ECG of the month. Cardiac failure and stroke in a 43-year-old woman. Coarse atrial fibrillation indicating left atrial enlargement and left ventricular hypertrophy with repolarization abnormality.
A 43-year-old woman with a long history of heavy cigarette smoking was in good health until she developed fatigue, dyspnea on exertion, and paroxysmal nocturnal dyspnea approximately three months before admission to our hospital. Four weeks before admission, she was admitted to another hospital for the sudden onset of a right hemiparesis. She was noted to be in atrial fibrillation, and cardiac catheterization and angiocardiography revealed triple-vessel coronary arterial disease and moderately severe mitral regurgitation. Because of repeated episodes of paroxysmal nocturnal dyspnea, she was referred to our hospital for cardiac surgery. On admission, an electrocardiogram was recorded (Figure).


Influence of Chemical, Mechanical, and Transport Processes on Wellbore Leakage from Geologic CO2 Storage Reservoirs.
Wells are considered to be high-risk pathways for fluid leakage from geologic CO2 storage reservoirs, because breaches in this engineered system have the potential to connect the reservoir to groundwater resources and the atmosphere. Given these concerns, a few studies have assessed leakage risk by evaluating regulatory records, often self-reported, documenting leakage in gas fields. Leakage is thought to be governed largely by initial well-construction quality and the method of well abandonment. The geologic carbon storage community has raised further concerns because acidic fluids in the CO2 storage reservoir, alkaline cement meant to isolate the reservoir fluids from the overlying strata, and steel casings in wells are inherently reactive systems. This is of particular concern for storage of CO2 in depleted oil and gas reservoirs with numerous legacy wells engineered to variable standards. Research suggests that leakage risks are not as great as initially perceived because chemical and mechanical alteration of cement has the capacity to seal damaged zones. Our work centers on defining the coupled chemical and mechanical processes governing flow in damaged zones in wells. We have developed process-based models, constrained by experiments, to better understand and forecast leakage risk. Leakage pathways can be sealed by precipitation of carbonate minerals in the fractures and deformation of the reacted cement. High reactivity of cement hydroxides releases excess calcium that can precipitate as carbonate solids in the fracture network under low brine flow rates. If the flow is fast, then the brine remains undersaturated with respect to the solubility of calcium carbonate minerals, and zones depleted in calcium hydroxides, enriched in calcium carbonate precipitates, and made of amorphous silicates leached of original cement minerals are formed. Under confining pressure, the reacted cement is compressed, which reduces permeability and lowers leakage risks. The broader context of this paper is to use our experimentally calibrated chemical, mechanical, and transport model to illustrate when, where, and in what conditions fracture pathways seal in CO2 storage wells, to reduce their risk to groundwater resources. We do this by defining the amount of cement and the time required to effectively seal the leakage pathways associated with peak and postinjection overpressures, within the context of oil and gas industry standards for leak detection, mitigation, and repairs. Our simulations suggest that for many damage scenarios chemical and mechanical processes lower leakage risk by reducing or sealing fracture pathways. Leakage risk would remain high in wells with a large amount of damage, modeled here as wide fracture apertures, where fast flowing fluids are too dilute for carbonate precipitation and subsurface stress does not compress the altered cement. Fracture sealing is more likely as reservoir pressures decrease during the postinjection phase where lower fluxes aid chemical alteration and mechanical deformation of cement. Our results hold promise for the development of mitigation framework to avoid impacting groundwater resources above any geologic CO2 storage reservoir by correlating operational pressures and barrier lengths.


Evaluating Terminologies to Enable Imaging-Related Decision Rule Sharing.
Purpose: Clinical decision support tools provide recommendations based on decision rules. A fundamental challenge regarding decision rule-sharing involves inadequate expression using standard terminology. We aimed to evaluate the coverage of three standard terminologies for mapping imaging-related decision rules. Methods: 50 decision rules, randomly selected from an existing library, were mapped to Systemized Nomenclature of Medicine (SNOMED CT), Radiology Lexicon (RadLex) and International Classification of Disease (ICD-10-CM). Decision rule attributes and values were mapped to unique concepts, obtaining the best possible coverage with the fewest concepts. Manual and automated mapping using Clinical Text Analysis and Knowledge Extraction System (cTAKES) were performed. Results: Using manual mapping, SNOMED CT provided the greatest concept coverage (83%), compared to RadLex (36%) and ICD-10-CM (8%) (p<0.0001). Combined mapping had 86% concept coverage. Automated mapping achieved 85% mapping coverage vs. 94% with manual mapping (p<0.001). Conclusion: Although some gaps remain, standard terminologies provide ample coverage for mapping imaging- related evidence.


Disorder of cellular immunity in pemphigus vegetans.
In an untreated 26-year-old female patient suffering from Neumann's pemphigus vegetans for 8 months (with neither preceding thymoma nor myasthenia gravis), several in vivo and in vitro phenomena of immunodeficiency involving both T and B cell system were disclosed. A diagnosis of defective immune state was established on the basis of the low IgG-serum level (though pemphigus antibodies were present), reduced T cell count in blood, weak PHA stimulation of lymphocytes, lack of skin reactivity to recall antigens and to most other bacterial antigens tested. Impaired chemotaxis and a deficient intracellular killing of Candida albicans by PMNL were also found. The conclusion is drawn that a combined disorder of both the B and T cell system is involved in the etiology of pemphigus vegetans, even when thymoma is ruled out.


Pseudoalteromonas rhizosphaerae sp. nov., a novel plant growth-promoting bacterium with potential use in phytoremediation.
Strain RA15T was isolated from the rhizosphere of the halophyte plant Arthrocnemum macrostachyum growing in the Odiel marshes (Huelva, Spain). RA15T cells were Gram stain-negative, non-spore-forming, aerobic rods and formed cream-coloured, opaque, mucoid, viscous, convex, irregular colonies with an undulate margin. Optimal growth conditions were observed on tryptic soy agar (TSA) plates supplemented with 2.5 % NaCl (w/v) at pH 7.0 and 28 °C, although it was able to grow at 4-32 °C and at pH values of 5.0-9.0. The NaCl tolerance range was from 0 to 15 %. The major respiratory quinone was Q8 but Q9 was also present. The most abundant fatty acids were summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C17 : 1 ω8c and C16 : 0. The polar lipids profile comprised phosphatidylglycerol and phosphatidylethanolamine as the most abundant representatives. Phylogenetic analyses confirmed the well-supported affiliation of strain RA15T within the genus Pseudoalteromonas, close to the type strains of Pseudoalteromonas neustonica, Pseudoalteromonas prydzensis and Pseudoalteromonas mariniglutinosa. Results of comparative phylogenetic and phenotypic studies between strain RA15T and its closest related species suggest that RA15T could be a new representative of the genus Pseudoalteromonas, for which the name Pseudoalteromonas rhizosphaerae sp. nov. is proposed. The type strain is RA15T (=CECT 9079T=LMG 29860T). The whole genome has 5.3 Mb and the G+C content is 40.4 mol%.


Possible role of gamma ray bursts on life extinction in the universe.
As a copious source of gamma rays, a nearby galactic gamma ray burst (GRB) can be a threat to life. Using recent determinations of the rate of GRBs, their luminosity function, and properties of their host galaxies, we estimate the probability that a life-threatening (lethal) GRB would take place. Amongst the different kinds of GRBs, long ones are most dangerous. There is a very good chance (but no certainty) that at least one lethal GRB took place during the past 5 gigayears close enough to Earth as to significantly damage life. There is a 50% chance that such a lethal GRB took place during the last 500×10^{6} years, causing one of the major mass extinction events. Assuming that a similar level of radiation would be lethal to life on other exoplanets hosting life, we explore the potential effects of GRBs to life elsewhere in the Galaxy and the Universe. We find that the probability of a lethal GRB is much larger in the inner Milky Way (95% within a radius of 4 kpc from the galactic center), making it inhospitable to life. Only at the outskirts of the Milky Way, at more than 10 kpc from the galactic center, does this probability drop below 50%. When considering the Universe as a whole, the safest environments for life (similar to the one on Earth) are the lowest density regions in the outskirts of large galaxies, and life can exist in only ≈10% of galaxies. Remarkably, a cosmological constant is essential for such systems to exist. Furthermore, because of both the higher GRB rate and galaxies being smaller, life as it exists on Earth could not take place at z>0.5. Early life forms must have been much more resilient to radiation.


Clinics in diagnostic imaging (31). Adrenal neuroblastoma.
A 3-year-old girl presented with epigastric pain and physical examination showed a hard right upper quadrant mass. Urine VMA and HVA were found to be raised. CT scan showed a large mass arising from the right adrenal gland, with necrotic areas and ring calcification There was midline extension. The diagnosis of neuroblastoma was confirmed by bone marrow aspiration biopsy. As the patient had inoperable stage IV neuroblastoma, she was treated with multi-drug chemotherapy. Follow-up CT scan showed excellent response to the chemotherapy, and the tumour was successfully resected. Harvesting of autologous peripheral bone marrow stem cells, megatherapy with Melphalan, and marrow rescue with the stem cells were effective. The child has been well for three years to date. The clinical and imaging features of neuroblastoma, particularly the role of imaging in staging, are emphasised.


Effect of amino acids on lower esophageal sphincter characteristics and gastroesophageal reflux in humans.
The effect of a commercially available mixed amino acids solution, when given either intravenously or intragastrically, on lower esophageal sphincter (LES) pressure, frequency of transient LES relaxations (TLESRs) and gastroesophageal reflux (GER) was investigated in six healthy volunteers. LES pressure and esophageal pH were simultaneously recorded on three separate occasions 1 hr before (basal) and 3 hr during intravenous or intragastric infusion of amino acids (250 mg protein/kg/hr) or saline (control). No significant changes in LES pressure were seen in the control experiment. Intravenous amino acids caused a rapid and sustained (P < 0.01) decrease in LES pressure whereas intragastric amino acids decreased LES pressure only gradually and temporarily (P < 0.01). In the three experiments no significant differences were observed in TLESR frequency, the number of GER episodes, the mechanism of reflux, or duration of acid exposure. In healthy subjects both intragastric and, especially, intravenous infusion of amino acids significantly decrease LES pressure but do not affect the frequency of TLESRs or GER episodes during a continuous liquid gastric load.


Identification of hub genes and pathways associated with bladder cancer based on co-expression network analysis.
The aim of the present study was to identify hub genes and signaling pathways associated with bladder cancer (BC) utilizing centrality analysis and pathway enrichment analysis. The differentially expressed genes (DEGs) were screened from the ArrayExpress database between normal subjects and BC patients. Co-expression networks of BC were constructed using differentially co-expressed genes and links, and hub genes were investigated by degree centrality analysis of co-expression networks in BC. The enriched signaling pathways were investigated by Kyoto Encyclopedia of Genes and Genomes database analysis based on the DEGs. The hub gene expression in BC tissues was validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. A total of 329 DEGs were screened, including 147 upregulated and 182 downregulated genes. The co-expression network constructed between BC and normal controls consisted of 182 nodes and 434 edges, and the two genes in each gene pair were differentially co-expressed genes. Centrality analysis of co-expression networks suggested that the top 5 hub genes with high degree included lectin, galactoside-binding, soluble, 4 (LGALS4), protein tyrosine phosphatase, receptor type N2 (PTPRN2), transmembrane protease, serine 11E (TMPRSS11E), tripartite motif containing 31 (TRIM31) and potassium voltage-gated channel subfamily D member 3 (KCND3). Pathway analysis revealed that the 329 DEGs were significantly enriched in 5 terms (cell cycle, DNA replication, oocyte meiosis, p53 signaling pathway and peroxisome proliferator-activated receptor signaling pathway). According to RT-qPCR and western blot analysis, 4/5 hub genes were significantly expressed, including LGALS4, PTPRN2, TMPRSS11E, TRIM31; however, KCND3 was not significantly expressed. In the present study, 5 hub genes were successfully identified (LGALS4, PTPRN2, TMPRSS11E, TRIM31 and KCND3) and 5 biological pathways that may be underlying biomarkers for early diagnosis and treatment associated with bladder cancer were revealed.


IDH2 mutation in gliomas including novel mutation.
Glioblastomas (GBMs) are the most aggressive type of primary brain tumors and provide a dismal prognosis. Thus far, several key genes have been identified in GBMs as prognostic and therapeutic targets. Mutations in two isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, commonly occur in low-grade gliomas and secondary high-grade gliomas, but are rare in primary GBMs. These mutations alter the catalytic activity of IDH proteins, promoting gliomagenesis. Gliomas with IDH1 or IDH2 mutation have better outcomes than do gliomas with wild-type IDH. The hot spots of IDH1 mutations (R132) and IDH2 mutations (R140 and R172) are well known and are considered as a possible biochemical explanation for the differing clinical characteristics of primary and secondary GBMs. We sought to find the incidence of IDH2 mutation and the characteristics of the gliomas with IDH2 mutation. Among 134 gliomas, which were operated in our hospital consecutively, we studied IDH1 and IDH2 mutations by Sanger sequencing and IDH2 mutation was identified in seven cases (5.2%, four oligodendrogliomas and three GBMs). IDH2 mutation was found in 3.3% of GBMs (3/90 cases) and 9.0% (4/44) of grades II to III gliomas. Here, we report the clinicopathological characteristics of the gliomas with IDH2 mutations including two cases of primary GBM carrying a novel missense IDH2 mutation (c. 484C>T, p. P162S).


Effectiveness of laser welding in cerclage wiring fixation: a biomechanical study.
Cerclage wiring is a common orthopedic procedure for fracture fixation. However, previous studies reported wiring-related perioperative complications, such as wire loosening or breakage, with an incidence rate of up to 77%. Recently, the use of laser welding on medical implants was introduced to connect biomedical materials. This study used laser technology to weld between wires after conventional cerclage fixation. We hypothesized that the laser welding could significantly increase the biomechanical properties of cerclage wiring fixation. Twenty-five wiring models underwent biomechanical tests in five cerclage wiring configurations (five models per group), namely, (1) single loop, (2) single loop with laser welding, (3) double loop, (4) double loop with one-side laser welding, and (5) double loop with two-side laser welding. Characteristics such as load to failure, mode of failure, and wiring failure were compared between groups. The biocompatibility for a 316L stainless steel wire with laser welding was evaluated via an in vitro hemolysis test. Mean load to failure of the double loop with one-side and two-side laser welding groups were 3,596 ± 346 N and 3,667 ± 240 N, which were significantly higher than for the double-loop group (2,919 ± 717 N) (p = 0.012 and p = 0.044, respectively). Conversely, no significant difference was shown in the comparison of the mean load to failure between the single loop and the single loop with laser-welded cerclage wire (1,251 ± 72 N, 1,352 ± 122 N, and p = 0.12). Untwisted wire and wire breakage were the most common mode of failure. All welding specimens revealed non-hemolytic effects from in vitro hemolysis test. Laser welding on cerclage wiring significantly increases the biomechanical property of double cerclage wire fixation. However, further biocompatibility tests and clinical studies are still recommended.


Visual and Refractive Outcomes of Cataract Surgeries Performed in One Year in a Private Practice Setting: Review of 2714 Procedures.
Our center's database was used to identify all isolated cataract procedures performed during 2017. The electronic records were reviewed to collect the preoperative information, presence of intra- or postsurgical complications, and visual and refractive outcomes one month after surgery. In 2017, 2714 eyes of 1543 patients underwent cataract surgery in our center. Mean patient age was 70.42 years. 775 eyes (28.55%) had prior ophthalmic pathologies, and 113 eyes (4.16%) had undergone previous surgical procedures. Surgical complications developed in 35 eyes (1.29%), including 9 posterior capsule tears (0.33%) and 3 cases of dropped lens fragments (0.11%). A toric or multifocal intraocular lens was implanted in 45.6% of eyes. As regards postoperative complications, 59 eyes (2.17%) required a return to the operating theater, including 29 eyes (1.07%) requiring reinterventions due to an unexpected refractive result. There were no cases of endophthalmitis. Mean LogMAR-corrected distance visual acuity (CDVA) improved from 0.25 (SD 0.34) preoperatively to 0.04 (SD 0.17) postoperatively; 86.5% of eyes achieved a CDVA ≤0.0, with 97.5% achieving ≤0.3. In 86.4% of eyes, the difference between target and residual spherical equivalent difference was of 0.50 D or lower; 88% of eyes had a spherical equivalent ±0.50 D. The visual and refractive outcomes of cataract surgery in a private practice setting were excellent, well over the benchmarks set by the ESCRS. The safety profile was also within expected standards. This study provides information for ophthalmologists in private practice on expected outcomes.


Dehydrogenative B-H/C(sp3 )-H Benzylic Borylation within the Coordination Sphere of Platinum(II).
The first examples of stoichiometric dehydrogenative B-H/C(sp3 )-H benzylic borylation reactions, which are of relevance to catalytic methylarene (di)borylation, are reported. These unusual transformations involving a (κ2 -P,N)Pt(η3 -benzyl) complex, and either pinacolborane or catecholborane, proceed cleanly at room temperature. Density functional calculations suggest that borylation occurs via successive σ-bond metathesis steps, whereby a PtII -H intermediate engages in C(sp3 )-H bond activation-induced dehydrogenation.


[The bond properties of Vitadur alpha on dental zirconia framework material].
To evaluate the bond properties of Vitadur alpha on dental zirconia framework material. Vitadur alpha was sintered on the surface of four groups' presintered zirconia ceramic plates which were dealt with respective procedures. SEM, energy distribution spectrum and thermal shock test were applied to evaluate the sintering properties of such interfaces. Shear bond strength of Vitadur alpha-zirconia interfaces were measured, and the results were analysed by ANOVA method. Satisfying result was obtained in Vitadur alpha sintered on the zirconia framework material, furthermore, chemical combination between the two laminates were confirmed by means of energy distribution spectrum. The shear bond strength of 3Y-TZP-Vitadur alpha dentin differed under different surface conditionings: highest shear bond strength appeared in the group conditioned with water sand paper (35.1662MPa), shear bond strength of the group conditioned with sandblast (27.8283MPa) was better than that of non-conditioning group (20.9677MPa), diamond condition group had the lowest shear bond strength (15.3025MPa), significant difference existed between each group (P<0.01). Further clinical research could be carried out on Vitadur alpha and zirconia ceramic framework under conditioning with sandblast.


Short-term rebound anxiolytic effects and long-term changes in platelet benzodiazepine binding after pentylenetetrazole-kindling in two strains of rat.
Although there were no differences in response to an acute injection of pentylenetetrazole (PTZ), there were strain differences in the development of kindled seizures to repeated injections (PTZ; 30 mg/kg 3 times weekly for 13 injections), with Wistar rats reaching stage 4 or 5 of clonic-tonic seizures, but hooded Lister rats reaching only stage 2 or 3 of convulsive waves axially through the body. The strains also reacted differently to a test dose of PTZ (20 mg/kg) one week after the end of kindling, with the Wistar strain showing stage 3 and the Lister strain stage 2 seizures. When the rats were tested 24 h after the end of the kindling injections there was an anxiolytic effect in the social interaction test, in both the low light, familiar and the low light, unfamiliar test conditions that reached significance in the Wistar strain. The Wistar kindled rats showed an anxiolytic effect in the elevated plus-maze test of anxiety when they were tested 24 h after the end of kindling. The anxiolytic effects found 24 h after kindling could not be due to the seizure 24 h earlier, since no changes were found in rats tested 24 h after a single seizure from PTZ (60 mg/kg). When the rats were tested 1 week after the end of kindling there were no changes, compared with vehicle-injected controls, in either test of anxiety. There was no change in benzodiazepine binding in platelets of the kindled Lister rats but there was a significant increase in the kindled Wistar rats 1 week after the end of kindling and also 24 h after a single PTZ seizure. The pattern of increased platelet benzodiazepine binding did not correspond with the time course of rebound anxiolytic effects. However, after kindling it seems that there are long-lasting changes in benzodiazepine binding that are similar to the short-term increases that are found following a single seizure.


Rafts, Nanoparticles and Neural Disease.
This review examines the role of membrane rafts in neural disease as a rationale for drug targeting utilizing lipid-based nanoparticles. The article begins with an overview of methodological issues involving the existence, sizes, and lifetimes of rafts, and then examines raft function in the etiologies of three major neural diseases-epilepsy, Parkinson's disease, and Alzheimer's disease-selected as promising candidates for raft-based therapeutics. Raft-targeting drug delivery systems involving liposomes and solid lipid nanoparticles are then examined in detail.


Phosphoglycerate Mutase 1 (PGAM1) Promotes Pancreatic Ductal Adenocarcinoma (PDAC) Metastasis by Acting as a Novel Downstream Target of the PI3K/Akt/mTOR Pathway.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors known, with an overall 5-year survival rate of less than 6% due to early local invasion and distant metastasis. Exploring suitable therapeutic targets associated with invasion and metastasis is required for improving the prognosis of PDAC. In this study, we investigated the role of the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) in PDAC. PGAM1 expression was examined in tissue samples of 54 PDAC patients using immunohistochemistry, and the correlation between clinicopathological expression and PGAM1 expression was determined. A survival curve was generated using the Kaplan-Meier method. After silencing PGAM1 by siRNA in pancreatic cancer cell lines Aspc-1 and Panc-1, the changes in proliferation, migration, and invasion, and signal pathways were determined. In this study, the expression of PGAM1 was found positively related to poor differentiation, metastasis, advanced clinical stage, and poor survival rate. Silencing PGAM1 decreased the proliferation of Aspc-1 and Panc-1 cells with an S phase arrest, but without influencing cell apoptosis. Migration and invasion also decreased significantly, independent of proliferation. PGAM1 was also found to promote EMT of PDAC cell lines by regulating the Wnt/β-catenin pathway. PGAM1 itself was modulated by the PI3K/Akt/mTOR pathway as a novel downstream target and has a positive mutual regulation with HIF-1α. This study indicates that PGAM1 is closely associated with clinical metastasis and poor prognosis of PDAC. PGAM1 is considered as a potential therapeutic target in PDAC metastasis.


Assessing the Knowledge, Attitudes and Behaviors of Human and Animal Health Students towards Antibiotic Use and Resistance: A Pilot Cross-Sectional Study in the UK.
The Global Action Plan on Antimicrobial Resistance highlights the importance of training all healthcare professionals. No study has assessed patterns of students' knowledge, attitudes and practices concerning antibiotic use simultaneously across different healthcare course types. We conducted a cross-sectional multi-center survey among UK students. The survey was advertised through local survey coordinators at 25 universities. The online survey was accessible from 10th October to 17th November 2016 (before European Antibiotic Awareness Day). A total of 255 students from 25 universities participated, including students on medicine, pharmacy, nursing, physician associate, dentistry and veterinary medicine courses. Antibiotic resistance was considered to be a more important global challenge than climate change, obesity or food security (p < 0.001). Most students (95%) believed that antibiotic resistance will be a problem for their future practice, but fewer (69%) thought that the antibiotics they will prescribe, administer or dispense will contribute to the problem. A fifth of students felt they had sufficient knowledge of antibiotic use for their future work. Our exploratory study suggests that UK human and animal healthcare students are aware of the importance of antibiotic resistance, but many still have certain misconceptions. Campaigns and improved educational efforts applying behavioral insights methodology could address these.


Psychological Adversity among Professional and Non-Professional Criminals in Pakistan.
The paper describes the psychological meaningfulness of a classification scheme of criminals proposed in the social and cultural context of Pakistan. On the basis of the suggested typology, 220 randomly selected male convicts were classified in to two groups of Professional and Non-professional Criminals. Social psychological and legal factors which formed the basis of classification included convict's Occupational Life Pattern, Type of Crime, Interpersonal Context, Premeditation, Criminal Associations and Past Criminal Record. Two groups thus obtained were compared on three psychological variables: Physically Broken Home, Psychologically Disrupted Home, and Defective Modes of Discipline indicating Psychological Adversity during childhood and early adolescence. Professional Criminals differed significantly (p < 0.008) from Non-professionals whose crimes are explained in terms of the social and cultural conditions of Pakistan. Implications for further research and handling of prison inmates have been pointed out.


HIV and the CCR5-Delta32 resistance allele.
The combination of molecular biology, epidemiology, virology, evolutionary and population genetics has enabled us to understand the delicate interplay between HIV and the CCR5-Delta32 HIV resistance allele. We here review and collect from the different approaches to show how they can be combined to elucidate the interaction between host and pathogen genetics in this system. We will present an overview of the normal role of CCR5, its involvement in HIV, the molecular biology of the CCR5-Delta32 allele and its probable origins. By focusing on this well-documented and important system we hope to demonstrate the power that such a "holistic" approach might offer in the study of infectious diseases.


[Risk of compartment syndrome in open and closed tibial fractures].
In orthopaedic traumatology; acute compartment syndrome is a common complication associated with tibial fractures. In our study, we investigate differences, if any, between open and closed tibialfractures in terms oftheir risk of compartment syndrome. Fourty-two tibial fractures of 39 patients, 29 (69%) closed and 13 (31%) open, having the risk of acute compartment syndrome according to the clinical examination, were monitored following traumas during which their DP (DP= Diastolic blood pressure -Absolute compartment pressure) and absolute compartment pressures were measured via intracompartmental pressure measuring equipment. Average absolute compartment pressure was found to be 31.25 mmHg in open and 29,32 mmHg in closed fractures (p=O,484) whereas average DP was measured to be 47,46 mmHg in open and 49,66 mmHg in closedfractures (p=O,415). According to student's test, the difference between the two groups was not significant. We found the incidence of acute compartment syndrome as 7, 7% in open fractures, 6.9% in closed and 7, 1 % in overall tibial fractures andfasciotomy was carried out in those cases. Statistically not significant difference between the pressure levels,found in open and closed tibialfractures, showed that open type oftibialfractures holds the risk of compartment syndrome as much as the closed one.


Influence of a silver salt on the nanostructure of a Au(111)/ionic liquid interface: an atomic force microscopy study and theoretical concepts.
Ionic liquids (ILs) form a multilayered structure at the solid/electrolyte interface, and the addition of solutes can alter it. For this purpose, we have investigated the influence of the silver bis(trifluoromethylsulfonyl)amide (AgTFSA) concentration in 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)amide ([Py1,4]TFSA) on the layering using in situ atomic force microscopy. AFM investigations revealed that the Au(111)/electrolyte interface indeed depends on the concentration of the salt where a typical " IL" multilayered structure is retained only at quite low concentrations of the silver salt (e.g. ≤200 μM). However, at 200 μM AgTFSA/[Py1,4]TFSA and above this "IL" multilayered structure is disturbed/varied. A simple double layer structure was observed at 500 μM AgTFSA in [Py1,4]TFSA. Furthermore, the widths of the innermost layers have been found to be dependent on the concentration and on the applied electrode potentials. Our AFM results show that the concentration of solutes strongly influences the structure of the electrode/electrolyte interface and can provide new insights into the electrical double layer structure of the electrode/ionic liquid interface. We also introduce a semi-continuum theory to discuss the double layer structure.


Factors determining electrostatic fields in molecular dynamics simulations of the Ras/effector interface.
Using molecular dynamics simulations, we explore geometric and physical factors contributing to calculated electrostatic fields at the binding surface of the GTPase Ras with a spectroscopically labeled variant of a downstream effector, the Ras-binding domain of Ral guanine nucleotide dissociation stimulator (RalGDS). A related system (differing by mutation of one amino acid) has been studied in our group using vibrational Stark effect spectroscopy, a technique sensitive to electrostatic fields. Electrostatic fields were computed using the AMBER 2003 force field and averaged over snapshots from molecular dynamics simulation. We investigate geometric factors by exploring how the orientation of the spectroscopic probe changes on Ras-effector binding. In addition, we explore the physical origin of electrostatic fields at our spectroscopic probe by comparing contributions to the field from discrete components of the system, such as explicit solvent, residues on the Ras surface, and residues on the RalGDS surface. These models support our experimental hypothesis that vibrational Stark shifts are caused by Ras binding to its effector and not the structural rearrangements of the effector surface or probe reorientation on Ras-effector binding, for at least some of our experimental probes. These calculations provide physical insight into the origin, magnitude, and importance of electrostatic fields in protein-protein interactions and suggest new experiments to probe the field's role in protein docking.


Effect of a polysaccharide-rich hydrolysate from Saccharomyces cerevisiae (LipiGo®) in body weight loss: randomised, double-blind, placebo-controlled clinical trial in overweight and obese adults.
In the present study we evaluated the weight loss effect of a polysaccharide-rich food supplement, LipiGo®, comprising a specific β-glucan-chitin-chitosan fraction (BGCC) obtained from the chemical hydrolysis of Saccharomyces cerevisiae, resulting as a by-product of the brewing process. A randomised, double-blind, placebo-controlled clinical trial was performed enrolling 56 overweight and obese subjects (body mass index, BMI, 25-35 kg m-2 ) who were not following any specific diet, and were given placebo or BGCC (3 g d-1 ) for 12 weeks. Results were analysed by intention-to-treat (ITT) and per-protocol (PP) methods. Body weight increased in the placebo group compared to baseline (ITT: 1.0 kg, P < 0.001; PP: 1.5 kg, P = 0.003), while it was slightly lowered in the BGCC group (ITT: -0.8 kg, P = 0.210; PP: -1.1 kg, P = 0.182). BGCC, but not the consumption of placebo, also resulted in a reduction of waist circumference and body fat compared to baseline. Results suggest that daily supplementation of BGCC may be useful for improving body weight and waist circumference in overweight and obese subjects, without relevant adverse effects. © 2017 Society of Chemical Industry.


Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond.
The intent of this article is to report the status of some of the pharmaceuticals currently in late stage development for possible use for individuals unwantedly and acutely injured as a result of radiological/nuclear exposures. The two major questions we attempt to address here are: (a) What medicinals are currently deemed by regulatory authorities (US FDA) to be safe and effective and are being stockpiled? (b) What additional agents might be needed to make the federal/state/local medicinal repositories more robust and useful in effectively managing contingencies involving radiation overexposures? A limited number (precisely four) of medicinals have been deemed safe and effective, and are approved by the US FDA for the 'hematopoietic acute radiation syndrome (H-ARS).' These agents are largely recombinant growth factors (e.g. rhuG-CSF/filgrastim, rhuGM-CSF/sargramostim) that target and stimulate myeloid progenitors within bone marrow. Romiplostim, a small molecular agonist that enhances platelet production via stimulation of bone marrow megakaryocytes, has been recently approved and indicated for H-ARS. It is critical that additional agents for other major sub-syndromes of ARS (gastrointestinal-ARS) be approved. Future success in developing such medicinals will undoubtedly entail some form of a polypharmaceutical strategy, or perhaps novel, bioengineered chimeric agents with multiple, radioprotective/radiomitigative functionalities.


Coagulation profiles in dogs with congenital portosystemic shunts before and after surgical attenuation.
Serious postoperative hemorrhage has been reported in dogs after closure of congenital portosystemic shunts (CPS). In dogs with portosystemic shunting, low coagulation factor activity is responsible for coagulopathy, which can cause complications after surgery. Thirty-four dogs with CPS and 39 healthy dogs. In a prospective study, coagulation times, platelet count, and the activity of 8 coagulation factors were measured in dogs before and after surgical shunt attenuation and in 31 healthy dogs. The effect of abdominal surgery on hemostasis was determined at ovariectomy in 8 healthy dogs. Dogs with CPS had lower platelet counts, lower activity of factors II, V, VII, and X, and increased factor VIII and activated partial thromboplastin time (APTT) compared to healthy dogs. After surgical attenuation, dogs with CPS had decreased platelet counts and activity of factors I, II, V, VII, IX, X, and XI and a prolonged prothrombin time (PT). Ovariectomy resulted in decreased activity of factors VII and X. Six weeks after surgery, portosystemic shunting persisted in 9 of 30 dogs, with no improvement of hemostatic values. CPS dogs without shunting had improved coagulation times and increased activity of factors II, V, VII, and X. Dogs with CPS have lower activity of clotting factors compared to healthy dogs, resulting in a prolonged APTT. Surgical attenuation of the shunt results in increased abnormalities in coagulation times and factors immediately after surgery. Hemostasis is normalized after complete recovery of shunting after attenuation, in contrast to dogs with persistent shunting.


The trend of ocular surface squamous neoplasia among ocular surface tumour biopsies submitted for histology from Sekuru Kaguvi Eye Unit, Harare between 1996 and 2000.
To determine the trend in the prevalence of ocular surface squamous neoplasia (OSSN) among ocular surface tumour biopsies submitted for histology from Sekuru Kaguvi Eye Unit (SKEU), Harare between January 1996 and August 2000. The study was a retrospective records review of patients who had biopsies of ocular surface tumours done during the study period. National Referral Centre for eye patients (Sekuru Kaguvi Eye Unit), Parirenyatwa Hospital, Harare, Zimbabwe. A total of 1,587 records of patients who had ocular surface tumour biopsies performed were reviewed. Period prevalence of OSSN among ocular surface tumour biopsy specimens submitted for histology during the period under review. The median age of patients with OSSN was significantly different from the median age of patients with other conjunctival tumours: 35 years (interquartile range [IQR] 25 to 47 years) versus 51 years (IQR 25 to 60 years), p < 0.0005 respectively. Four hundred and thirty out of 615 (70%) patients with OSSN were females. The overall period prevalence of OSSN was 615 of the total of 1,587 (38.8%). The annual prevalence of OSSN among ocular surface tumour biopsy specimens was found to be on the increase and ranged from 33% (115) in 1996 and 57.9% (165) during the year 2000. The Chi-squared test for trend analysis showed a significant upward linear trend (x2 = 27.4, p < 0.004). Fifty three percent of the tumours were OSSN, 42% were pterygium and 5% were pyogenic granulomas of the conjunctiva. OSSN is the commonest tumour of the ocular surface whose primary site is the conjunctiva. Its prevalence in Zimbabwe is on the increase and it has a predilection for females over males. Further studies on the natural history, treatment and patient profile would pave a way to better quality of patient care and establish its association with HIV/AIDS.


Effects of immunosuppression on circulating adeno-associated virus capsid-specific T cells in humans.
In humans adeno-associated virus (AAV)-mediated gene transfer is followed by expansion of AAV capsid-specific T cells, evidence of cell damage, and loss of transgene product expression, implicating immunological rejection of vector-transduced cells, which may be prevented by immunosuppressive drugs. We undertook this study to assess the effect of immunosuppression (IS) used for organ transplantation on immune responses to AAV capsid antigens. Recipients of liver or kidney transplants were tested before and 4 weeks after induction of IS in comparison with matched samples from healthy human adults and an additional cohort with comorbid conditions similar to those of the transplant patients. Our data show that transplant patients and comorbid control subjects have markedly higher frequencies of circulating AAV capsid-specific T cells compared with healthy adults. On average, IS resulted in a reduction of AAV-specific CD4⁺ T cells, whereas numbers of circulating CD8⁺ effector and central memory T cells tended to increase. Independent of the type of transplant or the IS regimens, the trend of AAV capsid-specific T cell responses after drug treatment varied; in some patients responses were unaffected whereas others showed decreases or even pronounced increases, casting doubt on the usefulness of prophylactic IS for AAV vector recipients.


Calcium mobilization and spontaneous transient outward current characteristics upon agonist activation of P2Y2 receptors in smooth muscle cells.
A quantitative model is provided that links the process of metabotropic receptor activation and sequestration to the generation of inositol 1,4,5-trisphosphate, the subsequent release of calcium from the central sarcoplasmic reticulum, and the consequent release of calcium from subsarcolemma sarcoplasmic reticulum that acts on large-conductance potassium channels to generate spontaneous transient outward currents (STOCs). This model is applied to the case of STOC generation in vascular A7r5 smooth muscle cells that have been transfected with a chimera of the P2Y(2) metabotropic receptor and green fluorescent protein (P2Y(2)-GFP) and exposed to the P2Y(2) receptor agonist uridine 5'-triphosphate. The extent of P2Y(2)-GFP sequestration from the membrane on exposure to uridine 5'-triphosphate, the ensuing changes in cytosolic calcium concentration, as well as the interval between STOCs that are subsequently generated, are used to determine parameter values in the model. With these values, the model gives a good quantitative prediction of the dynamic changes in STOC amplitude observed upon activation of metabotropic P2Y(2) receptors in the vascular smooth muscle cell line.


Energetics and dynamics of the fragmentation reactions of protonated peptides containing methionine sulfoxide or aspartic acid via energy- and time-resolved surface induced dissociation.
The surface-induced dissociation (SID) of six model peptides containing either methionine sulfoxide or aspartic acid (GAILM(O)GAILR, GAILM(O)GAILK, GAILM(O)GAILA, GAILDGAILR, GAILDGAILK, and GAILDGAILA) have been studied using a specially configured Fourier transform ion-cyclotron resonance mass spectrometer (FT-ICR MS). In particular, we have investigated the energetics and dynamics associated with (i) preferential cleavage of the methionine sulfoxide side chain via the loss of CH3SOH (64 Da), and (ii) preferential cleavage of the amide bond C-terminal to aspartic acid. The role of proton mobility in these selective bond cleavage reactions was examined by changing the C-terminal residue of the peptide from arginine (nonmobile proton conditions) to lysine (partially mobile proton conditions) to alanine (mobile proton conditions). Time- and energy-resolved fragmentation efficiency curves (TFECs) reveal that selective cleavages due to the methionine sulfoxide and aspartic acid residues are characterized by slow fragmentation kinetics. RRKM modeling of the experimental data suggests that the slow kinetics is associated with large negative entropy effects and these may be due to the presence of rearrangements prior to fragmentation. It was found that the Arrhenius pre-exponential factor (A) for peptide fragmentations occurring via selective bond cleavages are 1-2 orders of magnitude lower than nonselective peptide fragmentation reactions, while the dissociation threshold (E0) is relatively invariant. This means that selective bond cleavage is kinetically disfavored compared to nonselective amide bond cleavage. It was also found that the energetics and dynamics for the preferential loss of CH3SOH from peptide ions containing methionine sulfoxide are very similar to selective C-terminal amide bond cleavage at the aspartic acid residue. These results suggest that while preferential cleavage can compete with amide bond cleavage energetically, dynamically, these processes are much slower compared to amide bond cleavage, explaining why these selective bond cleavages are not observed if fragmentation is performed under mobile proton conditions. This study further affirms that fragmentation of peptide ions in the gas phase are predominantly governed by entropic effects.


A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin.
Aminoglycosides can bypass nonsense mutations and are the prototypic agents for translational bypass therapy (TBT). Initial results demonstrate the need for more potent drugs and an in vivo model system for quantitative assessment of TBT. Herein, we present an in vivo system for evaluating the efficacy of premature stop codon management therapies: in vivo quantitative stop codon management repli-sampling TBT efficacy assay (IQSCMaRTEA). Application of IQSCMaRTEA reveals that geneticin is much more efficacious in vivo than gentamicin. Treatment with geneticin elicits a multiday response, and residual F9 antigen can be detected after 3 weeks. These data demonstrate the utility of IQSCMaRTEA for evaluating drugs that bypass nonsense mutations. In addition, IQSCMaRTEA may be helpful for testing inhibitors of nonsense-mediated decay, as stop codon management therapy will sometimes require inhibition of nonsense-mediated decay and translational bypass of the nonsense mutation. Furthermore, geneticin, its metabolites, or better tolerated analogues should be evaluated as a general treatment with multiday response for severe genetic disease caused by nonsense mutation.


Comparison of Doppler sonography and multidetector-row computed tomography in the imaging findings of the deep inferior epigastric perforator artery.
Multidetector-row computed tomography (MDCT) has been recently introduced to detect the perforator vessels. The aim of this study is to compare the MDCT with Doppler ultrasound and assess the usefulness of the MDCT for the preoperative planning. Five healthy adult men were first assessed for the perforators and marked with rubber using the Doppler ultrasound before MDCT was performed. Using these images, the number and the location of the perforator were evaluated. We could detect 83 perforators on five cases, while could detect 35 perforators by the Doppler ultrasound. We measured the distance from the fascia perforating points to rubber markings points. It ranged from 0 to 22.47 mm (7.62 mm on average). MDCT angiography is useful for preoperative planning of deep inferior epigastric artery perforator flap at the point of more accurate anatomical findings and clear images of perforator vessels compared to the findings using Doppler ultrasound.


Enzymatic Hydrolysis of Water Extractable Polysaccharides from Leaves of Plantago major L.
Plantago major L. leaves have been used for centuries by the traditional medicine in the treatment of infectious disorders of the respiratory, urinary and digestive tracts. Researchers have reported that hot water extracts of Plantago major possess a broad-spectrum of anticancer, antioxidant and antiviral activities, as well as activities which modulate cell-mediated immunity. Their beneficial properties may be due to the significant content of polysaccharides. The polysaccharides that have been isolated from the leaves of Plantago major L. have different structures - pectic substances, galactans, arabinogalactans, glucomannans. The aim of this paper was to study the correlation between the structure of the water extractable polysaccharides isolated from Plantago major L. leaves and their enzymatic hydrolysis with different carbohydrate hydrolases. The hydrolysis reactions were performed with the enzymes hemicellulase and mannanase. Spectrophotometric total reducing sugars assay was used to examine the hydrolysis yield. The monosaccharide and oligosaccharide compositions were determined using HPLC analysis. The highest hydrolysis yield of the water extractable polysaccharides from Plantago major leaves was obtained by treatment with hemicellulase. The hydrolysis yield increased with the augmentation of the ratio of enzyme to polysaccharide. Galactose was the prevalent monosaccharide identified in the composition of the isolated polysaccharides. Oligosaccharides with different degree of polymerization were also detected. The enzymatic hydrolysis of water extractable polysaccharides from Plantago major leaves allows us to obtain different types of oligosaccharides with beneficial effects on both human health and industry.


Discovery of Unclustered Fungal Indole Diterpene Biosynthetic Pathways through Combinatorial Pathway Reassembly in Engineered Yeast.
The structural diversity and biological activities of fungal indole diterpenes (IDTs) are generated in large part by the IDT cyclases (IDTCs). Identifying different IDTCs from IDT biosynthetic pathways is therefore important toward understanding how these enzymes introduce chemical diversity from a common linear precursor. However, IDTCs involved in the cyclization of the well-known aflavinine subgroup of IDTs have not been discovered. Here, using Saccharomyces cerevisiae as a heterologous host and a phylogenetically guided enzyme mining approach, we combinatorially assembled IDT biosynthetic pathways using IDTCs homologues identified from different fungal hosts. We identified the genetically standalone IDTCs involved in the cyclization of aflavinine and anominine and produced new IDTs not previously isolated. The cyclization mechanisms of the new IDTCs were proposed based on the yeast reconstitution results. Our studies demonstrate heterologous pathway assembly is a useful tool in the reconstitution of unclustered biosynthetic pathways.


Congo Basin rainfall climatology: can we believe the climate models?
The Congo Basin is one of three key convective regions on the planet which, during the transition seasons, dominates global tropical rainfall. There is little agreement as to the distribution and quantity of rainfall across the basin with datasets differing by an order of magnitude in some seasons. The location of maximum rainfall is in the far eastern sector of the basin in some datasets but the far western edge of the basin in others during March to May. There is no consistent pattern to this rainfall distribution in satellite or model datasets. Resolving these differences is difficult without ground-based data. Moisture flux nevertheless emerges as a useful variable with which to study these differences. Climate models with weak (strong) or even divergent moisture flux over the basin are dry (wet). The paper suggests an approach, via a targeted field campaign, for generating useful climate information with which to confront rainfall products and climate models.


Direct versus indirect measures of mixed emotions in predictive models: a comparison of predictive validity, multicollinearity, and the influence of confounding variables.
Mixed emotions have been assessed using both direct measures that utilize self-report questionnaires as well as indirect measures that are computed from scores of positive and negative emotions. This study provides a pre-registered methodological examination on the use of direct and indirect measures of mixed emotions in predictive models. Two samples (N = 749) were collected, and path analyses were performed to compare direct measures and indirect measures in predicting psychological conflict, receptivity, and well-being, controlling for demographics, positive emotions, and negative emotions. We also tested whether trait dialecticism, need for cognition, social desirability, or acquiescence could account for these associations. In both samples, results suggest that indirect measures may be more susceptible to multicollinearity when controlling for positive and negative emotions. Specifically, variance inflation factors (VIF) were consistently higher for indirect measures calculated using the minimum index (MIN; VIFSample-1 = 3.53; VIFSample-2 = 9.46) than direct measures (VIFSample-1 = 2.52; VIFSample-2 = 1.68). Direct measures remained consistently associated with increased conflict and reduced coherence upon controlling for positive and negative emotions, while indirect measures remained consistently associated only with increased conflict. We found little evidence that response biases explained associations between direct measures or indirect measures with each of the outcomes. Specifically, associations between mixed emotions with psychological conflict, receptivity, and well-being largely remained unchanged in models that controlled for trait dialecticism, need for cognition, social desirability, or acquiescence. Implications and recommendations based on our findings are discussed.


Mediators of the effects of cold-warm communication on attraction toward online service providers.
Undergraduate students (N = 120) in Singapore sought advice from the experimenter's confederate via e-mail or phone. After receiving a scripted warm or cold reply from the online service provider, participants rated their general attitude toward the service provided, positive and negative affect, and attraction toward the service provider. The effect of warm versus cold communication on attraction toward the online service provider was partly mediated by general attitude, positive affect, and negative affect. The results indicate that attitude that influences attraction through affect can itself be a mediator when it is formed through online interactions.


The impact of robotics on employment and motivation of employees in the service sector, with special reference to health care.
The economy is being lifted by the new concept of robotics, but we cannot be sure of all the possible benefits. At this early stage, it therefore becomes important to find out the possible benefits/limitations associated with robotics, so that the positives can be capitalized, established, and developed further for the employment and motivation of employees in the health care sector, for overall economic development. The negatives should also be further studied and mitigated. This study is an exploratory research, based on secondary data, such as books on topics related to robotics, websites, public websites of concerned departments for data and statistics, journals, newspapers and magazines, websites of health care providers, and different printed materials (brochures, etc). The impact of robotics has both positive and negative impacts on the employment and motivation of employees in the retail sector. So far, there has been no substantial research done into robotics, especially in the health care sector. Replacing employees with robots is an inevitable choice for organizations in the service sector, more so in the health care sector because of the challenging and sometimes unhealthy working environments, but, at the same time, the researchers propose that it should be done in a manner that helps in improving the employment and motivation of employees in this sector.


Grounded Theory in Medical Education Research.
The grounded theory method provides a systematic way to generate theoretical constructs or concepts that illuminate psychosocial processes common to individual who have a similar experience of the phenomenon under investigation. There has been an increase in the number of published research reports that use the grounded theory method. However, there has been less medical education research, which is based on the grounded theory tradition. The purpose of this paper is to introduce basic tenants of qualitative research paradigm with specific reference to ground theory. The paper aims to encourage readers to think how they might possibly use the grounded theory method in medical education research and to apply such a method to their own areas of interest. The important features of a grounded theory as well as its implications for medical education research are explored. Data collection and analysis are also discussed. It seems to be reasonable to incorporate knowledge of this kind in medical education research.


Biochemical and molecular characterization of variant pyruvate kinase enzymes and genes from three patients with red blood cell pyruvate kinase deficiency.
Pyruvate kinase (PK) from red blood cells (RBC) of three patients with nonspherocytic hemolytic anemia due to PK deficiency was characterized according to internationally standardized methods. The variant enzymes, which were designated PK 'Memphis', PK 'Bartlett', and PK 'Pontotoc', had 11, 60, and 61%, respectively, of the normal enzyme activity. All variant PK enzymes had increased thermolability. Compared with control, Km (PEP) were 200-300% greater for PK 'Memphis', 50% less for PK 'Bartlett' and 300-400% greater for PK 'Pontotoc'. The Km (ADP) were 40 and 300% greater than normal for PK 'Bartlett' and PK 'Pontotoc', respectively. All variants required higher than normal concentrations of the allosteric modifier, fructose-1,6-diphosphate, to achieve 50% activation of maximal enzyme activity. To define the molecular basis of the gene defect, DNA samples from these patients were examined for restriction-fragment-linked polymorphisms. No differences were observed in the structure of the patients' PK genes compared with a normal control. These results are consistent with a mutation in coding sequences, rather than a large insertion, deletion or rearrangement of genetic information, as the underlying genetic defect that accounts for the altered enzyme properties in these PK-deficient patients.


Binding sequence of STAT4: STAT4 complex recognizes the IFN-gamma activation site (GAS)-like sequence (T/A)TTCC(C/G)GGAA(T/A).
Studies of transcriptional activation by interferons and various cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription (STAT). STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is required for IL-12 signal transduction. By immunoprecipitation and PCR amplification, a specific consensus sequence for DNA binding of the STAT4 complex was determined. The binding sequence of the STAT4 complex, (T/A)TTCC(C/G)GGAA(T/A), proved to be palindromic and similar to the IFN-gamma activated site (GAS)-like sequence. The first (T/A) and last (T/A) sites of the consensus sequence were critical for the binding affinity of the STAT4 complex.


Deficiency in T follicular regulatory cells promotes autoimmunity.
T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response. Until now, the physiological function of Tfr cells has been largely unknown. In this study, we developed a Bcl6fl/flFoxp3Cre mouse to analyze the function of Tfr cells in immune and autoimmune responses. These mice exhibited enhanced immunity to influenza virus; moreover, Bcl6fl/flFoxp3Cre/Cre mice developed late-onset spontaneous autoimmune diseases, affecting the salivary glands with lymphocyte infiltration and antibody deposition. In a mouse experimental Sjögren's syndrome model, ablation of Bcl6 in T reg cells greatly enhanced disease development. Conversely, Bcl6fl/flCd4Cre mice were protected in the model. Thus, our study indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.


Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase.
Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.


Neuromuscular electrical stimulation improves muscle atrophy induced by chronic hypoxia-hypercapnia through the MicroRNA-486/PTEN/FoxO1 pathway.
Previous work has confirmed that the chronic hypoxia-hypercapnia (CHH) associated with chronic obstructive pulmonary disease contributes to the development of skeletal muscle atrophy. Neuromuscular Electrical Stimulation (NMES) has shown some efficacy when used as a treatment to reduce skeletal muscle atrophy. The present study focuses on the MicroRNA-486/PTEN/FoxO1 pathway with the goal of identifying its physiological role in skeletal muscle atrophy induced by CHH as well as its role during NMES treatment. To test this, 32 male Sprague Dawley rats were randomly divided into four groups. After completion of the disease modeling, gastrocnemius muscles were collected from all animals and cross-sectional areas of muscular fiber were observed and analyzed via H&E staining. MiR-486 expression was further assessed by qRT-PCR, and protein levels of TNF-α, PTEN, p-Akt, Akt, FoxO1, atrogin-1 and MuRF1 were measured by immunohistochemistry and western blotting. CSA, miR-486, and the ratio p-Akt/Akt were significantly reduced in the CHH group, while the levels of TNF-α, PTEN, FoxO1, atrogin-1, and MuRF1 were markedly increased. Importantly, these findings were reversed as a result of NMES. Thus, the MicroRNA-486/PTEN/FoxO1 pathway functions in muscle protein synthesis and degradation. NEW & NOTEWORTHY: Our research provides a theoretical basis for the application of NMES as a means of improving muscle atrophy. Moreover, these therapeutic targets provide possible clues relevant to the treatment of amyotrophic diseases.


Erythema nodosum migrans in a male patient with hepatitis B infection.
Erythema nodosum migrans (ENM) is believed to represent a variant of chronic erythema nodosum; however, others consider it to be a separate clinical entity. It most commonly affects women in the third to sixth decade of life. Most cases are idiopathic, but some may be associated with streptococcal infection or thyroid disease. We present a case of ENM in a 33-year-old male patient with an erythematous, painful and infiltrated nodule on the lateral left lower leg. The lesion enlarged centrifugally, and a similar lesion appeared on the right lower leg. Both plaques exhibited a tendency to central clearing that made a peripheral ring evident. The patient was concurrently under treatment with antiviral drugs for hepatitis B infection and had an excellent response to treatment with potassium iodide. An association of ENM with the patient's viral hepatitis B could not be excluded.


Attenuation or absence of circadian and seasonal rhythms of acute myocardial infarction.
To examine the circadian, seasonal, and weekly rhythms of acute myocardial infarction, and to identify subgroups in whom the rhythms are attenuated or absent to provide further information about the mechanisms of the rhythms and the processes responsible for triggering plaque events. Prospective, observational study in a general hospital. 1225 consecutive patients admitted to a coronary care unit with acute myocardial infarction were studied. Admission rates were calculated according to the hour of the day (circadian rhythm), day of the week (weekly rhythm), and month of year (seasonal rhythm). The data were analysed for variations within the whole group and within subgroups. A weekly rhythm of acute myocardial infarction could not be demonstrated but there was a trend towards higher admission rates at the beginning of the week. However, the time of onset of symptoms showed significant circadian variation for the group as a whole, peaking in the morning (P = 0.006), against an otherwise fairly constant background rate. Subgroup analysis showed complete absence of the circadian rhythm in patients who were diabetic, South Asian, or taking beta blockers or aspirin on admission. Significant seasonal variation in admission rates was also demonstrated for the group as a whole with a winter peak and a summer trough (P = 0.009). Again, no seasonal rhythm could be demonstrated in patients who were diabetic, South Asian, or taking beta blockers or aspirin on admission. The absence of circadian and seasonal rhythms of acute myocardial infarction in almost identical subgroups suggests that common mechanisms are involved in driving these rhythms. The autonomic nervous system is a likely candidate because the rhythms were absent in patients taking beta blockers as well as in patients in whom derangement of autonomic function commonly occurs.


Comparison of three non-invasive ventilation strategies (NSIPPV/BiPAP/NCPAP) for RDS in VLBW infants.
Non-invasive ventilation (NIV) significantly changed the management of respiratory distress syndrome (RDS) in preterm infants. Further perspectives for neonatologists regard the assessment of different NIV strategies in terms of availability, effectiveness, and failure. The aim of the present study is to evaluate the effectiveness of three different NIV strategies: nasal continuous positive airway pressure (N-CPAP), nasal synchronized intermittent positive pressure ventilation (N-SIPPV), and nasal bilevel-CPAP (BiPAP), as first intention treatment for RDS in very low birth-weight infants (VLBW). A multicenter retrospective study was conducted in three neonatal intensive care unit (NICUs) that enrolled 191 VLBW infants complicated by RDS, who received, as first intention treatment for RDS, three different NIV approaches (N-CPAP: n = 66; N-SIPPV: n = 62, BiPAP: n = 63). We evaluated the performance of different NIV strategies by primary (failure within the first 5 d of life) and some selected secondary end-points. The incidence of NIV failure was significantly higher in the N-CPAP group (22/66) versus N-SIPPV/BiPAP groups (11/62; 11/63) (p < .05 for both), while no difference was observed between N-SIPPV and BiPAP groups. Moreover, no differences were found between the three groups regarding secondary outcomes. The present study shows that first intention N-SIPPV/BiPAP, as NIV support, augment the beneficial effects of N-CPAP contributing to a reduced risk of failure in VLBW infants complicated by RDS. Data open up to further RCTs on a wider population to evaluate NIV effectiveness on long-term outcomes.


The Role of Lithium in the Aging Precipitation Process of Al-Zn-Mg-Cu Alloys and Its Effect on the Properties.
It is well known that the development of lightweight alloys with improved comprehensive performance and application value are the future development directions for the ultra-high-strength 7xxx series Al-Zn-Mg-Cu alloys used in the aircraft field. As the lightest metal element in nature, lithium (Li) has outstanding advantages in reducing the density and increasing the elastic modulus in aluminum alloys, so Al-Zn-Mg-Cu alloys containing Li have gained widespread attention. Furthermore, since the Al-Zn-Mg-Cu alloy is usually strengthened by aging treatment, it is crucial to understand how Li addition affects its aging precipitation process. As such, in this article, the effects and mechanism of Li on the aging precipitation behavior and the impact of Li content on the aging precipitation phase of Al-Zn-Mg-Cu alloys are briefly reviewed, and the influence of Li on the service properties, including mechanical properties, wear resistance, and fatigue resistance, of Al-Zn-Mg-Cu alloys are explained. In addition, the corresponding development prospects and challenges of the Al-Zn-Mg-Cu-Li alloy are also proposed. This review is helpful to further understand the role of Li in Al-Zn-Mg-Cu alloys and provides a reference for the development of high-strength aluminum alloys containing Li with good comprehensive properties.


Nanoarrays: a method for performing enzymatic assays.
Conventional enzymatic assays for alcohol dehydrogenase, pyruvate kinase, and enolase performed in 96-well microtiter plates were compared with assays monitored in 25-well nanoarrays. All miniaturized reactions could be performed in maximum volumes of 6.3-8 nL and were read out with a conventional fluorescence microscope system equipped with a scientific grade CCD camera. Substrate and cofactor were already present inside the wells after having been presprayed, or they were applied in solution to the wells of the nanoarray shortly before the assays started. For all of the assays, commercially available enzymes and enzymes present in cell-free extracts were used. Assays carried out in premixed nanoarrays gave results comparable to those performed in presprayed nanoarrays. Enzyme activities determined in nanoarrays by using two different methods were in good agreement with assays performed in microtiter plates. Also, good correspondence was found between expected and observed enzyme levels. In short, enzymatic assays performed in premixed and in particular in presprayed nanoarrays are a promising low-volume and low-reagent- and sample-consuming alternative to current methodology and could find applications in many different areas of analytical chemistry.


A very large leiomyoma of the urethra: A case report.
Leiomyomas are benign mesenchymal tumours of smooth muscle origin. They are the most common uterine masses in women of reproductive age group and may be related to the hormonal status. Urethral leiomyomas are very rare. According to the literature, the mean diameter of the urethral leiomyomas is 3.7 cm. We report a case of a very large leiomyoma of the urethra. A 40-year-old women woman was admitted to our department for a giant vaginal mass. She complained of haematuria, dysuria, recurrent urinary tract infections and dyspareunia. The physical evaluation demonstrated a 6 × 5.5 cm neoformation involving the distal tract of the urethra. The patient underwent an ultrasonography and then a magnetic resonance that suggested the diagnosis of leiomyoma. The neoformation was excised through a suburethral incision. The patient was discharged after 3 days and no intraoperative and postoperative complications occurred. The Foley catheter was removed after a week. The patient was continent to urine, and at 6 months follow-up, the patient was symptom free and no recurrences occurred.


Design and validation of magnetic particle spectrometer for characterization of magnetic nanoparticle relaxation dynamics.
The design and validation of a magnetic particle spectrometer (MPS) system used to study the linear and nonlinear behavior of magnetic nanoparticle suspensions is presented. The MPS characterizes the suspension dynamic response, both due to relaxation and saturation effects, which depends on the magnetic particles and their environment. The system applies sinusoidal excitation magnetic fields varying in amplitude and frequency and can be configured for linear measurements (1 mT at up to 120 kHz) and nonlinear measurements (50 mT at up to 24 kHz). Time-resolved data acquisition at up to 4 MS/s combined with hardware and software-based signal processing allows for wide-band measurements up to 50 harmonics in nonlinear mode. By cross-calibrating the instrument with a known sample, the instantaneous sample magnetization can be quantitatively reconstructed. Validation of the two MPS modes are performed for iron oxide and cobalt ferrite suspensions, exhibiting Néel and Brownian relaxation, respectively.


A persistent problem with scabies in and outside a nursing home in Amsterdam: indications for resistance to lindane and ivermectin.
An ongoing outbreak of scabies in and outside a nursing home in Amsterdam is described. Despite standard treatment with lindane and ivermectin, many recurrences were observed which suggested resistance to these drugs. After treatment with 5% permethrine, the patients were finally cured.


Mutagenic nucleoside analog N4-aminocytidine: metabolism, incorporation into DNA, and mutagenesis in Escherichia coli.
N4-Aminocytidine, a nucleoside analog, is strongly mutagenic to various organisms including Escherichia coli. Using E. coli WP2 (trp), we measured the incorporation of [5-3H]N4-aminocytidine into DNA and at the same time measured the frequency of reversion of the wild type, thereby attempting to correlate the incorporation with mutation induction. First, we observed that N4-aminocytidine uptake by the E. coli cells was as efficient as cytidine uptake. High-pressure liquid chromatographic analysis of nucleoside mixtures obtained by enzymatic digestion of isolated cellular DNA showed that the DNA contained [3H]N4-aminodeoxycytidine, corresponding to 0.01 to 0.07% of the total nucleoside; the content was dependent on the dose of N4-aminocytidine. There was a linear relationship between the N4-aminocytosine content in DNA and the mutation frequency observed. These results constitute strong evidence for the view that the N4-aminocytidine-induced mutation in E. coli is caused by the incorporation of this agent into DNA as N4-aminodeoxycytidine. We also found that the major portion of radioactivity in DNA of cells that had been treated with [5-3H]N4-aminocytidine was in the deoxycytidine fraction. We propose a metabolic pathway for N4-aminocytidine in cells of E. coli. This pathway involves the formation of both N4-aminodeoxycytidine 5'-triphosphate and deoxycytidine 5'-triphosphate; the deoxycytidine 5'-triphosphate formation is initiated by conversion of N4-aminocytidine into uridine. In support of this proposed scheme, a cytidine deaminase preparation obtained from E. coli catalyzed the decomposition of N4-aminocytidine into uridine and hydrazine.


Hypoplasia and hypodontia in Van der Woude syndrome.
The purpose of this study was (1) to assess maxillary development in cleft individuals with Van der Woude syndrome (VWS) and (2) to compare hypodontia in VWS and nonsyndromic cleft matched controls. Retrospective case-control study from the Center for Craniofacial Anomalies, University of California, San Francisco, California. The sample consisted of 15 individuals with Van der Woude syndrome and 15 nonsyndromic cleft lip and/or palate controls paired for age, gender, and cleft type in the age range of 5 to 13 years. Cephalograms were digitized, and 31 linear and angular measurements were made. Serial panoramic radiographs were used to assess the presence or absence of permanent teeth. The maxillary sagittal position represented by midface length (Co-A) was significantly shorter in the Van der Woude syndrome subjects than in the matched controls (p = .031), suggesting a trend towards greater maxillary hypoplasia, particularly in Van der Woude syndrome with bilateral cleft lip and/ or palate. Measurements indicating sagittal jaw relationship (ANB angle and the Wits) were significantly smaller in the children with Van der Woude syndrome than in matched controls (p = .008 and p = .006). A significantly larger number of individuals with Van der Woude syndrome than matched controls had missing teeth (p = .014). The mandibular second premolar was missing more frequently in children with Van der Woude syndrome than in the matched controls (p = .031). The differences concerning both maxillary hypoplasia and hypodontia were most marked in the more severe cleft type, represented by bilateral cleft lip and/or palate. Based on these findings, the expectation is that there will be maxillary hypoplasia and hypodontia of greater severity in Van der Woude syndrome than in nonsyndromic clefts.


Safety of unsedated PEG placement using transoral ultrathin endoscopy in patients with amyotrophic lateral sclerosis.
In patients with amyotrophic lateral sclerosis (ALS), percutaneous endoscopic gastrostomy (PEG) placement under sedation often causes apnea or hypoventilation. The aim of the present study was to assess whether unsedated PEG placement in ALS patients using ultrathin endoscopy (UTE) via the transoral route can improve safety. Between 2003 and 2013, PEG placement was identified and reviewed in 45 patients with ALS. PEG was performed in 14 patients using transoral UTE without sedation (UTE group), 17 patients using conventional normal-diameter esophagogastroduodenoscopy (C-EGD) without sedation (unsedated C-EGD group) and 14 patients using C-EGD with sedation (sedated C-EGD group). We compared the clinical features, cardiopulmonary data before and during PEG placement, and complications related to PEG placement among the three groups. There were no significant differences in age, male/female ratio, forced vital capacity, blood pressure, oxygen saturation before and during PEG, or major complications among the three groups. No minor complications were observed in the UTE group, whereas apnea and/or hypoventilation were observed in the sedated C-EGD group and aspiration pneumonia was observed in the unsedated C-EGD group. Unsedated PEG placement using transoral UTE in ALS patients is a safe method.


Associations among Different Internet Access Time, Gender and Cyberbullying Behaviors in Taiwan's Adolescents.
With the increasing convenience of social networking sites and their interconnectedness with human interaction, verbal and image bullying have turned digital, making cyberbullying a new form of bullying attracting the attention of researchers, social workers, and schools. This study focuses on the status quo of attitude toward cyberbullying and cyberbullying behavior, explores associations of attitude toward behavior on cyberbullying behavior in gender and different internet access times. In a cross-sectional survey, adolescents were surveyed through self-report questionnaires, 13,864 respondents were received among 150 high schools in Taiwan. Statistical analyses were performed using structural equation modeling (SEM). The study revealed that attitude toward cyberbullying has a direct effect on cyberbullying behavior; among the greatest direct impact were when students use the Internet during the time frame 10:00-14:00. Parents and schoolteachers pay special attention to students using the Internet during this time frame 10:00-14:00 and give guidance, express care, and help those being bullied to communicate and use the Internet in a correct manner. Among genders, male student attitude toward behavior has a greater effect than those of female students. Both male and female students know what cyberbullying is and have witnessed, heard of, or personally encountered cyberbullying behavior. We recommend students talk to parents or teachers or other people who care to reduce the negative effects of cyberbullying. We hopeful that the conceptualization model presented in this study serves as an activator for researches on attitude toward cyberbullying and cyberbullying behavior, and serves a guide and a call to attract more researches in this area.


Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development.
De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.


Hepatitis C Treatment Regimens Are Cost-Effective: But Compared With What?
Numerous economic models have been published evaluating treatment of chronic hepatitis C virus (HCV) infection, but none provide a comprehensive comparison among new antiviral agents. Evaluate the cost-effectiveness of all recommended therapies for treatment of genotypes 1 and 4 chronic HCV. Using data from clinical trials, observational analyses, and drug pricing databases, Markov decision models were developed for HCV genotypes 1 and 4 to compare all recommended drugs from the perspective of the third-party payer over a 5-, 10-, and 50-year time horizon. A probabilistic sensitivity analysis (PSA) was conducted by assigning distributions for clinical cure, age entering the model, costs for each health state, and quality-adjusted life years (QALYs) for each health state in a Monte Carlo simulation of 10 000 repetitions of the model. In the lifetime model for genotype 1, effects ranged from 18.08 to 18.40 QALYs and total costs ranged from $88 107 to $184 636. The lifetime model of genotype 4 treatments had a range of effects from 18.23 to 18.43 QALYs and total costs ranging from $87 063 to $127 637. Grazoprevir/elbasvir was the optimal strategy followed by velpatasvir/sofosbuvir as the second-best strategy in most simulations for both genotypes 1 and 4, with drug costs and efficacy of grazoprevir/elbasvir as the primary model drivers. Grazoprevir/elbasvir was cost-effective compared with all strategies for genotypes 1 and 4. Effects for all strategies were similar with cost of drug in the initial year driving the results.


The 47,XYY male, Y chromosome, and tooth size.
Permanent teeth of 12 individuals with a 47,XYY chromosome constitution have been examined. The tooth sizes of 47,XYY males were found to be larger than those of control males and females. In many instances the differences were statistically significant. Using these results, it was possible to conclude that a factor or factors which influence excess growth of 47,XYY males probably are in effect during prenatal life, but without doubt must be in effect very early in postnatal life. The time period needed for the achievement of final excess growth is relatively short, in the case of first permanent molars probably only from 2 1/2 to 3 1/2 years. On the basis of the finding that the Y chromosome apparently carries genes affecting tooth sizes in normal males [1], it was suggested that gene products of the extra Y chromosome could cause the observed size difference between normal and 47,XYY males. The nature of the influence of one versus two Y chromosomes on growth was discussed in terms of the possible influence of the Y chromosome on the cell divisions within the developing tooth germ.


Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia.
Human breast cancer cells (MCF-7) overexpressing manganese-containing superoxide dismutase (MnSOD) by stable or transient transfection were challenged with the cytotoxicity of tumor necrosis factor alpha (TNF-alpha), hyperthermia, and a combination of both. In contrast to the vector control and wild-type MCF-7 cells, the stable MnSOD transfectants showed significant resistance to the cytotoxicity of TNF-alpha (100 units/ml), heat at 43 or 45 degrees C, and a combination of TNF-alpha and heat at 43 degrees C. To probe the correlation of MnSOD levels with cell survival, cell sensitivity to TNF-alpha, heat at 43 degrees C, or a combination of both was also measured after MnSOD cDNA transient transfection. The data showed that the level of cell resistance was proportional to the exogenous MnSOD gene expression. These results suggest that superoxide free radicals or their reaction products are responsible for much of the synergistic cytotoxicity of TNF-alpha and hyperthermia.


Hypertensive target organ damage predicts incident diabetes mellitus.
Whether patients with hypertensive preclinical cardiovascular disease (CVD) are at higher risk of incident diabetes has never been studied. We assessed incident diabetes in 4176 hypertensive non-diabetic patients (age 58.7 ± 8.9 years, 58% male) with ≥1 year follow-up (median: 3.57 years; inter-quartile range: 2.04-7.25). Left ventricular (LV) hypertrophy (LVH) was defined as LV mass index (LVMi) ≥51 g/m(2.7). Carotid atherosclerosis (CA) was defined as intima-media thickness >1.5 mm. During follow-up, diabetes developed in 393 patients (9.4%), more frequently in those with than without initial LVH or CA (odds ratio = 1.97 and 1.67, respectively; both P < 0.0001). In the Cox regression, the presence of either initial LVH or CA was associated with higher hazard of diabetes [hazards ratio (HR) = 1.30 and 1.38, respectively; both P = 0.03], independently of the type and number of anti-hypertensive medications, initial systolic blood pressure (P < 0.001), body mass index, fasting glucose, family history of diabetes (all P < 0.0001), and therapy with β-blockers. The presence of one of the, or both, markers of preclinical CVD increased the chance of incident diabetes by 63 or 64%, respectively (both P < 0.002), independently of significant confounders, a result that was confirmed (HR = 1.70 or 1.93, respectively; both P < 0.0001) using ATPIII metabolic syndrome (HR = 2.73; P < 0.0001) in the Cox model. Initial LVH and CA are significant predictors of new onset diabetes in a large population of treated hypertensive patients, independently of initial metabolic profile, anti-hypertensive therapy, and other significant covariates. This sequence may be attributable to risk factors common to preclinical CVD and diabetes, but a vascular origin of diabetes cannot be excluded.


Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species.
We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.


Computational Studies of a DNA-Based Aptasensor: toward Theory-Driven Transduction Improvement.
Aptamers are a class of bioreceptors intensively used in current analytical tools dedicated to molecular diagnostics due to their ability to perform large structural reorganization upon target binding. However, there is a lack of methodologies allowing us to rationalize their structure in order to improve the transduction efficiency in aptamer sensors. We choose here, as a model system, a three-strand DNA structure as the probe, composed of two DNA strands anchored on a gold surface and partially hybridized with an aptamer sequence sensitive to ampicillin (AMP). The DNA structure has been designed to show strong structural change upon AMP binding to its aptamer. Using a set of computational techniques including molecular dynamics simulations, we deeply investigated the structure change upon analyte binding, taking into account the grafting on the surface. Original analyses of ion distributions along the trajectories unveil a distinct pattern between both states which can be related to changes in capacitance of the interface between these states. To our knowledge, this work demonstrates the ability of computational investigations for the first time to drive, in silico, the design of aptasensors.


Automated glycemic pattern analysis: overcoming diabetes clinical inertia.
The OneTouch® Verio™ IQ Meter with PatternAlert™ Technology has been approved by the U.S. Food and Drug Administration as the first self-glucose monitor that can automatically determine glycemic patterns [high and low pre-meal blood glucose (BG)] for health care providers (HCPs) and patients. In this issue of Journal of Diabetes Science and Technology, Katz and coauthors demonstrate that this device was more accurate and quicker in detecting abnormal glucose patterns than the review by HCPs of 30-day handwritten BG logs and that its interpretations were positively accepted by the HCPs. Continued development of automated pattern analysis and decision-support software to overcome the "data-overload" associated with intensive glucose monitoring and diabetes management will reduce clinical inertia and could dramatically improve diabetes outcomes.


A decade of changes in clinical characteristics and management of elderly patients with non-ST elevation myocardial infarction admitted in Italian cardiac care units.
To describe the evolution of clinical characteristics, in-hospital management and early outcome of elderly patients with non-ST elevation myocardial infarction (NSTEMI). We analysed data from five consecutive Italian nationwide registries, conducted between 2001 and 2010, including patients with acute coronary syndromes admitted to cardiac care units (CCUs). Of 10 983 patients with NSTEMI enrolled in the 5 surveys, 4350 (39.6%) were ≥75 years old (mean age 81±5 years). Some clinical characteristics such as diabetes mellitus, hypertension, renal dysfunction and previous percutaneous coronary intervention increased significantly, whereas a history of stroke, myocardial infarction and heart failure decreased over time. An invasive approach increased from 26.6% in 2001 to 68.4% in 2010 (p<0.0001) and revascularisation rates increased from 9.9% to 51.7% (p<0.0001). Early use and prescription at discharge of β-blockers, statins and dual antiplatelet treatment increased significantly (p<0.0001). Thirty-day observed mortality decreased from 14.6% (95% CI 9.9 to 20.4) to 9.5% (95% CI 7.7 to 11.6). At the multivariate logistic regression analyses adjusted for baseline characteristics, compared with 2001, the risk of death was significantly lower in all the other studies performed at different times with reductions in adjusted mortality between 66% and 45%. Over the past decade, substantial changes have occurred in the clinical characteristics and management of elderly patients admitted with NSTEMI in Italian CCUs, with a greater use of revascularisation therapy and recommended medications. These variations have been associated with a reduction in 30-day adjusted mortality rate.


Effect of zinc supplementation on serum zinc and calcium levels in postmenopausal osteoporotic women in Tabriz, Islamic Republic of Iran.
Research on the zinc status of osteoporotic women is scarce. This randomized, double-blind, placebo-controlled clinical trial assessed the effect of zinc supplementation on serum zinc and calcium levels in postmenopausal osteoporotic women. A sample of 60 women referred to a rheumatology clinic in Tabriz were randomly divided into intervention (220 mg zinc sulfate daily) and placebo groups. Anthropometric indices, dietary intake of zinc and calcium and serum zinc and calcium were assessed at baseline and after 60 days. Mean serum zinc concentrations were markedly lower than the normal range at baseline, but mean serum calcium levels were normal. In the intervention group serum levels were significantly higher after 60 days [120.5 (SD 7.5) versus 70.5 (SD 4.6) micrograms/dL] while serum calcium levels were unchanged [8.6 (SD 0.1) versus 9.1 (SD 0.3) mg/dL]. The placebo group showed no significant changes in zinc or calcium levels. Postmenopausal osteoporotic women may benefit from zinc supplementation.


Sensitivity of NK1.1-negative NKT cells to transgenic BATF defines a role for activator protein-1 in the expansion and maturation of immature NKT cells in the thymus.
NKT cells are glycolipid-reactive lymphocytes that express markers and perform functions common to both T lymphocytes and NK cells. Although the genetic events controlling conventional T cell development are well defined, the transcription factors and genetic programs regulating NKT cell development are only beginning to be elucidated. Previously, we described the NKT cell-deficient phenotype of transgenic (Tg) mice constitutively expressing B cell-activating transcription factor (BATF), a basic leucine zipper protein and inhibitor of AP-1. In this study, we show that Tg BATF targets the majority of Valpha14Jalpha281 (Valpha14i(7)) NKT cells, regardless of CD4 expression and Vbeta gene usage. The residual NKT cells in the thymus of BATF-Tg mice are CD44(+), yet are slow to display the NK1.1 marker characteristic of mature cells. As a population, BATF-expressing NKT cells are TCRbeta/CD3epsilon(low), but express normal levels of CD69, suggesting a failure to expand appropriately following selection. Consistent with the sensitivity of NKT cells to BATF-induced changes in AP-1 activity, we detect a full complement of AP-1 basic leucine zipper proteins in wild-type NKT cells isolated from the thymus, spleen, and liver, and show that AP-1 DNA-binding activity and cytokine gene transcription are induced in NKT cells within a few hours of glycolipid Ag exposure. This study is the first to characterize AP-1 activity in NKT cells and implicates the integrity of this transcription factor complex in developmental events essential to the establishment of this unique T cell subset in the thymus.


Life-threatening hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a patient with the miller fisher syndrome.
We report a life-threatening hyponatremia due to SIADH which developed suddenly in a patient with the Miller Fisher syndrome (a variant of Guillian Barré syndrome characterized by complete ophthalmoplegia, ataxia, and areflexia). A 55 year-old female was admitted with a clinical picture of the Miller Fisher syndrome. Cerebrospinal fluid was acellular with elevated proteins, and electromyographic changes were characteristic of polyneuropathy. On the third day of admission the patient was found to be mentally confused with a serum sodium of 108 mmol/L. Serum osmolality was 236 mosm/L and urine osmolality was 636 mosm/L. Urine sodium was 103 mmol/L. The serum sodium normalized after treatment with a single dose of intravenous furosemide, hypertonic saline infusion and fluid restriction. To our knowledge, this is the first description of SIADH developing in a patient with the Miller Fisher syndrome.


An Enzyme-based 1:2 Demultiplexer Interfaced with an Electrochemical Actuator.
An enzyme-based 1:2 demultiplexer is designed in a flow system composed of three cells where each one is modified with a different enzyme: hexokinase, glucose dehydrogenase and glucose-6-phosphate dehydrogenase. The Input signal activating the biocatalytic cascade is represented by glucose, while the Address signal represented by ATP is responsible for directing the Input signal to one of the output channels, depending on the logic value of the Address. The biomolecular 1:2 demultiplexer is extended to include two electrochemical actuators releasing entrapped DNA molecules in the active output channel. The modular design of the system allows for easy exchange and extension of the functional elements. The present demultiplexer can be easily integrated in various biomolecular logic systems, including different logic gates based on the enzyme- or DNA-based reactions, as well as containing different chemical actuators, for example, with a biomolecular release function.


Management of Helicobacter pylori infection.
Helicobacter pylori is the cause of most peptic ulcer disease and a primary risk factor for gastric cancer. Eradication of the organism results in ulcer healing and reduces the risk of ulcer recurrence and complications. Testing and treatment have no clear value in patients with documented nonulcer dyspepsia; however, a test-and-treat strategy is recommended but for patients with undifferentiated dyspepsia who have not undergone endoscopy. In the office setting, initial serology testing is practical and affordable, with endoscopy reserved for use in patients with alarm symptoms for ulcer complications or cancer, or those who do not respond to treatment. Treatment involves 10- to 14-day multidrug regimens including antibiotics and acid suppressants, combined with education about avoidance of other ulcer-causing factors and the need for close follow-up. Follow-up testing (i.e., urea breath or stool antigen test) is recommended for patients who do not respond to therapy or those with a history of ulcer complications or cancer.