score (P < 0.001), microenvironment score (P < 0.001) and CD8+ T cells (P < 0.05), but an increase in M0 macrophages (P < 0.01) at osimertinib resistance compared to pre-treatment patients. It was demonstrated that exosomes from H1975OR cells could be taken up by macrophages and drove their polarisation towards the M2 phenotype, and the polarised M2 macrophages could reduce the inhibitory effect on tumour cell proliferation. Pre-activated peripheral blood mononuclear cells exhibited a more potent killing effect on H1975OR cells. We also detected a decrease in CD4+HLA-DR- T cells and an increase in CD4+PD1+ T cells after being co-cultured with H1975OR derived exosomes or conditioned medium. Further miRNA-seq and proteomics analysis of exosomes demonstrated that mir-1258-3p and miR-17-5p might participate in this interaction. An immunosuppressive environment, characterised by decreased T cell infiltration and activation, whereas increased macrophage infiltration and M2 polarisation, was identified at osimertinib resistance. This interaction may be carried out by tumour-derived exosomes.


Frühzeitiges Absetzen des paramedianen Stirn-Interpolationslappens unter Verwendung von kutanem Ultraschall.
Der paramediane Stirnlappen ist ein Interpolationslappen, bei dem Gewebe von der Stirn in die Nasenregion transplantiert wird. Die Blutversorgung erfolgt über die Arteria supratrochlearis. Üblicherweise wird der vaskuläre Stiel zwischen dem 14. und dem 21. postoperativen Tag abgesetzt; diese Zeit könnte allerdings zu lang bemessen sein. Wir wollen zeigen, dass der paramediane Stirnlappen bereits vor der in der Literatur angegebenen Zeit abgesetzt werden kann, und demonstrieren den Nutzen des kutanen Ultraschalls für die Bestimmung des optimalen Zeitpunkts. Unsere Studie mit Patienten, deren Nasendefekt durch eine paramediane Stirnlappenplastik rekonstruiert wurde, war als prospektive Beobachtungsstudie angelegt. Einschlusskriterium waren Hautdefekte von mehr als 2 cm Größe an der Nasenspitze, dem Nasenrücken oder den Nasenflügeln nach onkologischer Operation. Zwölf Patienten wurden in die Studie aufgenommen. Eine retrospektive Kohorte wurde zur Analyse der Kostenminderung herangezogen. Die durchschnittliche Dauer bis zur etablierten Vaskularisierung betrug 6,6 Tage, gemessen mittels Ultraschall. Die durchschnittliche Zeit bis zum Absetzen des Transplantatstiels betrug 6,9 Tage. Es wurden keine schwerwiegenden Komplikationen beobachtet. Der paramediane Stirnlappen kann bereits vor der traditionell üblichen Zeit abgesetzt werden. Ultraschall ist eine zuverlässige und kostengünstige Methode, um die individuell am besten geeignete Zeit zum Absetzen des Transplantatstiels zu bestimmen.


Erratum to clinical impact of the lung tissue transcriptome in a teenager with multifocal invasive mucinous adenocarcinoma-a case report.
[This corrects the article DOI: 10.21037/tlcr-20-177.].


Computational Investigation of Substituent Effects on the Fluorescence Wavelengths of Oxyluciferin Analogs.
Oxyluciferin, which is the light emitter for firefly bioluminescence, has been subjected to extensive chemical modifications to tune its emission wavelength and quantum yield. However, the exact mechanisms for various electron-donating and withdrawing groups to perturb the photophysical properties of oxyluciferin analogs are still not fully understood. To elucidate the substituent effects on the fluorescence wavelength of oxyluciferin analogs, we applied the absolutely localized molecular orbitals (ALMO)-based frontier orbital analysis to assess various types of interactions (i.e. permanent electrostatics/exchange repulsion, polarization, occupied-occupied orbital mixing, virtual-virtual orbital mixing, and charge-transfer) between the oxyluciferin and substituent orbitals. We suggested two distinct mechanisms that can lead to red-shifted oxyluciferin emission wavelength, a design objective that can help increase the tissue penetration of bioluminescence emission. Within the first mechanism, an electron-donating group (such as an amino or dimethylamino group) can contribute its highest occupied molecular orbital (HOMO) to an out-of-phase combination with oxyluciferin's HOMO, thus raising the HOMO energy of the substituted analog and narrowing its HOMO-LUMO gap. Alternatively, an electron-withdrawing group (such as a nitro or cyano group) can participate in an in-phase virtual-virtual orbital mixing of fragment LUMOs, thus lowering the LUMO energy of the substituted analog. Such an ALMO-based frontier orbital analysis is expected to lead to intuitive principles for designing analogs of not only the oxyluciferin molecule, but also many other functional dyes.


Thyroid carcinoma in intrathoracic goiter.
Most cases of intrathoracic goiter can be managed by cervical incision alone. A thoracic approach may be needed when adhesions or an anomalous blood supply are present or carcinoma is suspected. Only 44 patients out of 5263 operated on for goiter needed a thoracic incision. A sternotomy was performed in 29 cases and a thoracotomy in 15; a malignancy was present in 9 cases. Symptoms, surgical approach, histology, survival and pTN staging of these 9 patients were reviewed and discussed; no perioperative mortality was observed. A thoracic approach is more frequently needed for treatment of intrathoracic thyroid carcinoma as it offers a greater chance of radical excision and better control of intraoperative bleeding. Histologically, thyroid carcinoma in intrathoracic goiter is often anaplastic or rare and has a poor long-term survival rate when compared to cervical forms.


Detection of phosphorylated Akt and MAPK in cell culture assays.
This article describes an immunocytochemistry (ICC) method for staining against phosphorylated forms of the kinases Akt (pAkt) and MAPK (pMAPK). Phosphorylation is induced upon their activation by a number stimuli including insulin and brain-derived neurotrophic factor (BDNF), and is prerequisite for a number of cellular processes including cell proliferation and survival [1], [2], [3], [4], [5], [6]. ICC using antibodies raised against specific phosphorylation sites allows cell-type specific and subcellular monitoring of kinase activation. Here, we test how four different antibodies against pAkt and pMAPK, respectively perform in different cell types following insulin or BDNF stimulation using different protocol conditions. We find that phospho-specific-antibodies generally perform better when using Triton X-100 as a permeabilization agent compared to Saponin. In addition, two antibodies against pAkt and two against pMAPK gave a clear increase in signal in cells stimulated with insulin or BDNF compared to the signal obtained in unstimulated cells. These antibodies also performed well when tested with western blotting. Our results illustrate that both the choice of antibody as well as protocol details are critical parameters for successful detection of phosphorylated forms of kinases by ICC. This article includes: •A protocol for subcellular detection of phosphorylated Akt and MAPK.•Validation of 8 antibodies by immunocytochemistry.•Confirmation by western blotting.


Molecular characterization of the microRNA-138-Fos-like antigen 1 (FOSL1) regulatory module in squamous cell carcinoma.
MicroRNA-138 is one of the most frequently down-regulated microRNAs in cancer. We recently identified 51 candidate targets of microRNA-138 (Jiang, L., Dai, Y., Liu, X., Wang, C., Wang, A., Chen, Z., Heidbreder, C. E., Kolokythas, A., and Zhou, X. (2011) Hum. Genet. 129, 189-197). Among these candidates, Fos-like antigen 1 (FOSL1) is a member of Fos gene family and is a known proto-oncogene. In this study, we first confirmed the microRNA-138-mediated down-regulation of FOSL1 in squamous cell carcinoma cell lines. We then demonstrated the effect of this microRNA-138-FOSL1 regulatory module on downstream genes (homolog of Snail 2 (Snai2) expression and the Snai2-mediated repression of E-cadherin expression), as well as its contributions to tumorigenesis. The microRNA-138-directed recruitment of FOSL1 mRNA to the RNAi-induced silencing complex was confirmed by a ribonucleoprotein-immunoprecipitation assay. Three canonical and three high affinity non-canonical microRNA-138 (miR-138) targeting sites were identified on the FOSL1 mRNA: one in the 5'-UTR, three overlapping sites in the coding sequences, and two overlapping sites in the 3'-UTR. The direct targeting of miR-138 to these sites was confirmed using luciferase reporter gene assays. In summary, we describe an important microRNA regulatory module, which may play an important role in cancer initiation and progression. Our results also provide evidence that microRNAs target both canonical and non-canonical targeting sites located in all areas of the mRNA molecule (e.g. 5'-UTR, coding sequences, and 3'-UTR).


Do consumers substitute opium for hashish? An economic analysis of simultaneous cannabinoid and opiate consumption in a legal regime.
To analyze interrelationships in the consumption of opiates and cannabinoids in a legal regime and, specifically, whether consumers of opiates and cannabinoids treat them as substitutes for each other. Econometric dynamic panel data models for opium consumption are estimated using the generalized method of moments (GMM). A unique dataset containing information about opiate (opium) consumption from the Punjab province of British India for the years 1907-1918 is analyzed (n=252) as a function of its own price, the prices of two forms of cannabis (the leaf (bhang), and the resin (charas, or hashish)), and wage income. Cross-price elasticities are examined to reveal substitution or complementarity between opium and cannabis. Opium is a substitute for charas (or hashish), with a cross price elasticity (βˆ3) of 0.14 (p<0.05), but not for bhang (cannabis leaves; cross price elasticity=0.00, p>0.10). Opium consumption (βˆ1=0.47 to 0.49, p<0.01) shows properties of habit persistence consistent with addiction. The consumption of opium is slightly responsive (inelastic) to changes in its own price (βˆ2=-0.34 to -0.35, p<0.05 to 0.01) and consumer wages (βˆ1=0.15, p<0.05). Opium and hashish, a form of cannabis, are substitutes. In addition, opium consumption displays properties of habit persistence and slight price and wage income responsiveness (inelasticity) consistent with an addictive substance.


The cardiorespiratory response to submaximal exercise in subjects with asthma following pretreatment with controlled release oral salbutamol and high-dose inhaled salmeterol.
Treatment for exercise induced asthma (EIA) in sporting competition is controlled to prevent the use of agents which might enhance physical performance. There is little information concerning the effects of the long-acting inhaled, and oral, sustained release type bronchodilators on the cardiorespiratory effects of submaximal exercise. The aim of this study was to compare the cardiorespiratory effects of submaximal exercise in patients with EIA before and after pretreatment with high-dose inhaled salmeterol xinafoate (SX) and controlled release oral salbutamol (CR). Patients were treated with SX (100 micrograms b.d.) and CR (8 mg b.d.) for > or = 3 days in a double-blind randomized cross-over design, with a 5-14 day washout period between treatments. A submaximal exercise test (total exercise time 6 min, final 3 min at 60% of VEpeak) was performed prior to each treatment period, and repeated at 1, 6, and 12 h postdose at the end of the treatment period. Two subjects were withdrawn from the study. Three subjects required relief medication after 1 h (CR) and one subject after 6 h (SX) and they did not perform further exercise tests. Both treatments increased baseline FEV1, with SX producing significantly greater pre-exercise bronchodilation than CR (P = 0.04). Following CR, there were no significant differences from the pretreatment values for VO2, VE, respiratory exchange ratio, heart rate, ventilatory equivalents for VO2, and oxygen pulse during the submaximal exercise challenge. Following SX, there were no significant differences for any of the exercise variables except for VE at 6 and 12 h (mean increase 4.27 l min-1 at 6 h, P < 0.01 and 4.69 l min-1 at 12 h, P = 0.05). The changes in ventilation following SX did not have an effect on oxygen consumption, and the ventilatory efficiency (VE/VO2) remained unchanged. The findings from this study demonstrate that, despite exercising from a higher baseline FEV1, short pretreatment periods with controlled release oral salbutamol and with inhaled salmeterol do not confer any cardiorespiratory advantage during submaximal exercise in subjects with EIA.


Brain insulin resistance accelerates Aβ fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes.
Type 2 diabetes mellitus is thought to be a significant risk factor for Alzheimer's disease. Insulin resistance also affects the central nervous system by regulating key processes, such as neuronal survival and longevity, learning and memory. However, the mechanisms underlying these effects remain uncertain. To investigate whether insulin resistance is associated with the assembly of amyloid β-protein (Aβ) at the cell surface of neurons, we inhibited insulin-signalling pathways of primary neurons. The treatments of insulin receptor (IR)-knockdown and a phosphatidylinositol 3-kinase inhibitor (LY294002), but not an extracellular signal-regulated kinase inhibitor, induced an increase in GM1 ganglioside (GM1) levels in detergent-resistant membrane microdomains of the neurons. The aged db/db mouse brain exhibited reduction in IR expression and phosphorylation of Akt, which later induced an increase in the high-density GM1-clusters on synaptosomes. Neurons treated with IR knockdown or LY294002, and synaptosomes of the aged db/db mouse brains markedly accelerated an assembly of Aβs. These results suggest that ageing and peripheral insulin resistance induce brain insulin resistance, which accelerates the assembly of Aβs by increasing and clustering of GM1 in detergent-resistant membrane microdomains of neuronal membranes.


Comparative evaluation of angiogenesis using a novel platelet-rich product: An in vitro study.
In vivo angiogenesis is normal and vital process in growth and development, wound healing, and formation of granulation tissue wherein new blood vessels form from preexisting vessels as part of revascularization. Platelet-rich products promote wound healing associated with angiogenesis. Biomaterials such as titanium were found to be angiogenic. Unlike in vivo situations, in vitro angiogenesis, study cells, within a controlled environment. The aim of this study is to evaluate the angiogenic potential of a novel platelet-rich product. Blood was drawn from volunteers with informed consent. Blood samples were centrifuged to obtain platelet-rich products. Platelet concentrates prepared were platelet-rich plasma (PRP), platelet-rich fibrin, and a novel platelet-rich product which is titanium-prepared PRP (TPRP), obtained using titanium. The study which compared platelet concentrate was divided into four groups subjected to tissue culture. Phase-contrast microscope was used to determine the rate of growth by cell counting. ANOVA was used for comparison within groups and post hoc for multiple comparisons. TPRP group showed granular ground substance. Group with platelet-rich fibrin (PRF) shows a high rate of growth whereas those with TPRP showed better growth rate when compared to its counterpart, PRP. This is the first study which introduces TPRP. Previous studies have proved that titanium-prepared PRF has better structural quality than its counterpart platelet-rich fibrin. This study concludes that TPRP has better angiogenic potential than its counterpart PRP. Further in vivo studies are needed to promote TPRP as a new generation of platelet products.


Vascular smooth muscle growth in genetic hypertension: evidence for multiple abnormalities in growth regulatory pathways.
To gain insight into the mechanisms which contribute to the development of vascular hypertrophy in the spontaneously hypertensive rat (SHR). These experiments were performed under conditions which most closely mimic the growth of smooth muscle in blood vessels, i.e. once cell-cell contact has been achieved. A comparison of the growth characteristics (growth rates and cell density at quiescence) of vascular smooth muscle cells (VSMC) from SHR and normotensive Wistar-Kyoto (WKY) rats. In the presence of foetal calf serum (1, 2.5, 5 and 10%), early passaged VSMC from SHR exhibited higher growth rates and reached higher densities at quiescence than VSMC from WKY rats. Accelerated growth rates could not be attributed to differences in cell-cell interactions. Also, growth rates and cell density at quiescence appear to be regulated by distinct mechanisms. Transforming growth factor-beta 1 (TGF-beta 1) caused an inhibition of serum-stimulated proliferation of confluent VSMC from WKY rats. In contrast, TGF-beta 1 had little, if any, inhibitory action upon the growth of VSMC from SHR. Scatchard analysis of 125I-TGF-beta 1 binding to VSMC from both strains yielded a single class of high affinity binding sites. VSMC from SHR exhibit enhanced proliferation, attain a higher cell density at quiescence and are less susceptible to growth inhibition by TGF-beta 1 than VSMC from WKY rats. All these characteristics of SHR VSMC may contribute to the development of vascular hypertrophy in this strain.


Global access to surgical care: a modelling study.
More than 2 billion people are unable to receive surgical care based on operating theatre density alone. The vision of the Lancet Commission on Global Surgery is universal access to safe, affordable surgical and anaesthesia care when needed. We aimed to estimate the number of individuals worldwide without access to surgical services as defined by the Commission's vision. We modelled access to surgical services in 196 countries with respect to four dimensions: timeliness, surgical capacity, safety, and affordability. We built a chance tree for each country to model the probability of surgical access with respect to each dimension, and from this we constructed a statistical model to estimate the proportion of the population in each country that does not have access to surgical services. We accounted for uncertainty with one-way sensitivity analyses, multiple imputation for missing data, and probabilistic sensitivity analysis. At least 4·8 billion people (95% posterior credible interval 4·6-5·0 [67%, 64-70]) of the world's population do not have access to surgery. The proportion of the population without access varied widely when stratified by epidemiological region: greater than 95% of the population in south Asia and central, eastern, and western sub-Saharan Africa do not have access to care, whereas less than 5% of the population in Australasia, high-income North America, and western Europe lack access. Most of the world's population does not have access to surgical care, and access is inequitably distributed. The near absence of access in many low-income and middle-income countries represents a crisis, and as the global health community continues to support the advancement of universal health coverage, increasing access to surgical services will play a central role in ensuring health care for all. None.


Dendritic cell tumor in a salivary gland lymph node: a rare differential diagnosis of salivary gland neoplasms.
Dendritic cell tumors are extremely rare neoplasms arising from antigen-presenting cells of the immune system. We report a case of a 69-year-old man with an unremarkable medical history who presented with a 2-months history of a gradually enlarging painless, firm, mobile, 2 × 2-cm swelling at the caudal pole of the left parotid gland without systemic symptoms. Histologically, the tumor consisted of a spindle cell proliferation in an intraparotideal lymph node. Based on the histopathologic, immunohistochemical and electron microscopic findings, a dendritic cell tumor, not otherwise specified (NOS) in an intraparotideal lymph node was diagnosed.The patient underwent complete tumor resection, and is currently free of disease, 2 years after surgery. These extremely rare tumors must be distinguished from other more common tumors in the salivary glands. Awareness that dendritic cell tumors may occur in this localization, careful histologic evaluation and ancillary immunohistochemical and electron microscopical analyses should allow for recognition of this entity.


"In the office nine to five, five days a week… those days are gone": qualitative exploration of diplomatic personnel's experiences of remote working during the COVID-19 pandemic.
Many employees had to work remotely during the COVID-19 pandemic. Literature suggests there are both challenges and benefits to remote working and that remote working can have detrimental effects on mental health. This study aimed to explore diplomatic personnel's perceptions and experiences of working from home during the pandemic. Twenty-five employees of the Foreign, Commonwealth and Development Office took part in semi-structured interviews. Thematic analysis was carried out to extract recurring themes from the data. Seven main themes emerged from the data: impact of the pandemic on work; relationships with colleagues; benefits of working from home; challenges of working from home; family; moving posts during the pandemic; and perceptions and predictions of post-pandemic work. Participants provided mixed views on how remote working had affected productivity and relationships with colleagues. Benefits of working from home included greater freedom and flexibility; new opportunities; and inclusivity of remote meetings. Challenges included being in different time zones to the countries they were working for; unsuitable home ergonomics; technological issues; and difficulties finding appropriate work-life balance. Those with young children reported difficulties juggling work and childcare. Adjusting to new posts at a time when staff were working remotely appeared particularly challenging. However, most did not want or expect to return to entirely office-based work. They predicted a hybrid model of working in the future, involving both office work and remote work; they stressed the importance of flexibility and suggested there would not be a one-size-fits-all approach to returning to face-to-face work. Remote working during the COVID-19 pandemic has changed the ways in which employees work, showing them that they do not have to be in the office to successfully achieve their work goals and leaving many wanting flexibility to make their own decisions about working from home (or not). There are both benefits and challenges to remote working; managers can take steps to reduce some of the challenges by being available to support their employees, organising regular remote meetings and allowing employees autonomy in terms of when and where they work.


Proton pump inhibitor use and the risk of peritoneal dialysis associated peritonitis.
The use of proton-pump inhibitors (PPI) has been associated with an increased risk of developing spontaneous bacterial peritonitis in patients with cirrhosis. Whether PPI use confers a similar risk in developing peritonitis in peritoneal dialysis (PD) patients remains unclear. To assess whether PPI use is associated with an increased risk of PD peritonitis. Patients on PD were retrospectively identified. Data such as PPI use during PD, underlying diagnoses, comorbidities, and baseline serum tests were collected. Univariable and multivariable analysis was conducted using logistic regression to assess whether PPI use and other factors were associated with PD peritonitis. Fifty-seven patients were identified with a median (interquartile range (IQR)) age of 65.0 (51.5-74.0) years. The median (IQR) time on PD was 29.0 (17.5-45.0) months. Twenty-eight patients were on a PPI during PD. Fifty-seven percent of the PPI group went on to develop peritonitis, compared with 31% of patients without PPI exposure (odds ratio (OR) = 2.96; 95% confidence interval (CI): 1.00, 8.78; P = 0.050). Months on PD (OR = 1.03; 95% CI: 1.00, 1.06; P = 0.026), serum urea (OR = 0.88; 95% CI: 0.80, 0.97; P = 0.017), congestive cardiac failure (OR = 5.44; 95% CI: 1.29, 23.00; P = 0.021) and renovascular disease (OR = 14.59; 95% CI: 1.68, 126.67; P = 0.015) were identified as possible risk factors for peritonitis on univariable analysis. Following adjustment for covariates, serum urea, but not PPI use, was associated with PD peritonitis (OR = 0.87; 95% CI: 0.78, 0.98; P = 0.020). PPI use during PD was not associated with peritonitis. Due to the small number of patients and the limited number of studies investigating the effect of PPI use on PD peritonitis, further research is needed.


Examining the role of youth empowerment in preventing adolescence obesity in low-income communities.
Youth empowerment programs have increasingly gained attention in public health as emphasis shifts on children and adolescents as decision makers in their health and well-being. Adolescence obesity is among the public health concerns that require more active engagement at individual and community level while empowering adolescents to take charge of their own health. This study examines the influence of youth empowerment on nutritional and physical activity factors associated with adolescence obesity. Data were gathered through a self-administered survey among adolescents (N = 410) ages 11-15 years in three U.S. States - Kansas, Ohio and South Dakota. Findings show that youth empowerment significantly influences adolescents' self-efficacy, perceptions for healthy food choice, healthy eating, attitudes towards physical activity and the overall motivation for health. Gender differences exist in adolescents' self-efficacy for physical activity whereas ethnicity played a role in perceived youth empowerment and perceived barriers to healthy eating. Age was also a significant contributor in efficacy for healthy food choice and perception of healthy food availability. This study suggests more focus on youth empowerment in interventions that seek to reduce obesity and improve adolescents' overall health by creating environments where they can play a more active decision-making role. With empowerment, adolescents are more likely to be motivated to adopt healthier dietary habits and engage more in physical activity. Further research would establish the impact of youth empowerment on obesity reduction and other public health problems that impact children across ages.


Reactivity Properties of Mixed- and High-Valent Bis(μ-Hydroxide)-Dinickel Complexes.
Despite their potential role in enzymatic systems, there is a dearth of hydroxide-bridged high-valent oxidants. We recently reported the synthesis and characterization of NiIINiIII(μ-OH)2 (2) and Ni2 III(μ-OH)2 (3) species supported by a dicarboxamidate ligand (N,N'-bis(2,6-dimethyl-phenyl)-2,2-dimethylmalonamide). Herein, we explore the oxidative reactivity of these species using a series of para-substituted 2,6-di-tert-butyl-phenols (4-X-2,6-DTBP, X = -OCH3, -CH2CH3, -CH3, -C(CH3)3, -H, -Br, -CN, and -NO2) as a mechanistic probe. Interestingly, upon reaction of 3 with the substrates, the formation of a new transient species, 2', was observed. 2' is postulated to be a protic congener of 2. All three species were demonstrated to react with the substituted phenols through a hydrogen atom transfer reaction mechanism, which was elucidated further by analysis of the postreaction mixtures. Critically, 3 was demonstrated to react at far superior rates to 2 and 2', and oxidized substrates more efficiently than any bis-μ-oxo-Ni2 III reported to date. The kinetic superiority of 3 with respect to 2 and 2' was attributed to a stronger bond in the product of oxidation by 3 when compared to those calculated for 2 and 2'.


5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets.
Caffeic acid and 5-caffeoylquinic acid are naturally occurring phenolic acid and its quinic acid ester found in plants. In this article, potential effects of 5-caffeoylquinic acid and caffeic acid on P-selectin expression were investigated due to its significant involvement in platelet activation. First, the effects of 5-caffeoylquinic acid and caffeic acid on cyclooxygenase (COX) enzymes were determined due to their profound involvement in regulating P-selectin expression on platelets. At the concentration of 0.05 microM, 5-caffeoylquinic acid and caffeic acid were both able to inhibit COX-I enzyme activity by 60% (P<.013) and 57% (P<.017), respectively. At the same concentration, 5-caffeoylquinic acid and caffeic acid were also able to inhibit COX-II enzyme activity by 59% (P<.012) and 56% (P<.015), respectively. As expected, 5-caffeoylquinic acid and caffeic acid were correspondingly able to inhibit P-selectin expression on the platelets by 33% (P<.011) and 35% (P<.018), at the concentration of 0.05 microM. In animal studies, 5-caffeoylquinic acid and caffeic acid orally administered to mice were detected as intact forms in the plasma. Also, P-selectin expression was respectively reduced by 21% (P<.016) and 44% (P<.019) in the plasma samples from mice orally administered 5-caffeoylquinic acid (400 microg per 30 g body weight) and caffeic acid (50 microg per 30 g body weight). These data suggest that both 5-caffeoylquinic acid and caffeic acid orally administered can be absorbed and suppress P-selectin expression on mouse platelets.


Squamous-cell carcinoma of the proximal colon: report of a case and review of the literature.
A case of an undoubted squamous-cell carcinoma arising at the hepatic flexure in the colon of a middle-aged man is reported. Review of the literature and exclusion of cases not strictly comparable suggest that pure squamous-cell carcinoma of the colon is rare, this being only the fifteenth such tumor reported, and only the second recorded case of such a tumor of the hepatic flexure. Possible pathogenesis is suggested.


A 3-year retrospective cohort study of predictors of relapse in first-episode psychosis in Hong Kong.
Relapses in psychosis are costly and may have irreversible consequences. Relapse prevention is thus critical in the treatment of schizophrenia. Apart from medication discontinuation, a consistent relapse predictor has not been identified due to limitations in previous studies. We aim to investigate relapse predictors in a large cohort of patients with first-episode psychosis. This is a retrospective cohort study designed to evaluate relapses in first-episode psychosis patients in 3 years. A total of 1400 patients' case records were retrieved from a hospital database. Potential relapse predictors including demographic variables, baseline clinical measures, medication adherence, and residual positive symptoms upon clinical stabilization were collected. The cumulative relapse rates were 19.3% by year 1, 38.4% by year 2, and 48.1% by year 3. Multivariate Cox-proportional hazards regression analysis revealed that medication non-adherence, smoking, schizophrenia diagnosis, younger age, and shorter baseline hospitalization were associated with an increased risk of relapse in 3 years. Nearly half of patients relapsed after 3 years following their first-episode psychosis. Smoking as a predictor of relapse is an intriguing new finding supportive of a link between nicotinic receptors and the dopamine system. Their relationship deserves further investigations with potential clinical implications for relapse prevention.


Mathematical analysis of affinity membrane chromatography.
A mathematical model including convection, diffusion and Freundlich adsorption is developed. To examine the validity of the model, the affinity membranes were prepared by coating chitosan on the nylon membranes, a ligand of poly-L-lysine was bound to the chitoan-coating membranes, and the adsorption behavior of bilirubin through the stacked affinity membranes was investigated. The agreements between the theoretical and experimental results are exceptional. Using our new model, we show that: (1) As Pe increases, the breakthrough curves become sharper. For Pe greater than 30, the effect of axial diffusion is insignificant; (2) As m increases, the time of total saturation is delayed and the loading capacity at the point of breakthrough is increased; (3) As n decreases, the time of total saturation is delayed and the loading capacity at the point of breakthrough is increased; (4) As r increases, both the time of total saturation and the loading capacity at the point of breakthrough are increased; (5) adsorption rate influences the time of total saturation strongly but contributes little to the loading capacity.


VSIG-3 as a ligand of VISTA inhibits human T-cell function.
B7 family members and their receptors play a central role in the regulation of T-cell responses through T-cell co-stimulation and co-inhibition pathways that constitute attractive targets for the development of immunotherapeutic drugs. In this study, we report that VSIG-3/IGSF11 is a ligand of B7 family member VISTA/PD-1H and inhibits human T-cell functions through a novel VSIG-3/VISTA pathway. An extensive functional ELISA binding screening assay reveals that VSIG-3 binds to the new B7 family member VISTA but does not interact with other known members of the B7 family. Under the same experimental conditions, we did not observe any significant interaction between VSIG-8 and VISTA. In addition, VSIG-3 inhibits human T-cell proliferation in the presence of T-cell receptor signaling. Furthermore, VSIG-3 significantly reduces cytokine and chemokine production by human T cells including IFN-γ, IL-2, IL-17, CCL5/Rantes, CCL3/MIP-1α, and CXCL11/I-TAC. Anti-VISTA neutralization antibodies attenuate the binding of VSIG-3 and VISTA, as well as VSIG-3-induced T-cell inhibition. Hence, we have identified a novel ligand for VISTA that is able to inhibit human T-cell proliferation and cytokine production. This unique VSIG-3/VISTA co-inhibitory pathway may provide new strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may aid in the design of better vaccines.


Unexpected ultrastructral changes in bone osteiod collagens in osteogenesis imperfecta.
Osteogenesis Imperfecta (OI) is a heterogeneous, inherited bone disorder usually resulting from a defect in collagen synthesis or function. The Sillence classification recognises four OI subtypes of which type III is the severe, progressively deforming form. Here, we report distinctive ultrastructural abnormalities of bone osteoid collagen fibrils from three patients with OI type III and compared with normal controls. Collagen biochemistry of these patients showed normal alpha1(I) and alpha2(I) chains, despite the structurally abnormal collagen fibrils. The expected lamellar organisation of normal osteoid was absent in the bone biopsies of these patients. In addition their collagen fibrils had frayed edges and no periodicity was observed in most of these fibrils. These collagen fibrils were also flower like, twisted, spiralled and sparsely distributed throughout a very thick osteoid with patchy mineralisation. These structurally abnormal collagens may not be able to provide the nucleating and scaffolding sites for normal mineralisation and may lead to the bone fragility observed in OI.


Lack of evidence for sustained blood acetaldehyde concentrations during alcohol detoxification.
Contrary to a published report, blood acetaldehyde concentrations become undetectable in patients 1--2 days following admission for alcohol detoxification. The persistently elevated blood acetaldehydes reported by others probably were due to artifactual formation during analysis. Nevertheless, our admission blood acetaldehyde concentrations are significant enough to support the contention that acetaldehyde has a cytotoxic role in alcoholic disease.


Possible involvement of the inactivation of the Rho-Rho-kinase pathway in oncogenic Ras-induced transformation.
Recent evidence has strongly suggested the involvement of Rho family small guanosine triphosphatases (GTPases) in Ras-induced transformation. To further clarify the role of Rho family GTPases in Ras-induced transformation, we examined the effects of dominant active or dominant negative forms of Rho family GTPases on the morphological changes induced by oncogenic Ras (RasV12) in Rat1 fibroblasts. The cells expressing RasV12 showed the severe disruption of actin stress fibers and cell adhesions. The coexpression of dominant active form of Rho (RhoV14) reverted not only the formation of stress fibers and focal adhesions but also cell-cell adhesions in Ras-transformed Rat1 cells. In addition, the coexpression of constitutively activated Rho-kinase, a downstream effector of Rho, restored the assembly of stress fibers and focal adhesions. Treatment of Ratl cells with lysophosphatidic acid, which is known to activate the Rho-Rho-kinase pathway, enhanced the stress fiber formation, whereas it failed to induce the stress fiber formation in the cells expressing RasV12. These results suggest that the Rho-Rho-kinase pathway may be inactivated in the cells expressing RasV12, and this may contribute to oncogenic Ras-induced transformation.


"Positive deviants": a qualitative study of physically active adults in rural environments.
Rural residents, particularly those in the South, are less physically active than their urban counterparts and often live in areas with limited walkability (e.g., no sidewalks) and minimal access to recreational facilities. The purpose of this study was to gain an understanding of what makes certain rural residents physically active despite their environment. Qualitative interviews (N = 29) were conducted with physically active adults who live in rural areas (e.g., outside of town) in southwest Georgia. Participants were 65.5% male and 24.1% African American, with a mean age of 55.9 years. Results suggest that physically active adults in rural areas are motivated by their health and perceive their local surroundings as a resource for physical activity. Understanding how these physically active adults take advantage of their living situations to be physically active has the potential to inform interventions that encourage physical activity in this high-risk population.


Analgesic effect of vibration and cooling on pain induced by intraneural electrical stimulation.
Psychophysical experiments were carried out on 16 human subjects to determine how low intensity mechanical and thermal skin stimuli interfere with the sensation of pain. Moderate or intense pain was induced by low frequency (2 Hz) electrical stimulation within cutaneous fascicles of the median nerve at wrist level, and vibration, pressure, cooling or warming were applied for short periods (usually 20-60 sec) within or outside the skin area to which the pain was projected. Vibration within the area of projected pain reduced the sensation of pain more efficiently than vibration outside that area. Moderate pain was sometimes completely inhibited but intense pain was only moderately reduced. Pressure and cooling produced some pain relief whereas mild warming had an ambiguous effect. Since the painful input derived from stimulation of fibres in the nerve trunk, and not from peripheral nociceptors, the pain suppressing effects of vibration and cooling are not explicable in terms of lowered excitability of the nociceptive nerve endings in the skin. Instead, the results indicate that activity in low threshold mechanoreceptive and cold sensitive units suppresses pain at central (probably segmental) levels.


Rare Giant Pedunculated Liposarcoma of the Hypopharynx: Case Report and Review of Literature.
Liposarcoma is considered the most common soft tissue sarcoma in adults. It represents approximately 20 % of all mesenchymal malignancies, and most frequently it involves the retroperitoneum, trunk, and extremities. Hypopharyngeal localization of liposarcoma is extremely rare. We report a new rare case of giant pedunculated liposarcoma arising from the left antero-lateral wall of the hypopharyngeal-esophageal junction, and we present a complete review of the literature. An 81-year-old man presented with a 5-month history of dysphagia and 30-kg weight loss, due to a giant pedunculated liposarcoma of the hypopharynx, which is resected with cervical approach. CT scan imaging revealed a 25-cm-long pedunculated heterogeneous mass with fat-like density originating from the anterior wall of hypopharyngeal-esophageal junction protruding into the lumen. The polypoid mass was identified as well as the stalk, and it was completely delivered through the cervical incision. Histopatological examination showed a dedifferentiated liposarcoma, without positive or close margins. No further chemoradiation therapy was performed due to the patient's age, comorbidities, negative margins, and absence of distant metastases. Dysphagia solved 1 month after surgery. No evidence of tumor recurrence was seen in the 12 months following surgery. When base of the tumor is located in hypopharynx or cervical portion of the esophagus, and tumor is not aggressive, cervical approach is better, irrespective of the tumor size, except for cases in which an endoscopic approach is feasible.


Ontogeny of radial glia, astrocytes and vasoactive intestinal peptide immunoreactive neurons in hamster suprachiasmatic nucleus.
Circadian rhythmicity of rodents is a property of the suprachiasmatic nucleus (SCN). Such rhythmicity can be demonstrated in the prenatal SCN, yet there is little information about the cells in which rhythmicity is generated. The present study was performed to discover the developmental relationships of SCN glial cells and a class of identifiable SCN neurons. Toward this end, vimentin- (VIM), glial fibrillary acidic protein- (GFAP) and vasoactive intestinal peptide- (VIP) immunoreactivity were investigated in SCN radial glia, astrocytes and neurons, respectively. VIP-IR first appears at embryonic day 13 (E13) and is clearly identifiable in neurons at E14. Substantial axon extension begins at E15 and the postnatal day 10 (P10) SCN is adult-like. VIM-IR radial glia fill the SCN region at E13, but by P0, most are absent. On P3, the remaining processes are beaded suggesting degeneration. The first GFAP-IR elements are visible on E15 with a few clear astrocytes present at P0. The number of astrocytes lateral to and in the SCN continues to increase during the postnatal period achieving an adult-like appearance by P21. The data do not support the view that prenatal circadian rhythmicity is derived from astrocytes. VIP-IR neurons are apparently present sufficiently early to be part of the rhythm generating mechanism. These tissues are discussed in the context of development of the SCN.


Informed choice: understanding knowledge in the context of screening uptake.
This study evaluates a scale measuring knowledge about a screening test and investigates the association between knowledge, uptake and attitudes towards screening. One thousand four hundred ninety-nine pregnant women completed the knowledge scale of the multidimensional measure of informed choice (MMIC). Three hundred forty-five of these women and 152 professionals providing antenatal care also rated the importance of the knowledge items. Item characteristic curves show that, with one exception, the knowledge items reflect a spread of difficulty and are able to discriminate between people. All items were seen as essential or helpful by both women and health professionals, with two items seen as particularly important and one as unimportant. There were some differences between health professionals, women with low risk results and women with high risk results. Knowledge was not associated with uptake, attitude, or the extent to which uptake was consistent with women's attitudes towards undergoing the test.


Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats.
Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.


The effects of different ventilatory settings on pulmonary and systemic inflammatory responses during major surgery.
Mechanical ventilation with high tidal volumes (V(T)) and zero or low positive end-expiratory pressure increased mediator release to inflammatory stimuli or acute lung injury. We studied whether mechanical ventilation modifies the inflammatory responses during major thoracic or abdominal surgery. Sixty-four patients undergoing elective thoracotomy (n = 34) or laparotomy (n = 30) were randomized to receive either mechanical ventilation with V(T) = 12 or 15 mL/kg ideal body weight, respectively, and zero end-expiratory pressure, or V(T) = 6 mL/kg ideal body weight with positive end-expiratory pressure of 10 cm H(2)O. In 62 patients who completed the study, arterial oxygenation was not different between groups. Tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12 were determined by cytometric bead array in plasma after 0, 1, 2, and 3 h and in tracheal aspirates after 3 h of mechanical ventilation. Data were log-transformed and analyzed using parametric or nonparametric tests, as indicated. All plasma mediators increased more during abdominal than during thoracic surgery, although the differences were small. However, neither time course nor concentrations of pulmonary or systemic mediators differed between the two ventilatory settings. Our data suggest that the ventilatory settings we studied do not affect inflammatory reactions during major surgery within 3 h. In 62 patients undergoing elective major thoracic or abdominal surgery, mechanical ventilation with low tidal volumes and positive end-expiratory pressure or high tidal volumes and zero end-expiratory pressure did not result in different pulmonary or systemic levels of measured inflammatory markers.


[The nephelometric method in the study of the hyperlipoproteinaemia: comparative analysis with chemical and electrophoretic methods (author's transl)].
On 814 subjects the cholesterolemia, the triglyceridemia and serum lipoproteins were determined; also the nephelometric analysis of the serum was conducted. The statistical analysis of the results allowed the following conclusions. 1) Approximately 98% of the pathological results are found in 3 types: type IV (about 49%), IIa (about 40%), IIb (about 11%). 2) The nephelometric determination of the M particles is particularly useful in the distinction between types IIa and IIb, because in type IIb there are pathologically increased values also when the triglycerides are normal or almost normal. There exists a significant correlation between the M particles determined by nephelometric analysis and the triglycerides determined by chemical methods.


3-(4-Methyl-phen-yl)-4H-chromen-4-one.
In the title compound, C16H12O2, the dihedral angle formed between the plane of the chromenone ring system (r.m.s. deviation = 0.031 Å) and the pendant benzene ring is 31.09 (5)°. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into C(6) chains propagating along the a-axis direction.


Mechanism of p-hydroxyphenylacetate-3-hydroxylase. A two-protein enzyme.
p-Hydroxyphenylacetate-3-hydroxylase purified from Pseudomonas putida is a two-protein enzyme requiring a flavoprotein and a coupling protein for productive hydroxylation (Arunachalam, U., Massey, V., and Vaidyanathan, C. S. (1992) J. Biol. Chem. 267, 25848-25855). This paper presents information on the mechanism of the enzyme from absorbance and fluorescence stopped-flow studies. The reduction of the substrate-free flavoprotein by NADH was slow and was not altered by the presence of the coupling protein. In contrast, the coupling protein has a dramatic effect in the oxidative half-reaction. The flavoprotein when present alone, both in the absence and presence of the aromatic substrate, reacts in a second-order fashion with oxygen to form oxidized flavoprotein, with no indication of flavin-oxygen intermediates. However, an intermediate identified as the C4a-flavin hydroperoxide is stabilized when the flavoprotein-coupling protein complex reacts with oxygen in the absence of the aromatic substrate, p-hydroxyphenylacetate, and at least three flavin-oxygen intermediates, attributed to the anionic (I) and protonated (I*) forms of the flavin hydroperoxide and the hydroxyflavin (III), are formed in the oxidative half-reaction in the presence of the aromatic substrate. A reaction mechanism for the two-protein complex is proposed in which the aromatic substrate has little effect on the rate of reduction of the enzyme flavin but has strict control in the oxidative half-reaction. In this phase the flavin hydroperoxide is remarkably stable in the absence of the substrate but disappears rapidly upon encountering the aromatic substrate.


A true aneurysm of the superficial temporal artery: Is there an underlying pre-disposition to such rarities?
A 32 year old man presented to our vascular clinic with a lump over the left eyebrow. It had become larger in size and was cosmetically unacceptable. Clinical examination of the lump demonstrated a pulsatile swelling consistent with an aneurysm of the superficial temporal artery (STA). Doppler ultrasound demonstrated arterial flow within the lump that could be controlled with pressure over the proximal branch of the vessel. The STA aneurysm was excised under local anaesthesia by ligation of the feeding and draining branches. It measured 3.4cm×3.7cm. Histological examination confirmed a rare finding of a true aneurysm of the STA. Aneurysms are classified into false or true types, with false aneurysms of the STA accounting for 95% of cases reported. It has therefore been suggested that true aneurysms of the STA may develop from a yet unknown pre-existing vessel condition. The histological findings in our case demonstrated myxoid/mucoid deposits replacing elastin fibres of the media layer, in addition to cystic lesions seen in the adventitia. These features were thought to be nonspecific but have been reported in rare conditions known as cystic adventitial disease and cystic medial necrosis. Such is their obscurity that we speculate that both of these may represent variations of the same underlying pathology. As myxoid/mucoid changes are also noted in more well-known connective tissue disorders including Marfan's syndrome, imaging was arranged to screen our patient for thoracic and abdominal aneurysms. These proved negative and there were no Marfanoid features noted prior. Aneurysms of the STA are easily treated by surgical excision. This should be considered when they become large, painful or are cosmetically undesirable. Unusual histological findings in the specimen may indicate a connective tissue disorder that should be investigated if indicated.


A Comparative Study of Type-I Underlay Tympanoplasty with Temporalis Fascia Graft Alone and with Conchal Cartilage.
Tympanoplasty which is the repair of the tympanic membrane using temporalis fascia, has been done worldwide and has stood the test of time. However in cases of reperforation or large/subtotal perforations, we are often left in need of some sturdy material for grafting. To compare the graft uptake and hearing improvement in patients undergoing type I tympanoplasty using temporalis fascia alone and temporalis fascia along with conchal cartilage. The current research is a prospective study of 60 patients with chronic suppurative otitis media (Tubo tympanic type), undergoing type I tympanoplasty, using temporalis fascia alone and temporalis fascia along with conchal cartilage. The graft uptake and hearing improvement was much better using temporalis fascia along with conchal cartilage graft as compared to cartilage alone. The use of temporalis fascia along with conchal cartilage graft is beneficial for patients with chronic suppurative otitis media (tubotympanic type) undergoing type I tympanoplasty than using temporalis fascia alone.


Features of In Vitro Degradation and Physical Properties of a Biopolymer and In Vivo Tissue Reactions in Comparison with Polypropylene.
We compared in vitro degradation and physical properties of polypropylene and a biodegradable polymer synthesized by electrospinning and consisting of 65% polycaprolactone and 35% polytrimethylene carbonate as a possible alternative material for use in surgery for pelvic floor muscle failure. Samples of the studied polymers were implanted to 10 male Wistar rats into the interfascial space on the back (polypropylene on the right side and biodegradable polymer on the left side). The synthesized biopolymer was characterized by elongation and tear resistance, similar to those of polypropylene. During the period from the third to the sixth month after implantation, the area of fibrosis around individual polypropylene and biopolymer fibers increased by 16.7 and 107.9%, respectively, while remaining reduced compared to polypropylene. The total fibrosis area in 6 months after implantation of polypropylene and biopolymer samples significantly increased by 18% (p=0.0097) and 48% (p=0.05), respectively, i.e. fibrosing processes were more intense in case of biopolymer. Induction of more pronounced fibrosis can be an advantage of the synthesized biopolymer when choosing the material for fabrication of implants and their use for correction of incompetence of the ligamentous and muscular apparatus.


The effect of internal and external 4-aminopyridine on the potassium currents in intracellularly perfused squid giant axons.
1. The effect of 4-aminopyridine (4-AP) on the K outward and inward currents in perfused giant axons of Loligo forbesi has been studied with the voltage-clamp technique.2. Small internal or external 4-AP concentrations (10-100 muM) considerably delay the rise of the K outward current. Repetitive pulsing with a pulse interval of 0.1-5 sec leads to a faster rise of the K current; in 10 muM 4-AP a small effect is visible even with a pulse interval of 60 sec.3. The phenomenon has been studied quantitatively by using a prepulse of varying height and duration, followed after 5 sec by a constant test pulse. The effect of changing the holding potential has been investigated.4. The effect of repetitive pulsing disappears in higher 4-AP concentrations; 1-10 mM 4-AP markedly reduce the size of the K outward current; the blocking effect is less pronounced for large depolarizing pulses than for small.5. In K-rich sea water 4-AP reduces both the K outward current and the K inward current; the blocking effect on the K outward current is smaller than in K-free sea water.6. The K outward current in fibres treated with 10 muM 4-AP and immersed in K-rich sea water is increased and accelerated by repetitive depolarizing pulses. The effect of repetitive pulsing is not dependent on the size of the K outward current (which can be increased by removing K inactivation).7. The effect of repetitive pulsing and the voltage dependence of the 4-AP block can be explained by the hypothesis that 4-AP molecules are displaced from their blocking sites during the pulse and slowly rebound afterwards. Removal of the 4-AP block by a depolarizing pulse seems to be a direct effect of the potential during the pulse and not related to K current.


BsTLR1: A new member of the TLR family of recognition proteins from the colonial ascidian Botryllus schlosseri.
Toll-like receptors (TLRs) represent a well-known family of conserved pattern recognition receptors the importance of which, in non-self recognition, was demonstrated in both vertebrates and invertebrates. Tunicates represent the vertebrate sister group and, as invertebrates, they rely only on innate immunity for their defence. As regards TLRs, two transcripts have been described and characterised in the solitary species Ciona intestinalis, referred to as CiTLR1 and CiTLR2. Using the Ciona TLR nucleotide sequences, we mined our available transcriptome of the colonial ascidian Botryllus schlosseri looking for similar sequences. We were able to identify a sequence, with similarity to CiTLR2 and, through in silico transduction and subsequent sequence analysis, we studied the domain content of the putative protein. The sequence, called BsTLR1, has a TIR and a transmembrane domain, four LLR and two LRR-CT domains. It is actively transcribed by both phagocytes and morula cells, the two circulating immunocyte types. In addition, we analysed bstlr1 transcription in vivo and in vitro, in different phases of the Botryllus blastogenetic cycle and under various experimental conditions. Our data show that there is a change in gene expression and mRNA location, according to the blastogenetic phase. Furthermore, we used a commercial antibody raised against the ectodomain of hTLR5 to study the possible functional role of Botryllus TLR(s). We observed that anti-hTLR5 significantly decreased in vitro phagocytosis and morula cell degranulation, two typical responses to the recognition of nonself. Collectively, our data add new information on the mechanisms of nonself recognition in a colonial ascidian.


Mössbauer study of iron bleomycin and its activation intermediates.
Using Mössbauer spectroscopy, we have examined iron-bleomycin in various oxidation states and in complexes with dioxygen or carbon monoxide. Ferrous bleomycin is a high spin ferrous complex. Addition of O2 converts it into an EPR-silent oxygenated complex. Mössbauer studies in strong applied magnetic fields show that oxygenated bleomycin is diamagnetic. At 4.2 K, the quadrupole splitting delta EQ = -2.96 mm/s and the isomer shift delta = 0.16 mm/s suggest that its electronic structure is best described as low spin ferric iron bound to superoxide anion. A single electron reduction yields activated bleomycin, an EPR-active form that still retains oxygen and which is kinetically competent to initiate DNA cleavage. We have produced this complex by exposing ferrous bleomycin to O2 or by reacting ferric bleomycin with H2O2. The Mössbauer spectra give convincing evidence that the iron of activated bleomycin is low spin ferric. The decay of activated bleomycin yields low spin ferric bleomycin, a complex with Mössbauer parameters nearly identical with those reported for ferric cytochrome P-450. Although iron bleomycin does not have a polyaromatic structure like heme, many features of its electronic structure at the iron are very similar to those produced by the sulfur-coordinated heme iron of ferric cytochrome P-450, a protein that catalyzes a similar oxygen-dependent reaction.


The clinical differences between dengue and scrub typhus with acute respiratory failure in southern Taiwan.
For both dengue and scrub typhus, acute respiratory failure (ARF) is a serious complication. The present study was carried out in order to investigate the clinical courses and outcomes of adult dengue and scrub typhus patients with ARF, and to identify the clinical differences between adult dengue and scrub typhus patients with ARF. We conducted a retrospective study of the serologically confirmed adult dengue or scrub typhus patients admitted between 1998 and 2008 at Kaohsiung Chang Gung Memorial Hospital. A total of 980 dengue and 102 scrub typhus adult patients were included in our study. Eighteen of the 980 adult dengue patients and 8 of the 102 adult scrub typhus patients had ARF. There were significant differences that existed for eschar (P = 0.001; dengue 0%; scrub 62.5%), cough (P = 0.016; dengue 55.6%; scrub typhus 100%), white blood cell (WBC) count [P = 0.026; dengue 7.40 ± 5.74; scrub typhus 11.84 ± 4.95 (×10(3)/μL)], platelet count [P = 0.008; dengue 42.2 ± 33.9; scrub typhus 104.1 ± 93.3 (×10(9)/L)], prothrombin time (PT) [P = 0.007; dengue 12.82 ± 1.36; scrub typhus 10.74 ± 0.98 (s)], activated partial thromboplastin time (APTT) [P = 0.002; dengue 50.81 ± 10.08; scrub typhus 37.44 ± 4.06 (s)], blood urea nitrogen (BUN) [P < 0.001; dengue 64.6 ± 43.2; scrub typhus 20.9 ± 9.1 (mg/dL)], creatinine [P < 0.001; dengue 3.77 ± 3.37; scrub typhus 1.05 ± 0.37 (mg/dL)], admission day (A-day) [P = 0.027; dengue 2.9 ± 1.3; scrub typhus 5.4 ± 2.6 (days)], and ventilator duration [P = 0.022; dengue 9.4 ± 14.0; scrub typhus 14.8 ± 10.4 (days)] between both groups. This study provides relatively rare data regarding the clinical differences between adult dengue and scrub typhus patients with ARF.


Uncommon virus infections of the mother, fetus, and newborn: influenza, mumps and measles.
The literature contains reports of epidemics of varying sizes, which in the aggregate suggest that congenital malformations are not attributable to maternal measles infection during pregnancy, that the incidence of prematurity may be somewhat higher among infected mothers, and that the incidence of abortion also may be somewhat higher. Before the introduction of measles vaccine in this country, the universality of childhood experience rendered adult infection a rare event. Gestational measles was thus uncommon. With the introduction of measles vaccine, these numbers can be expected to have decreased substantially.


The effect of phenylalanine on intracellular pH and sodium activity in proximal convoluted tubule cells of the frog kidney.
The present study was performed to test the influence of sodium coupled transport of neutral substrates on intracellular pH and sodium activity in proximal tubules of the amphibian kidney. To this end, kidneys of rana esculenta have been isolated and perfused both through the portal vein (peritubular capillaries) and the aorta (luminal perfusate). The potential difference across the peritubular membrane of proximal tubule cells has been reduced with conventional (PDpt) as well as with sodium (PDna) and hydrogen ion (PDh) selective microelectrodes continuously before, during, and after the luminal application of 10 mmol/l phenylalanine, replacing 10 mmol/l raffinose. PDh and PDna allowed the calculation of intracellular pH (pHi) and sodium activity (Nai), respectively. In the absence of phenylalanine in the tubule lumen, PDpt approximates -57.5 +/- 2.3 mV (n = 27), pHi 7.73 +/- 0.04 (n = 14, extracellular pH 7.77), and Nai 13.3 +/- 0.9 mmol/l (n = 13, extracellular sodium activity 74 mmol/l). Within 1 min the luminal application of phenylalanine leads to a depolarisation of PDpt by +32 +/- 2 mV, as well as an increase of pHi by 0.24 +/- 0.04 and of Nai by 5.2 +/- 1.0 mmol/l. At 8 min from luminal application of phenylalanine, Nai plateaus 5 +/- 1 mmol/l above control value, PDpt increases again to a value of +12 +/- 2 mV below and pHi decreases to a value 0.04 +/- 0.07 above their respective control values. All changes are fully reversed after removal of phenylalanine from the tubule lumen.(ABSTRACT TRUNCATED AT 250 WORDS)


Dimethyl 2-amino-biphenyl-4,4'-di-carboxyl-ate.
The title compound, C16H15NO4, exhibits two near-planar aromatic ester groups with a maximum aryl-ester torsion angle of 1.9 (2)°. The dihedral angle between the benzene rings is 44.7 (1)°. In the crystal, N-H⋯O hydrogen bonding is observed along with C-H⋯O contacts, forming chanins along [101]. No π-π inter-actions were noted between the benzene rings.


HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma.
Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive. The purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. The methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival. HNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis. Overall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM.


Improved preparation of perallylated cyclodextrins: facile synthesis of cyclodextrin-based polycationic and polyanionic compounds.
An improved procedure for the perallylation of cyclodextrins allowed the preparation of O-perallylated alpha-, beta-, and gamma-cyclodextrins in 89, 91, and 88% yields, respectively. These were converted into two cyclodextrin-based functionalized compounds, the polycationic heptakis[2,3,6-tri-O-(6-amino-3-thiahexyl)]-beta-cyclodextrin hydrochloride (3), and the polyanionic heptakis[2,3,6-tri-O-(sodium 5-carboxyl-3-thiapentyl)]-beta-cyclodextrin (4), a potential inhibitor of HIV-1 replication.


Megalencephaly: definition and classification.
The various definitions and classifications of megalencephaly are reviewed, and numerous diseases and syndromes associated with megalencephaly are listed. A new definition of megalencephaly based on quantitative radiographic features is proposed. We define megalencephaly as a brain volume which exceeds the mean by more than twice the standard deviation. Furthermore, a modified etiopathogenic classification of megalencephaly results in three main groups, viz anatomic, metabolic and dynamic megalencephaly. The clinical pictures in these main groups of megalencephaly, and the largest subgroup of anatomic megalencephaly, familial anatomic megalencephaly, appear to be quite different.


The Open Insulin Project: A Case Study for 'Biohacked' Medicines.
New innovation ecosystems are emerging that challenge the complex intellectual property and regulatory landscape surrounding drug development in the United States (US). A prime example is an initiative known as the Open Insulin Project. The goal of the project is to sidestep patents and enable generic manufacturers to produce cheaper insulin. However, the US regulatory environment, not patent exclusivity, is the main barrier to insulin affordability. If the Open Insulin Project succeeds in releasing an open protocol for insulin manufacturing, follow-on work could enable a number of new insulin production ecosystems, including 'home-brewed' insulin. Regulators will need to consider how to proceed in a future where commercial pharmaceuticals remain unaffordable, but patients are empowered to produce drugs for their personal use.


Predictors of the frequency of Australian children's consumption of unhealthy foods.
Child obesity interventions need to be based on a sound understanding of the factors that influence children's diets. To investigate the relationship between a range of predictor variables and the frequency with which Australian children consume energy-dense, nutrient-poor (EDNP) foods. A web panel provider was used to access 1302 parents of Australian children aged 8-14 years who responded to an online survey about their children's diets. Structural equation modelling was conducted to test a model of the factors contributing to the frequency of children's unhealthy food consumption. Of the tested variables, consumption of EDNP foods was primarily influenced by parents' attitudes to these foods, children's pestering behaviours and perceived social norms relating to children's consumption of these products. Both pestering and social norms had significant direct effects on consumption frequency as well as indirect effects via their impact on parents' attitudes to EDNP foods. Environmental factors that contribute to both pestering and social norms are likely to be critical considerations in the development of child obesity interventions.


[Primary health care organization in the context of social exclusion/inclusion processes].
This article reports on a primary health care and training center in São Paulo, Brazil, and the organization of its activities based on equity and positive discrimination. Operating in the city center of São Paulo, the policy aims to provide health services access to certain target groups (homeless, sex workers, and slum-dwellers). It also raises discussion on the various forms of social life found in downtown areas, mainly those of vulnerable groups lacking access to public goods and services. The experience demonstrates the feasibility of implementing health policies based on universal access.


Pharyngeal colonization with Haemophilus influenzae type b in children in a day care center without invasive disease.
During an 18-month period, monthly pharyngeal cultures for Haemophilus influenzae type b (Hib) were obtained from 66 children and their caretakers in a day care center in which no systemic disease caused by Hib occurred. The average colonization rate for Hib was 10%, and ranged from 0% to 23% for a single month. Infants housed in a separate building with a cohorted staff were not colonized by Hib. However, 71% of the toddler group and 48% of the preschool group became colonized by Hib at some time during the 18-month-study. Of 89 Hib isolates, 93% were biotype 1 (Kilian), and 90% of these had a similar outer membrane protein profile, designated subtype 1L. This strain was recovered from children at the center for 15 of 18 months. No invasive disease occurred. Thus, Hib may be widespread among preschool children in a day care center and persist for longer than a year without resulting in systemic disease.


XenDB: full length cDNA prediction and cross species mapping in Xenopus laevis.
Research using the model system Xenopus laevis has provided critical insights into the mechanisms of early vertebrate development and cell biology. Large scale sequencing efforts have provided an increasingly important resource for researchers. To provide full advantage of the available sequence, we have analyzed 350,468 Xenopus laevis Expressed Sequence Tags (ESTs) both to identify full length protein encoding sequences and to develop a unique database system to support comparative approaches between X. laevis and other model systems. Using a suffix array based clustering approach, we have identified 25,971 clusters and 40,877 singleton sequences. Generation of a consensus sequence for each cluster resulted in 31,353 tentative contig and 4,801 singleton sequences. Using both BLASTX and FASTY comparison to five model organisms and the NR protein database, more than 15,000 sequences are predicted to encode full length proteins and these have been matched to publicly available IMAGE clones when available. Each sequence has been compared to the KOG database and approximately 67% of the sequences have been assigned a putative functional category. Based on sequence homology to mouse and human, putative GO annotations have been determined. The results of the analysis have been stored in a publicly available database XenDB http://bibiserv.techfak.uni-bielefeld.de/xendb/. A unique capability of the database is the ability to batch upload cross species queries to identify potential Xenopus homologues and their associated full length clones. Examples are provided including mapping of microarray results and application of 'in silico' analysis. The ability to quickly translate the results of various species into 'Xenopus-centric' information should greatly enhance comparative embryological approaches.


Surgical management of rotator cuff tears in adults: Prospective study of 50 consecutive patients and professional practice self-assessment.
As part of quality-improvement efforts, we self-assessed our professional practices regarding the surgical management of rotator cuff tears comparatively to recommendations issued by the French National Authority for Health (HAS). An independent observer prospectively evaluated 50 consecutive patients with rotator cuff tears treated surgically over a 1-year period. For each patient, we identified divergences with the 20 relevant HAS recommendations. Initially, 54% of practices were found to diverge from HAS recommendations, 10% regarding the preoperative work-up, 14% the duration of initial medical treatment, and 30% the nature of the surgical procedure. A review of the data showed that 26% of practices diverged from recommendations, 10% regarding the preoperative work-up, 2% the duration of initial medical treatment, and 14% the nature of the surgical procedure. Overall, for the 26% of divergent practices, 10% were related to judgement or evaluation errors and 16% to a deliberate and substantiated decision made by the surgeons. The clinical practice guidelines issued by the HAS, although useful and necessary, were shown by our study to exhibit a number of limitations. Thus, our data illustrate the complexity of surgical management decisions. Level IV (cases series).


Carotenoid enrichment in eggs: From biochemistry perspective.
The emergence of safe and functional eggs for consumer acceptance has gained focus. The production of carotenoid-enriched eggs has received attention due to its multifunctional biological properties. Nutritional modification of laying hens' diet can be a strategy to produce such eggs. This review presents the chemistry of carotenoids in nature and eggs, the accumulation process of carotenoids into eggs, and the functions of carotenoids in eggs. Our findings showed that carotenoids can be deposited into the egg and contribute to improving its nutritive value. The biosynthesis, chemical structure, and metabolism pathways of carotenoids lead to the deposition of carotenoids into eggs in their original or metabolized forms. Also, some factors modulate the efficiency of carotenoids in fowls before accumulation into eggs. Carotenoid-enriched eggs may be promising, ensuring the availability of highly nutritive eggs. However, further studies are still needed to comprehend the full metabolism process and the extensive functions of carotenoids in eggs.


Enlarged occipital spur and craniofacial morphology: a cephalometric analysis.
This cross-sectional study aimed to investigate the association between the occipital spur length and craniofacial morphology in individuals with occipital spur (OS). The study included cephalometric images from 451 individuals (196 females, 255 males, age range was 9-84 years). The spur length and craniofacial characteristics were evaluated using cephalograms. Based on spur length, subjects were divided into two groups: the OS group (N = 209) and the enlarged occipital spur (EOS) group (N = 242). Descriptive statistics, Independent T-test, Mann-Whitney U test, chi-square test, Kruskal-Wallis test, and age- and sex-based stratified analyses were performed. The level of significance was set at p < 0.05. Males had significantly larger spur length than females. Spur length was shorter in individuals under 18 than the groups over 18. After adjusting for gender and age, ramus height, mandibular body length, effective length of maxilla, effective length of mandible, anterior cranial base length, posterior cranial base length, anterior facial height, posterior facial height, facial height index, and lower anterior facial height had statistically significant differences between OS group and EOS group. Males exhibit greater spur length than females. Patients under 18 had a shorter spur length than adults. Linear craniofacial measurements were found to be greater in subjects with EOS than the individuals with OS. The craniofacial growth and development of an individual might be associated with EOS. The causal relationship between EOS and craniofacial development requires further longitudinal studies.


Risk stratification in medullary thyroid cancer: moving beyond static anatomic staging.
Much progress has been made over the last 10 years with regard to risk estimation in non-medullary differentiated thyroid cancer with risk of recurrence systems and response to therapy re-evaluation approaches being used to augment initial risk estimates obtained using standard anatomic staging systems. Furthermore, risk stratification is being increasingly viewed as an active, evolving, dynamic process that requires re-evaluation during follow-up rather than a single static risk estimate predicted by initial staging. As with differentiated thyroid cancer, multiple clinico-pathologic factors have been demonstrated to correlate with the risk of disease specific mortality, risk of death, likelihood of disease progression, likelihood of cure with initial therapy, and likelihood of cure with additional therapy in medullary thyroid cancer. In this review, we re-examine the clinically important initial risk factors in medullary thyroid cancer and then re-evaluate how some of these risk factors can be used to alter risk estimates over time as they reflect the response to therapy and the clinical course of the disease. We demonstrate that the same response to therapy nomenclature that we have proposed and validated in differentiated thyroid cancer (excellent response, biochemical incomplete response, structural incomplete response, indeterminant response) can be easily applied to medullary cancer and used to guide on-going clinical management.