Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase.
Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications. Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress. By means of serial section electron microscopy, the structural remodeling of medial prefrontal cortex glutamate synapses was assessed soon after acute stressor cessation and stress hormone levels were measured. Foot-shock stress induced a remarkable increase in the number of docked vesicles and small excitatory synapses, partially and strongly prevented by desipramine pretreatment, respectively. Acute stress-induced corticosterone elevation was not affected by drug treatment. Since desipramine pretreatment prevented the stress-induced structural plasticity but not the hormone level increase, we hypothesize that the preventing action of desipramine is located on pathways downstream of this process and/or other pathways. Moreover, because enhancement of glutamate system remodeling may contribute to overexcitation dysfunctions, this aspect could represent a crucial component in the pathophysiology of stress-related disorders.


"Magical thinking," suicide, and malpractice litigation.
Prospective clinical assessment of suicidality differs significantly from that used retrospectively in malpractice litigation. In the latter context, the judge or jury may be susceptible to hindsight reasoning and a disproportionate emphasis on the specific method of suicide, exaggerating its foreseeability and "magically" linking the means of death to the treating clinician, especially in the case of suicide by an overdose of prescribed medication. Such magical thinking, moreover, is rooted in the clinical context of suicide: The errors of reasoning observed in the courtroom exhibit striking parallels with the mind-set of the suicidal patient. An understanding of these dynamics suggests appropriate precautions for the clinician and thus contributes to the prevention both of suicide and of malpractice litigation.


Rho GTPases and the downstream effectors actin-related protein 2/3 (Arp2/3) complex and myosin II induce membrane fusion at self-contacts.
Actin regulation is required for membrane activities that drive cell adhesion and migration. The Rho GTPase family plays critical roles in actin and membrane dynamics; however, the roles of the Rho GTPase family are not limited to cell adhesion and migration. Using micron-sized obstacles to induce the formation of self-contacts in epithelial cells, we previously showed that self-adhesion is distinct from cell-to-cell adhesion in that self-contacts are eliminated by membrane fusion. In the current study, we identified Rho GTPases, RhoA, Rac1, and Cdc42, as potential upstream regulators of membrane fusion. The RhoA downstream effector myosin II is required for fusion as the expression of mutant myosin light chain reduced membrane fusion. Furthermore, an inhibitor of the Arp2/3 complex, a downstream effector of Rac1 and Cdc42, also reduced self-contact-induced membrane fusion. At self-contacts, while the concentration of E-cadherin diminished, the intensity of GFP-tagged Arp3 rapidly fluctuated then decreased and stabilized after membrane fusion. Taken together, these data suggest that the Arp2/3 complex-mediated actin polymerization brings two opposing membranes into close apposition by possibly excluding E-cadherin from contact sites, thus promoting membrane fusion at self-contacts.


The effect of tantalum incorporation on the physical and chemical properties of ternary silicon-calcium-phosphorous mesoporous bioactive glasses.
Synthesis and characterization of the first mesoporous bioactive glasses (MBGs) containing tantalum are reported here, along with their potential application as hemostats. Silica MBGs were synthesized using with the molar composition of (80-x)% Si, 15% Ca, 5% P, and x% Ta. It was found that incorporation of >1 mol % Ta into the MBGs changes their physical and chemical properties. Increasing Ta content from 0 to 10 mol % causes a decrease in the surface area and pore volume of ~20 and ~35%, respectively. This is due to the increase in nonbridging oxygens and mismatch of thermal expansion coefficient which created discontinuities in the ordered channel structure. However, the effect is not significant on the amount of ions (Si, Ca, P, and Ta) released, from the sample into deionized water, for short durations (<60 min). In a mouse tail-cut model, a significant decrease in bleeding time (≥50% of average bleeding time) was found for Ta-MBGs compared to having no treatment, Arista, and MBG without Ta. Further studies are proposed to determine the mechanism of Ta involvement with the hemostatic process. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2229-2237, 2019.


Job control and job strain: a test of three models.
The relationship between job control and job strain is examined. Three models of that relationship provide a framework for the study hypotheses: (H1) Control is inversely related to job strain, (H2) job demands interact with job control such that job strain will be highest when job demands are high and job control is low, and (H3) strain increases as the discrepancy between actual and desired levels of job control increases. Study participants (N = 316) were health care workers in 2 hospitals in the northeastern United States. Objective measures of job control and job demands were obtained through supervisor evaluations of incumbents' job characteristics, and perceptual measures were obtained through incumbents' self-reports. Results provide support for Hypotheses 1 and 3; little support was found for an interaction between job control and job demands.


The stem cell system.
The stem cell is defined as that cell in a tissue which, under normal circumstances, maintains its own population, undiminished in function and size, and furnishes daughters to provide new functional cells of that tissue. The daughters may, or may not, have to undergo further differentiation and/or maturation in order to achieve their functional stage. The fundamental characteristic of a stem cell, therefore, is self-renewal. Evidence is presented which implicates the microenvironment as a major component of the stem cell system, without which stem cells cannot be maintained. Furthermore, it is suggested that stem cell properties do not reside in one specific cell type in the population but, when necessary, cells other than those normally playing the stem cell role, can have stem cell function imposed upon them by the appropriate microenvironment. The stem cell "niche" hypothesis is presented to explain the dependence of stem cells upon their microenvironment. The postulate is offered that there are no cells which are intrinsically stem cells but that a range of cells in a tissue possess stem cell potential to a greater or lesser extent.


Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia.
Activin A is a member of the transforming growth factor-beta superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1beta, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-mug dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases.


Elective Venovenous Extracorporeal Membrane Oxygenation for Resection of Endotracheal Tumor: A Case Report.
We present a case in which we electively used venovenous extracorporeal membrane oxygenation (VV-ECMO) to facilitate safe resection of a nearly obstructing airway tumor near the carina in a 37-year-old male. The patient was brought to the operating room and underwent bifemoral cannulation for VV-ECMO under light sedation while maintaining spontaneous ventilation. After VV-ECMO was initiated, general anesthesia was induced, and the tumor was resected via rigid bronchoscopy. After resection, the patient was intubated, weaned from ECMO, decannulated, awoken, extubated, and taken to the postanesthesia care unit for recovery.


Mithramycin- and 4'-6-diamidino-2-phenylindole (DAPI)-DNA staining for fluorescence microspectrophotometric measurement of DNA in nuclei, plastids, and virus particles.
The properties of two DNA-specific fluorochromes, 4'-6-diamidino-2-phenylindole (DAPI) and mithramycin, have been analyzed as reagents to quantitate cellular DNA by fluorescence microspectrophotometry. Optimal staining conditions and concentrations, and the effects of other cellular materials to which the dyes bind, have been evaluated in measurements of the DNA of rat, chick, and yeast nuclei, Gonyostomum chloroplasts, and T4 particles. Use of either fluorochrome permits a high degree of resolution of different DNA quantities in nuclei and in cell organelles, and the DAPI-DNA complex is sufficiently fluorescent to permit quantitation of the DNA content in genomes as small as those of individual T4 bacteriophage particles. Fluorescence of mithramycin- or DAPI-stained DNA is proportional to DNA quantity when DNA of the same has composition is compared. Quantitation does not appear to be affected discernably by the state of the DNA, whether in different stages of the cell cycle, in condensed chromosomes, or in noncycling, differentiated nuclei. The use of chicken red blood cells is recommended as an internal monitor for variations in staining conditions.


Application of an ESI-QTOF method for the detailed characterization of GSK-3β inhibitors.
The crucial role of Glycogen Synthase Kinase 3 (GSK-3β) as a pivotal player in Alzheimer's Disease (AD) has recently inspired significant attempts to design and synthesize potent kinase inhibitors. In fact GSK-3β is considered the main kinase which catalyzes the microtubule-associated protein tau hyper-phosphorylation and the neurofibrillary tangles (NFT) in vitro and in vivo, The first classes of GSK-3β inhibitors were classified as ATP-competitive and, therefore, they lack of an efficient degree of selectivity over other kinases. In light of this consideration, many efforts are devoted to characterize new non ATP-competitive GSK-3β inhibitors, endowed with high selectivity. In parallel, there is an urgent need to develop new analytical methodologies for the hit selection (highthroughput screening) and ligand binding characterization in terms of potency, affinity and mechanism of action. The new methodology for GSK-3β enzymatic activity determination can be adopted as a realistic alternative to the currently used radioactive, luminescence and fluorescence detection methods, each showing limitations in terms of safety and interferences. Herein, we propose an alternative and selective electrospray ionization quadrupole time-of-flight (ESI-QTOF) method, based on the direct quantification of phosphorylated substrate muscle glycogen synthase GSM, a peptide resembling the high affinity sequence of natural substrate muscle glycogen synthase 1, for the detailed characterization of GSK-3β inhibitors. The method was validated in terms of accuracy and reproducibility of GSM signal intensity with a relative standard deviation RSD% value of 3.55%; Limit of Detection (LOD): 0.006μM; Lower Limit of Quantification (LLOQ): 0.02μM; linearity r2 0.9951. The kinetic constants (KM and vmax) of the GSK-3β catalyzed kinase reaction and the inhibitory potency of known ligands (IC50), were determined. All the obtained results were in agreement with those reported in literature or obtained in house by the standard reference luminometric approach. The proposed method was applied to the elucidation of well known inhibitors mechanism of action by the construction of a Lineweaver-Burk plot and the Ki determination. Furthermore, the potency, affinity and mechanism of action of a new non ATP-competitive compound were established. We demonstrated the ESI-QTOF method to be more feasible than the classic kinase assays since it avoids drawbacks inherently connected with radioisotope labeling or the indirect detection of kinase activity, so far. It is also scalable to the screening of large library collections and suitable for pharmaceutical industries purposes.


A Prospective Study Measuring Resident/Faculty Contour Concordance: A Potential Tool for Quantitative Assessment of Residents' Performance in Contouring and Target Delineation in Radiation Oncology Residency.
Accurate target delineation/contouring is essential for radiation treatment planning and radiotherapy efficacy. As a result, improving the quality of target delineation is an important goal in the education of radiation oncology residents. The purpose of this study was to track the concordance of radiation oncology residents' contours with faculty physicians' contours over the course of one year to assess for patterns. Residents in PGY levels of 2-4 were asked to contour target volumes which were compared to the finalized, faculty physician-approved contours. Concordance between resident and faculty physician contours was determined by calculating the Jaccard Concordance Index (JCI), ranging from 0 or no agreement to 1 or complete agreement. Multivariate mixed effect models were used to assess the association of JCI to the fixed effect of PGY level and its interactions with cancer type and other baseline characteristics. Post hoc means of JCI were compared between PGY levels after accounting for multiple comparisons using a Tukey's method. In total, 958 structures from 314 patients collected during the 2020-2021 academic year were studied. The mean JCI was 0.77, 0.75, and 0.61 for the levels of PGY-4, PGY-3, and PGY-2, respectively. JCI score in PGY-2 was found lower than those of PGY-3 and PGY-4 respectively (P's<0.001). No statistically significant difference of JCI score was found when comparing between PGY-3 and PGY-4 levels. The average JCI score was lowest (0.51) for primary head/neck cancers and highest (0.80) for gynecologic cancers. Tracking and comparing the concordance of resident contours and faculty physician contours is an intriguing method of assessing resident performance in contouring and target delineation and could potentially serve as a quantitative metric in radiation oncology resident evaluation, which is lacking currently. However, additional study is necessary before this technique can be incorporated into residency assessments.


Insecticidal activity of Bacillus thuringiensis strains isolated from soil and water.
We attempted to search novel Bacillus thuringiensis strains that produce crystals with potential utility in plant protection and with higher activity than strains already used in biopesticide production. Seven B. thuringiensis soil and water isolates were used in the research. We predicted the toxicity of their crystals by cry gene identification employing PCR method. The isolate MPU B63 with interesting, according to us, genes content was used in evaluating its crystal toxicity against Cydia pomonella caterpillars. The strain MPU B63 was cultured from water sample and had cry1Ab, cry1B, and cry15 genes. The LC₅₀ crystals of MPU B63 were compared to LC₅₀ of commercial bioinsecticide Foray determined against C. pomonella (codling moth). The activity of MPU B63 inclusions against codling moth larvae was approximately 24-fold higher than that of Foray. The results are a promising introduction for further study evaluating the potential usefulness of isolate MPU B63 crystals in plant protection.


Aspirin resistance determined from a bed-side test in patients suspected to have acute coronary syndrome portends a worse 6 months outcome.
Coronary patients resistant to aspirin may have increased risk for ischemic events. Little data were available for patients presenting acutely with chest pain. We used the VerifyNow Aspirin to determine aspirin responsiveness of 314 patients regularly taking aspirin 75-300 mg daily for >or=4 weeks who presented with suspected acute coronary syndrome in Emergency Department. Aspirin resistance was defined as an aspirin reaction unit (ARU) >or=550, and the clinical team was blinded to the ARU reading. The pre-specified study endpoints were the diagnosis of acute myocardial infarction (AMI) for the index admission and major adverse cardiac events including cardiovascular death or recurrent acute coronary syndrome requiring hospitalization within 6 months. Aspirin resistance was noted in 30 (9.6%) patients. There was no difference in the diagnosis of AMI for the index presentation (3/30, 10% vs. 25/284, 8.8%, P = 0.91). Among the 312 hospital survivors, aspirin resistant patients had increased adverse events over 6 months with an overall hazard ratio of 10.0 [95% confidence interval (CI) 4.6-22.0]. After adjusted for elevated Troponin-T, the only confounder in the model, the hazard ratio was 11.1 (95% CI 4.7-26.0). Results were similar in patients treated only medically without revascularization (adjusted hazard ratio 12.1, 95% CI 4.7-26.4). The increased events were observed both from discharge to 30 days and from 30 days to 6 months. Aspirin resistance occurs in approximately 10% of patients presenting with suspected acute coronary syndrome and is associated with adverse cardiac events.


Characterization of proteoglycans synthesized by cultured arterial smooth muscle cells of the rat.
Arterial smooth muscle cells cultured from rat aorta were labelled with sodium [35S]-sulfate in combination with either [3H]glucosamine or [3H]mannose. The newly synthesized hyaluronate and sulfated proteoglycans obtained from the growth medium (M-PG) and extracted from the cell layer (C-PG) with 4M guanidinium chloride in the presence of proteinase inhibitors were purified by sequential fractionation on Sepharose 4B CL, equilibrium density gradient centrifugation and ion exchange chromatography under dissociative conditions. Gel filtration of M-PG resulted in the separation of free hyaluronate and two size classes of [35S]-proteoglycan populations eluted at Kav 0.15 (fraction M-A) and 0.48 (fraction M-B). On further fractionation M-A dissociated into hyaluronate (Mr 1.6 X 10(6)) and a proteoglycan monomer (M-PG A, Mr 180 000), which contained chondroitin 4-sulfate (Mr 21 000) as the main glycosaminoglycan moiety. The proteoglycan isolated from M-B (M-PG B) was identified as a proteoglycan monomer (Mr 200 000) containing mainly chondroitin sulfate/dermatan sulfate hybrid side chains (Mr 34 000). [3H]Mannose labelling and binding to ConA Sepharose of both M-PG A and B indicated the presence of oligosaccharides of the glycoprotein type. An analogous fractionation of proteoglycans associated with the cell layer yielded two hyaluronate-proteoglycan complexes (C- PreA and C-A). The proteoglycan monomers of these complexes (C-PG PreA and C-PG A) had Mr values of 420 000 and 130 000. A non-complexed proteoglycan monomer C-PG B (Mr 90 000) was also found. All cell layer bound proteoglycans had glycosaminoglycan side chains with Mr approximately 36 000 but the predominant glycosaminoglycan component was either heparan sulfate, chondroitin sulfate or dermatan sulfate. All cell layer bound proteoglycans contained [3H]mannose radioactivity, about 15% of which was bound to ConA Sepharose.


Pheomelanin-based plumage coloration predicts survival rates in birds.
Higher vertebrates synthesize two forms of melanin: eumelanin and pheomelanin. While the adaptive functions of eumelanin are diverse, those of pheomelanin, which is phototoxic and whose production consumes a key intracellular antioxidant (glutathione), are not clear apart from being involved in color patterns that confer concealment. The factors that have favored the evolution of pheomelanin thus remain a mystery, causing this pigment even to have been considered an "accident of nature." A recent hypothesis posits that pheomelanin has evolved because it represents an alternative mechanism to remove excess dietary cysteine, which can be toxic because of its oxidation. We tested for links between pheomelanin-based color and survival in both an intraspecific study of barn swallows Hirundo rustica and an interspecific study of 58 species of birds from North and Central America. As predicted on the basis that birds degrade excess dietary amino acids by transferring their amino group to uric acid synthesis, we found that under equal levels of uric acid in plasma, individuals or species with a higher intensity or greater proportion of plumage colored by pheomelanin (brown and chestnut coloration) had higher relative annual survival rates while controlling for the potentially confounding effects of age, sex, body size, and phylogenetic descent. Likewise, barn swallows with more intense pheomelanin-based coloration had higher prospects to survive the winter after controlling statistically for age, sex, body size, and level of uric acid. This supports the idea that pheomelanic traits evolve because of the removal of excess cysteine in nonstressful conditions, thus avoiding its toxic effects.


Task-related suppression of the brainstem frequency following response.
Recent evidence has shown top-down modulation of the brainstem frequency following response (FFR), generally in the form of signal enhancement from concurrent stimuli or from switching between attention-demanding task stimuli. However, it is also possible that the opposite may be true--the addition of a task, instead of a resting, passive state may suppress the FFR. Here we examined the influence of a subsequent task, and the relevance of the task modality, on signal clarity within the FFR. Participants performed visual and auditory discrimination tasks in the presence of an irrelevant background sound, as well as a baseline consisting of the same background stimuli in the absence of a task. FFR pitch strength and amplitude of the primary frequency response were assessed within non-task stimulus periods in order to examine influences due solely to general cognitive state, independent of stimulus-driven effects. Results show decreased signal clarity with the addition of a task, especially within the auditory modality. We additionally found consistent relationships between the extent of this suppressive effect and perceptual measures such as response time and proclivity towards one sensory modality. Together these results suggest that the current focus of attention can have a global, top-down effect on the quality of encoding early in the auditory pathway.


Antiviral Lipopeptide-Cell Membrane Interaction Is Influenced by PEG Linker Length.
A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals.


[Health registries: methodological issues].
Health registries and observational studies are different entities, and although several registries are conceived as observational cohort studies, or provide the data that are needed for cohort or case-control studies, this is not always true: many registries have specific aims that imply methodological standards that differ completely from those of an observational study. Of course, whenever a Registry is conceived with the aim of conducting an observational study, this will dictate its methods. The difference between a registry and the simple assembling and analysis of routine clinical data must be stressed as well: a registry may require that collection of data from different administrative sources, or of original data not available elsewhere, and must guarantee the quality and completeness of the information it contains. It has been repeatedly suggested that the huge databases of health information that are currently assembled by most health governing bodies should be exploited directly for evaluations of appropriateness and effectiveness. This is extremely dangerous, because the inherent potential biases already affecting all observational studies may completely undermine their validity if the currently accepted methodological standards are relaxed. Similarly, the use of observational studies for the assessment of the effectiveness of health technologies must be considered with caution.


[Heart functions in monkeys during a 2-week antiorthostatic hypokinesia].
Dynamics of the left heart ventricular muscle contractility and compliance was studied in 4 monkeys in the head down position (antiorthostatic hypokinesia) with the body angle 10 during 2 weeks. Functional tests on a tilt table and under two conditions of centrifuge rotation were performed prior to and after the antiorthostatic hypokinesia. No changes in the left heart ventricular muscle contractility was found. However, the sensitivity level of the baroreflex control decreased. Compliance of the left heart myocardial fibre increased in the first hours and days of the antiorthostatic hypokinesia.


Healing of excimer laser ablated monkey corneas. An immunohistochemical evaluation.
The healing response of the cornea following excimer laser anterior keratomileusis (a 4-mm-diameter ablation to a depth of 11, 23, or 46 microns) was analyzed immunohistochemically in adult rhesus monkeys. The ablated surface had reepithelialized and the synthesis of type VII collagen (a major component of anchoring fibrils) was evident by 7 days; the reestablishment of a nearly continuous anchoring fibril zone was evident after 12 weeks. Stromal fibroblasts, activated in response to wounding, expressed a fetal antigen for approximately 6 weeks. Although fibronectin and type VII collagen were present only transiently in the regenerating subepithelial stromal matrix in the subepithelial regions, some other alterations, including the presence of type III collagen, increased levels of keratan sulfates, and discontinuities in the anchoring fibril zone were evident even 18 months after wounding. The depths of the regenerated stroma, which were estimated from the depths of remnant staining for type VII collagen in the stromal matrix, generally, but not always, corresponded to the depths of the calculated ablation.


Optimal strategies and complexity: a theoretical analysis of the anti-predatory behavior of the hare.
Predator-prey relationships involving rabbits and hares are widely studied at a long-term population level, while the short-term ethological interactions between one predator and one prey are less well documented. We use a physiologically-based model of hare behavior, developed in the framework of artificial intelligence studies, to analyse its sophisticated anti-predatory behavior. The hares use to stand to the fox in order to inform it that its potential prey is alerted. The behavior of the hare is characterized by specific standing and flushing distances. We show that both hare survival probability and body condition depend on habitat cover, as well as on the ability of the predator to approach-undetected-a prey. We study two anti-predatory strategies, one based on the maximization of the survival probability and the other on the maximization of the body conditions of the hare. Despite the fact that the two strategies are not independent, they are characterized by quite different behavioral patterns. Field estimates of flushing and standing distances are consistent with survival maximization. There exists an optimal anti-predatory strategy, characterized by a flushing distance of 20 m and a standing distance of 30 m, which is optimal in a large set of environmental conditions with a sharp fitness advantage with respect to suboptimal strategies. These results improve our understanding of the anti-predatory behavior of the hare and lend credibility to the optimality approach in the behavioral analysis, showing that even for complex organisms, characterized by a large network of internal constraints and feedback, it is possible to identify simple optimal strategies with a large potential for selection.


Spontaneous left atrial thrombus during patent foramen ovale closure.
A 52-year-old male smoker suffered a left-sided stroke. Bubble contrast echocardiography demonstrated an aneurysmal atrial septum and patent foramen ovale (PFO). The patient was referred for percutaneous closure of his PFO to reduce his risk of further stroke. Despite dual antiplatelet therapy and pre-procedural heparin, he developed a spontaneous thrombus during balloon sizing of the defect identified by transoesophageal echocardiography. The balloon was immediately withdrawn to the right side and removed. Periprocedural echocardiography using either transoesophageal or intracardiac echo is essential to monitor for this potential procedural complication of percutaneous PFO closure.


Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake.
The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.


Antibiotic Resistance, Virulence, and Genetic Background of Community-Acquired Uropathogenic Escherichia coli from Algeria.
The aim of the study was to investigate antibiotic resistance mechanisms, virulence traits, and genetic background of 150 nonrepetitive community-acquired uropathogenic Escherichia coli (CA-UPEC) from Algeria. A rate of 46.7% of isolates was multidrug resistant. bla genes detected were blaTEM (96.8% of amoxicillin-resistant isolates), blaCTX-M-15 (4%), overexpressed blaAmpC (4%), blaSHV-2a, blaTEM-4, blaTEM-31, and blaTEM-35 (0.7%). All tetracycline-resistant isolates (51.3%) had tetA and/or tetB genes. Sulfonamides and trimethoprim resistance genes were sul2 (60.8%), sul1 (45.9%), sul3 (6.7%), dfrA14 (25.4%), dfrA1 (18.2%), dfrA12 (16.3%), and dfrA25 (5.4%). High-level fluoroquinolone resistance (22.7%) was mediated by mutations in gyrA (S83L-D87N) and parC (S80I-E84G/V or S80I) genes. qnrB5, qnrS1, and aac(6')-Ib-cr were rare (5.3%). Class 1 and/or class 2 integrons were detected (40.7%). Isolates belonged to phylogroups B2+D (50%), A+B1 (36%), and F+C+Clade I (13%). Most of D (72.2%) and 38.6% of B2 isolates were multidrug resistant; they belong to 14 different sequence types, including international successful ST131, ST73, and ST69, reported for the first time in the community in Algeria and new ST4494 and ST4529 described in this study. Besides multidrug resistance, B2 and D isolates possessed virulence factors of colonization, invasion, and long-term persistence. The study highlighted multidrug-resistant CA-UPEC with high virulence traits and an epidemic genetic background.


Usefulness of Nonenhanced Computed Tomography for Diagnosing Urolithiasis without Pyuria in the Emergency Department.
We compared the clinical utility of nonenhanced computed tomography (NECT) and intravenous urography (IVU) in patients with classic symptoms of renal colic without evidence of a urine infection. This was a retrospective analysis of IVU and NECT performed in adult patients with suspected renal colic at an emergency department between January 2005 and December 2013. The records of all patients in NECT and IVU groups were reviewed, and the patients were categorized according to the cause of their symptoms. A total of 2218 patients were enrolled. Of these patients, 1525 (68.8%) underwent IVU and 693 (31.2%) underwent NECT. The patients in NECT group were older (45.48 ± 14.96 versus 42.37 ± 13.68 years, p < 0.001), had less gross hematuria (7.6 versus 2.9%, p < 0.001), and were admitted more often (18.6 versus 12.0%, p < 0.001) than the patients in IVU group. Urinary stones were detected in 1413 (63.7%) patients. NECT had a higher detection rate of urolithiasis than IVP (74.0 versus 59.0%, p < 0.001). No significant difference was observed in the incidence of urinary stones greater than 4mm between groups from the radiologic findings (p = 0.79) or the full medical record review (p = 0.87).


The Effects of a Multi-Ingredient Performance Supplement Combined with Resistance Training on Exercise Volume, Muscular Strength, and Body Composition.
The effects of a multi-ingredient performance supplement (MIPS) incorporating a mixture of branched chain amino acids, beta-alanine, glutamine, creatine, and piperine on resistance training (RT)-induced adaptations remains unclear. Therefore, the purpose of this study was to investigate the effects of this investigational MIPS during six weeks of RT on performance and body composition. Thirty recreationally trained males and females were recruited for this pair-matched, double-blind, placebo-controlled investigation. Subjects were assigned to consume either an experimental MIPS (MIPS) (n = 15) or a placebo (PLA) (n = 15) concurrently with a six-week periodized RT program. Body composition, one-repetition maximum (1RM), and muscular power were assessed at pre- and post-training. Weekly relative volume load was compared between groups. The MIPS and PLA groups demonstrated a significant increase in total body mass (MIPS = +2.9 ± 1.3%; PLA = +2.5 ± 1.7%) and lean mass (MIPS = +5.0 ± 2.1%; PLA = +3.1 ± 1.9%) (p < 0.001) with no changes in fat mass. There were no group × time interactions for any of the body composition measures. Both groups demonstrated similar improvements in maximum strength for the back squat, bench press, and deadlift as well as lower body power from pre- to post-training (p < 0.001). Within the limitations of the current investigation, results failed to demonstrate the benefits of the experimental MIPS for muscular strength and body composition across six weeks of RT compared to PLA.


LHX3 is an early stage and radiosensitivity prognostic biomarker in lung adenocarcinoma.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. We previously identified LHX3 as a new preferentially expressed gene in NSCLC. In the present study, we sought to determine its expression, the clinical relevance and the functional roles in NSCLC. LHX3 expression is sharply increased in carcinoma tissues compared to non-carcinoma tissues. Relational analysis reveals a significant association between LHX3 expression and clinical stage (n=172, p=0.032) or radiotherapy (n=167, p=0.022) of patients. LHX3 expression is much higher in the patients at advanced stages (stage III-IV) than in the patients at early stages (stage I-II, p=0.0304), and LHX3 expression is remarkably increased in the patients with radiotherapy treatment (p=0.0002). Survival analyses indicate that LHX3 is associated with unfavorable survival (n=180, p=0.002) and represents an independent prognostic factor [hazard ratio (HR)=1.834, p=0.004] of the NSCLC patients. Furthermore, LHX3 is associated with unfavorable overall survival (n=866, p=0.004) and represents an independent prognostic factor (HR=2.36, p=0.000) in lung adenocarcinoma (ADC) patients, but is not associated with overall survival of squamous cell carcinoma (SCC) patients (n=524, p=0.27). Further analyses found that LHX3 is an early-stage (n=94, p=0.003) and radiosensitivity (n=45, p=0.002) prognostic factor in ADC patients. The patients without radiotherapy have a significantly prolonged survival compared to those with radiotherapy (p=0.0069). Further functional studies show that forced expression of LHX3 in lung cancer cells obviously promotes cell proliferation and invasion, whereas inhibits cell apoptosis. In summary, LHX3 is an early-stage and radiosensitivity prognostic biomarker, and a novel potential oncogene in ADC.


Oblique incidence for broad monoenergetic proton beams.
The depth dose of a monoenergetic broad parallel proton beam has been modeled in a number of ways, but evidently not yet for oblique incidence. The purpose of this investigation is to find an accurate analytic formula for this case, which can then be used to model the depth dose of a broad beam with an initial Gaussian angular distribution. The Bortfeld model of depth dose in a broad normally incident proton beam has been extended to the case of oblique incidence. This extension uses an empirically determined Gaussian parameter sigma(x) which (roughly) characterizes the off-axis dose of a proton pencil beam. As with Bortfeld's work, the modeling is done in terms of parabolic cylinder functions. To obtain the depth dose for an initial angular distribution, the result is integrated over the angle of incidence, weighted by a Gaussian probability function. The predictions of the theory have been compared to MCNPX Monte Carlo calculations for four phantom materials (water, bone, aluminum, and copper) and for initial proton energies of 50, 100, 150, 200, and 250 MeV. Comparisons of the depth dose predicted by this theory with Monte Carlo calculations have established that with very good accuracy, sigma(x) can be taken to be independent both of the depth and of the angle of incidence. As a function of initial proton range or of initial proton energy, sigma(x) has been found to obey a power law to very high accuracy. Good fits to Monte Carlo calculations have also been found for an initial Gaussian angular distribution. This investigation is the first step in the accurate modeling of a proton pencil beam with initial Gaussian angular distribution. It provides the longitudinal factor, with its Bragg peak buildup and sharp distal falloff. A transverse factor must still be incorporated into this theory and this will give the lateral penumbra of a collimated proton beam. Also, it will be necessary to model the dose of product particles from nuclear interactions of the proton beam. With the accurate modeling of a pencil beam, it will be possible to accurately take into account the effect of localized tissue inhomogeneities.


Hydrocolloid to prevent breakdown of nares in preterm infants.
To determine if a double-barrier hydrocolloid dressing prevents trauma to the nares and columella in very low birthweight (VLBW) infants (<1,500 grams) receiving heated humidified high-flow nasal cannula (HHHFNC) oxygen. Retrospective two-group comparative study design. Medical records (N = 53) of VLBW infants receiving HHHFNC were reviewed. Control infants (n = 27) did not have a double-barrier hydrocolloid dressing. Intervention infants (n = 26) had a double-barrier hydrocolloid dressing. Groups were similar on sex, race, birthweight, and gestational age. Control infants were significantly older than intervention infants at study entry (4.3 weeks and 1.5 weeks, respectively, p = .001). Skin condition of nares was scored daily ranging from 3 (no breakdown) to 9 (extensive breakdown). Skin scores were abstracted from medical records at baseline then weekly for comparison over time. There were no significant differences in skin scores between groups or over time. Week 1 mean skin score was 3.4 (±0.1) in both groups. Mean skin score at week 4 was 3.4 (±0.1) in Control infants and 3.1 (±0.08) in Intervention infants. HHHFNC is more frequently being used in infants of extreme prematurity. The dressing may have protected the more immature skin of the intervention infants; however, vigilant nursing observation of the infants' nares during HHHFNC cannot be ruled out. Nurses need adequate education on the consistent application of the hydrocolloid barrier and on documenting skin assessment scores each shift to promote skin protection in this vulnerable population.


A Network Neuroscience of Human Learning: Potential to Inform Quantitative Theories of Brain and Behavior.
Humans adapt their behavior to their external environment in a process often facilitated by learning. Efforts to describe learning empirically can be complemented by quantitative theories that map changes in neurophysiology to changes in behavior. In this review we highlight recent advances in network science that offer a sets of tools and a general perspective that may be particularly useful in understanding types of learning that are supported by distributed neural circuits. We describe recent applications of these tools to neuroimaging data that provide unique insights into adaptive neural processes, the attainment of knowledge, and the acquisition of new skills, forming a network neuroscience of human learning. While promising, the tools have yet to be linked to the well-formulated models of behavior that are commonly utilized in cognitive psychology. We argue that continued progress will require the explicit marriage of network approaches to neuroimaging data and quantitative models of behavior.


Large intraperitoneal lipoma in pregnancy.
Intraperitoneal lipomas causing high-grade bowel obstruction in advanced pregnancy are rare. We report an unusual case which presented at 33 weeks with faecal vomitus and abdominal pain. Lipomas are benign adipose tissue tumours that are usually asymptomatic. The constraints of diagnosis, investigation and treatment of such tumours in pregnancy are also discussed.


Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.
The hemodynamic effects of the inotropic agents prenalterol and dobutamine were compared in a canine model of acute ischemic heart failure following two-vessel coronary artery constriction. Intravenous infusions of both inotropic agents resulted in improvement of cardiac output, left ventricular maximum dP/dt, and contractile force in the nonischemic zone and in a decrease in systemic vascular resistance. No significant changes occurred in ischemic zone contractile force or left ventricular end-diastolic pressure following either inotropic agent compared to saline controls. Significant differences between the two inotropic agents consisted of prenalterol's markedly longer duration of action (hemodynamic half life of 3 hr after discontinuation compared to a value of 1.7 min after dobutamine discontinuation) and greater augmentation of cardiac output at high-dose dobutamine due to greater increases in heart rate. However, similar hemodynamic effects were noted with prenalterol and dobutamine at doses which increased nonischemic contractile force 50%. Both inotropic agents were associated with ventricular arrhythmias in the acute ischemic state. Implications regarding the use of prenalterol and dobutamine in clinical acute ischemic low-output states are discussed.


Carbon monoxide‑releasing molecules protect against blue light exposure and inflammation in retinal pigment epithelial cells.
The most common cause of vision loss among the elderly is age‑related macular degeneration (AMD). The aim of the present study was to investigate the potential cytoprotective and anti‑inflammatory effects of carbon monoxide‑releasing molecules (CORMs), and their ability to activate the expression of nuclear factor erythroid 2‑related factor 2 (Nrf2)‑related genes in human retinal pigment epithelium (RPE) cells, as well as the inhibition of endothelial cell migration. It was first determined that CORM2 and CORM3 suppressed blue light‑induced cell damage. In addition, a decrease in the level of cleaved poly(ADP‑ribose) polymerase 1 protein and dissipation of mitochondrial membrane potential were considered to reflect the anti‑apoptotic activity of CORMs. Furthermore, CORM2 induced Nrf‑2 activation and the expression of the Nrf2‑related genes heme oxygenase‑1 and glutamate‑cysteine ligase. Pretreatment with CORM2 abolished the blue light‑induced increase in oxidative stress, suggesting that CORM2‑induced antioxidant activity was involved in the cytoprotection against blue light. It was also demonstrated that CORMs markedly suppressed tumor necrosis factor (TNF)α‑induced intercellular adhesion molecule‑1 expression. Moreover, it was further observed that CORMs exert their inhibitory effects through blocking nuclear factor‑κB/p65 nuclear translocation and IκBα degradation in TNFα‑treated RPE cells. It was observed that CORM2, but not CORM3, protected against oxidative stress‑induced cell damage. CORMs abolished vascular endothelial growth factor‑induced migration of endothelial cells. The findings of the present study demonstrated the cytoprotective, antioxidant and anti‑inflammatory effects of CORMs on RPE cells and anti‑angiogenic effects on endothelial cells, suggesting the potential clinical application of CORMs as anti‑AMD agents.


Diagnosis of preterm rupture of membranes: is testing for alpha-fetoprotein better than ferning or nitrazine?
This article evaluates the role of alpha-fetoprotein (AFP) testing in the diagnosis of ruptured membranes in the preterm patient. AFP is normally found in amniotic fluid and is not present in vaginal secretions. Testing for AFP in vaginal fluid was compared with nitrazine evaluation and ferning in two groups of preterm patients, those with intact membranes and those with ruptured membranes. There was no difference in the sensitivities of AFP, nitrazine, or ferning in diagnosing ruptured membranes. The specificities of AFP and ferning were similar and both were significantly better than nitrazine. Duration of membrane rupture for greater than 24 hours negatively affected the accuracy of all three tests. Blood-tinged amniotic fluid interfered with AFP and nitrazine evaluation. AFP does not appear to offer a significant advantage over nitrazine testing and ferning in the evaluation of patients with possible ruptured membranes.


Biochemical characteristics of a rice (Oryza sativa L., IR36) G-protein alpha-subunit expressed in Escherichia coli.
A cDNA encoding the alpha-subunit of the heterotrimeric G-protein in rice (RGA1) was overexpressed in Escherichia coli and then isolated by Ni2+-nitrilotriacetic acid affinity chromatography. The molecular mass of RGA1 bearing a His tag was approx. 49 kDa. Immunoblot analysis using anti-RGA1 revealed that the RGA1 protein is most abundant in seedling leaves and least abundant in mature roots. It exists at particularly high levels in the immature embryo after pellicle extrusion. In addition, the RGA1 antiserum exhibited a difference in binding affinity for Galpha proteins from monocots (maize and rice) and dicots (Arabidopsis, pea, soya bean and tomato); whereas it cross-reacted with Galpha proteins of monocots, it did not with those of dicot plants. When bound to guanosine 5'-(gamma-thio)triphosphate (GTP[S]), the RGA1 protein was partially protected from tryptic proteolysis. In the presence of GTP[S], trypsin cleaved the RGA1 protein into four fragments 24, 14, 11 and 5 kDa in size. When RGA1 was bound to GDP, only the 5 kDa polypeptide was seen on SDS/PAGE after trypsin digestion. Photoaffinity labelling with [alpha-32P]GTP and a GTP[S]-binding assay revealed that RGA1 incorporated 32P and showed specific binding to a guanine nucleotide. Guanidine binding of RGA1 was affected by the concentration of MgCl2 (maximum at 2 mM). The rate of guanine nucleotide binding of RGA1 (kon,GTP[S]=0.0141+/-0.0014 min-1) and, at steady state, the kcat value for GTP hydrolysis (0.0075+/-0.0001 min-1) were very low even at 2 mM MgCl2. The binding affinity for the nucleotides examined was in the order GTP-S- >/= GTP > GDP > CTP > ATP >/= dTTP.


Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy.
Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease. The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma. A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up. There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P < .036), during the 2-year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P < .005 for all 5 years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen-specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo. Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma.


Secured remote health monitoring system.
Wireless medical sensor network is used in healthcare applications that have the collections of biosensors connected to a human body or emergency care unit to monitor the patient's physiological vital status. The real-time medical data collected using wearable medical sensors are transmitted to a diagnostic centre. The data generated from the sensors are aggregated at this centre and transmitted further to the doctor's personal digital assistant for diagnosis. The unauthorised access of one's health data may lead to misuse and legal complications while unreliable data transmission or storage may lead to life threatening risk to patients. So, this Letter combines the symmetric algorithm and attribute-based encryption to secure the data transmission and access control system for medical sensor network. In this work, existing systems and their algorithm are compared for identifying the best performance. The work also shows the graphical comparison of encryption time, decryption time and total computation time of the existing and the proposed systems.


Assessment of a direct hybridization microarray strategy for comprehensive monitoring of genetically modified organisms (GMOs).
Detection of GMO material in crop and food samples is the primary step in GMO monitoring and regulation, with the increasing number of GM events in the world market requiring detection solutions with high multiplexing capacity. In this study, we test the suitability of a high-density oligonucleotide microarray platform for direct, quantitative detection of GMOs found in the Turkish feed market. We tested 1830 different 60nt probes designed to cover the GM cassettes from 12 different GM cultivars (3 soya, 9 maize), as well as plant species-specific and contamination controls, and developed a data analysis method aiming to provide maximum throughput and sensitivity. The system was able specifically to identify each cultivar, and in 10/12 cases was sensitive enough to detect GMO DNA at concentrations of ⩽1%. These GMOs could also be quantified using the microarray, as their fluorescence signals increased linearly with GMO concentration.


The multifaceted role of extracellular vesicles in prostate cancer-a review.
Prostate cancer is the second most prominent form of cancer in men and confers the highest mortality after lung cancer. The term "extracellular vesicles" refers to minute endosomal-derived membrane microvesicles and it was demonstrated that extracellular vesicles affect the environment in which tumors originate. Extracellular vesicles' involvement is also established in the development of drug resistance, angiogenesis, stemness, and radioresistance in various cancers including prostate cancer. Extracellular vesicles influence the general environment, processes, and growth of prostate cancer and can be a potential area that offers a significant lead in prostate cancer therapy. In this review, we have elaborated on the multifaceted role of extracellular vesicles in various processes involved in the development of prostate cancer, and their multitude of applications in the diagnosis and treatment of prostate cancer through the encapsulation of various bioactives.


Effect of continuous LDL apheresis with dextran-sulfate cellulose column system on a child with homozygous familial hypercholesterolemia.
A new system for selective low density lipoprotein apheresis with an automated regenerating column using dextran-sulfate (DS) as ligand was evaluated for six months in a 13-year-old boy homozygous for familial hypercholesterolemia. Two columns each containing 150 ml of DS cellulose were alternately used after rinsing with a regenerating solution. The patient could well tolerate the volume in the system. The values of plasma total cholesterol decreased by 79.4 +/- 4.9% of the pretreatment levels after a total of 5l plasma apheresis, while those of high density lipoprotein cholesterol did not change. Although the values of CH50 decreased, no adverse reaction was seen during the period of treatment. It was concluded that the present apheresis system was highly efficacious and safe for children homozygous for the mutant LDL receptor gene.


Spectral Tuning Mechanism of Primate Blue-sensitive Visual Pigment Elucidated by FTIR Spectroscopy.
Protein-bound water molecules are essential for the structure and function of many membrane proteins, including G-protein-coupled receptors (GPCRs). Our prior work focused on studying the primate green- (MG) and red- (MR) sensitive visual pigments using low-temperature Fourier transform infrared (FTIR) spectroscopy, which revealed protein-bound waters in both visual pigments. Although the internal waters are located in the vicinity of both the retinal Schiff base and retinal β-ionone ring, only the latter showed differences between MG and MR, which suggests their role in color tuning. Here, we report FTIR spectra of primate blue-sensitive pigment (MB) in the entire mid-IR region, which reveal the presence of internal waters that possess unique water vibrational signals that are reminiscent of a water cluster. These vibrational signals of the waters are influenced by mutations at position Glu113 and Trp265 in Rh, which suggest that these waters are situated between these two residues. Because Tyr265 is the key residue for achieving the spectral blue-shift in λmax of MB, we propose that these waters are responsible for the increase in polarity toward the retinal Schiff base, which leads to the localization of the positive charge in the Schiff base and consequently causes the blue-shift of λmax.


Evidence of neurodegeneration in individuals with only mildly elevated blood pressure.
Initiation of antihypertensive drug treatment in low-risk individuals with grade 1 hypertension is under debate. The aim of this study was to examine the impact of mildly elevated blood pressure (BP) on early neurodegenerative processes independent of ageing. Sixty-two individuals were included in this study: 25 young (aged <40 years) and 37 older (aged ≥40 years) individuals at low cardiovascular risk and grade 1 hypertension at most. Macular retinal layer volumes of both eyes were determined by SD-OCT. Total retinal volume but also each inner retinal layer volume separately including retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL-IPL were measured in each individual. Retinal layer volumes were lower among older individuals compared with young individuals (RNFL right eye: P = 0.037/left eye: P = 0.021; GCL and GCL-IPL: both eyes P < 0.001; IPL right eye: P = 0.005/left eye: P = 0.002; total retinal volume: both eyes P = 0.002) and there was an inverse correlation between retinal layer volumes and age. Partial correlation analysis, excluding age as a cofactor, revealed an inverse association between retinal layer volumes and DBP. In multiple regression analysis, DBP was identified as a determinant of retinal neurodegenerative processes. In the current study, we observed an inverse association between retinal neurodegenerative processes and DBP, suggesting that BP-lowering therapy by early antihypertensive drug-treatment might be beneficial to avoid early neurodegeneration.


NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors.
NK cells are able to discriminate between normal cells and cells that have lost MHC class I (MHC-I) molecule expression as a result of tumor transformation. This function is the outcome of the capacity of inhibitory NK receptors to block cytotoxicity upon interaction with their MHC-I ligands expressed on target cells. To investigate the role of human NK cells and their various receptors in the control of MHC-I-deficient tumors, we have isolated several NK cell clones from lymphocytes infiltrating an adenocarcinoma lacking beta2-microglobulin expression. Unexpectedly, although these clones expressed NKG2D and mediated a strong cytolytic activity toward K562, Daudi and allogeneic MHC-class I+ carcinoma cells, they were unable to lyse the autologous MHC-I- tumor cell line. This defect was associated with alterations in the expression of natural cytotoxicity receptor (NCR) by NK cells and the NKG2D ligands, MHC-I-related chain A, MHC-I-related chain B, and UL16 binding protein 1, and the ICAM-1 by tumor cells. In contrast, the carcinoma cell line was partially sensitive to allogeneic healthy donor NK cells expressing high levels of NCR. Indeed, this lysis was inhibited by anti-NCR and anti-NKG2D mAbs, suggesting that both receptors are required for the induced killing. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition.


Port-a-Cath extravasation of vesicant cytotoxics: surgical options for a rare complication of cancer chemotherapy.
Although implantation of a central venous device such as a Port-a-Cath was initially considered safe, extravasation rates up to 4.7% have been reported. Therefore, the objective of this study was to propose a structured procedure for the management of extravasation of a cytotoxic treatment. A total of eight patients were evaluated after port extravasation of epirubicin (n = 3), platinum compounds (n = 3), paclitaxel (n = 1), or trabectedin (n = 1) into the subcutaneous space. Immediate explantation of the port was performed in combination with a "Subcutaneous Wash-Out Procedure" (SWOP). When removal of the port was delayed, débridement and flap coverage were performed as necessary. Epirubicin concentrations present in the samples obtained during surgical intervention were subsequently analysed using high-performance liquid chromatography (HPLC). Patients were followed for at least six months and were examined for sequelae such as pain, induration, redness, and limited movement. All three patients whose extravasation event was detected during chemotherapy administration benefited from SWOP with acceptable side effects (e.g., erythema). The analysis of epirubicin concentrations demonstrated the active removal of relevant amounts of the compound by wound rinsing. In contrast, late detection of extravasation led to major débridement and flap coverage in four out of five patients. A high body mass index (BMI) value was associated with all of the patients that experienced port extravasation. Depending on when Port-a-Cath extravasations into subcutaneous tissue are detected, different treatments are appropriate. When extravasation is detected early, the SWOP was found to be beneficial.


Effects of cortisol on prostaglandin F2α secretion and expression of genes involved in the arachidonic acid metabolic pathway in equine endometrium - In vitro study.
Glucocorticoids (GCs) are known to play an important role in maintaining basal and stress-related homeostasis by interacting with endocrine mediators and prostaglandins (PGs). Although a growing body of evidence shows that GCs exert their regulatory action at a multitude of sites in the reproductive axis through corticosteroid receptors, little is known about the direct role of cortisol, an active form of GCs, in the equine endometrium. Thus, the study aimed to determine the effect of cortisol on PGF2α synthesis in the endometrial tissue and cells in vitro. In Exp.1, the immunolocalization and the expression of the glucocorticoid receptor (GCR) in the endometrium throughout the estrous cycle were established. In Exp. 2 and 3, the effects of cortisol on PGF2α secretion and transcripts associated with the arachidonic acid (AA) cascade in endometrial tissues, and cells were defined. Endometrial tissues obtained from the early, mid, and late luteal phases and the follicular phase of the estrous cycle were exposed to cortisol (100, 200, and 400 nM) for 24 h. Endometrial epithelial and stromal cells (early phase of estrous cycle) were exposed to cortisol (100 nM) for 24 h. Then, PGF2α secretion and transcripts associated with the AA cascade (PLA2G2A, PLA2G4A, PTGS2, and PGFS) were assessed. GCR was expressed in the cytoplasm and the nucleus in the luminal and glandular epithelium as well as in the stroma. Endometrial GCR protein abundance was up-regulated at the late luteal phase compared to the mid-luteal phase of the estrous cycle. Cortisol dose-dependently decreased PGF2α secretion, PLA2G2A and PLA2G4A transcripts in endometrial tissues. Additionally, cortisol treatment decreased PGF2α secretion from endometrial epithelial and stromal cells. Moreover, it affected PLA2G2A, PLA2G4A, and PTGS2 transcripts in endometrial stromal cells. These findings suggest that cortisol suppresses the synthesis of PGF2α by affecting the AA cascade in the equine endometrium during the estrous cycle.


[Availability of antidotes in the event of accidents or attacks with chemical weapons].
In this report, we aimed to determine the availability of six antidotes for victims of accidents or attacks with chemical weapons. Telephone interviews with 6 Catalan hospitals and 8 hospitals from the community of Castilla y León. We evaluated the availability of antidotes in the hypothetical event of a massive intoxication with 600 affected people. Only 3 out of the 14 hospitals had all 6 antidotes. Only atropine and, in Catalan hospitals, sodium thiosulfate were available in enough quantities to treat all victims. With regard to the remaining antidotes, the percentage of treated patients would have been fewer than 50%. The less available antidote was hydroxocobalamine. We have found both qualitative and quantitative deficiencies of antidotes for the treatment of people intoxicated by chemical weapons.


3D transoesophageal echocardiography in the TAVI sizing arena: should we do it and how do we do it?
Transcatheter aortic valve implantation (TAVI) was initially proven as an alternative to valve replacement therapy in those beyond established risk thresholds for conventional surgery. With time the technique has been methodically refined and offered to a progressively lower risk cohort, and with this evolution has come that of the significant imaging requirements of valve implantation. This review discusses the role of transoesophageal echocardiography (TOE) in the current TAVI arena, aligning it with that of cardiac computed tomography, and outlining how TOE can be used most effectively both prior to and during TAVI in order to optimise outcomes.


The sympathetic control of blood supply is different in the spleen and lymph nodes.
The noradrenergic innervation of lymphoid organs controls several immune cell functions and local blood perfusion. Considering that cell and antigen uptake depend on the blood supply to lymphoid organs, the hypothesis was tested that feedback signals from activated immune cells control sympathetic vasomotor activity. We determined the blood flow in spleen and mesenteric lymph nodes (mLN) of Wistar Kyoto rats during immune stimulation with endotoxin (LPS; 10 microg/kg) and following disruption of the noradrenergic transmission. Our data indicate that (a) the splenic noradrenaline content, which reflects the density of the sympathetic innervation, is 5 times higher in the spleen than in other peripheral organs and the spleen receives stronger tonic sympathetic input than mLN; (b) immune stimulation with LPS causes a 4-fold increase in the IL-1beta production in the spleen, but only 2-fold in mLN; (c) IL-1beta causes an inhibition of the sympathetic vasoconstrictor tonus in the spleen, but has no significant effect on the noradrenergic vascular tonus in mLN, and (d) in mLN, the local hyperemia induced by LPS is attenuated by the degranulation of vesicular stores of histamine and serotonin, indicating that these monoamines participate in the vasodilator effect of LPS in mLN. The present experiments, taken together with our previous studies, indicate that the control of blood supply to the spleen and mLN involves different mechanisms. While blood perfusion in the spleen depends on the inhibition of the noradrenergic vasoconstriction by endogenously produced IL-1beta, other vasoactive mediators such as serotonin and histamine play a role in the control of mLN perfusion.


Linking epigenetic function to electrostatics: The DNMT2 structural model example.
The amino acid sequence of DNMT2 is very similar to the catalytic domains of bacterial and eukaryotic proteins. However, there is great variability in the region of recognition of the target sequence. While bacterial DNMT2 acts as a DNA methyltransferase, previous studies have indicated low DNA methylation activity in eukaryotic DNMT2, with preference by tRNA methylation. Drosophilids are known as DNMT2-only species and the DNA methylation phenomenon is a not elucidated case yet, as well as the ontogenetic and physiologic importance of DNMT2 for this species group. In addition, more recently study showed that methylation in the genome in Drosophila melanogaster is independent in relation to DNMT2. Despite these findings, Drosophilidae family has more than 4,200 species with great ecological diversity and historical evolution, thus we, therefore, aimed to examine the drosophilids DNMT2 in order to verify its conservation at the physicochemical and structural levels in a functional context. We examined the twenty-six DNMT2 models generated by molecular modelling and five crystallographic structures deposited in the Protein Data Bank (PDB) using different approaches. Our results showed that despite sequence and structural similarity between species close related, we found outstanding differences when they are analyzed in the context of surface distribution of electrostatic properties. The differences found in the electrostatic potentials may be linked with different affinities and processivity of DNMT2 for its different substrates (DNA, RNA or tRNA) and even for interactions with other proteins involved in the epigenetic mechanisms.


[Models of health behavior].
One of the challenges for health professionals is to understand how individuals adopt and maintain healthy behaviours that lead to a better quality of life. This review of health behaviour models will help nurses determine appropriate interventions, and enhance programs that promote health and prevent sickness in individuals or groups of individuals. In order to establish priorities and to prevent omitting important points in planning such health programs, many theoretical and conceptual models have attempted to explain health behaviours as well as the indicators of compliance. The purpose of this article is to summarise the most utilised health behaviour models, to offer a schematic representation, and to explain the advantages and disadvantages of each model. Until now, no article had reviewed these models into the same work. This article will be of assistance to nurse researchers and clinicians working in health prevention, who are interested in choosing a health behaviour model to plan a scientific research, or to develop a clinical program. The models are presented according to the following classifications: cognitive value expectation; theories of personality; communication theories; models of program planning; and models of integration.


An anti-peptide monoclonal antibody recognizing the tobacco etch virus protease-cleavage sequence and its application to a tandem tagging system.
Peptide-based affinity tags are commonly used in recombinant production/purification of proteins, and are often preceded or followed by a protease recognition sequence to allow tag removal. We describe a rat monoclonal antibody 2H5 recognizing an undecapeptide tag called "eTev", which contains a recognition sequence for Tobacco Etch Virus (TEV) protease. In the crystal structure of 2H5-eTev complex, the long eTev peptide assumes compact α-helical conformation in the binding groove, exposing both ends to the solution. This architecture allowed us to connect eTev with another peptide tag called PA tag via linker sequence, ensuring the simultaneous access of two anti-tag antibodies. When this tandem double tag was attached at one end of various proteins, it enabled highly sensitive and protein-independent detection by sandwich ELISA. Utilizing this system during a rapid cell line screening, we succeeded in isolating stable cell clones expressing high level of mouse Wise protein.


GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling.
Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.


An unusual case of biliary bezoar causing small bowel obstruction in a patient with ampullary diverticulum and stapled gastroplasty.
Primary small bowel bezoars constitute 0.44% of small bowel obstructions (SBO). We report a case of a man with a history of gastroplasty who presented with lower abdominal pain. Initial examination revealed leucocytosis and serum lipase. CT of the abdomen/pelvis was consistent with pancreatitis, cholelithiasis and a stable, 3.8 cm, ampullary diverticulum, without obstruction of the pancreatic/common bile duct. Considering this was the patient's first episode of pancreatitis with evidence of cholelithiasis, it seemed prudent that he would benefit from cholecystectomy but not diverticulectomy. Post-cholecystectomy he represented to the hospital with biliary emesis. CT of the abdomen/pelvis revealed postsurgical changes. Owing to non-resolution of the symptoms, 48 h later a small bowel follow-through was obtained that suggested partial SBO. Ultimately, the patient was taken for exploratory laparoscopy and small bowel resection, after a large intramural mass was encountered in the small bowel. Final pathology revealed a 3 cm biliary bezoar causing obstruction and stercoral ulceration.


The Influence of Emotional Experience on Semantic Processing of Concrete Concepts.
Parallel distributed processing theory (PDP theory) holds that all brain regions involved in conceptual representation perform a series of activities at the same time. However, the role of emotional experience information in concrete conceptual representation is still unknown. This study further explores whether the emotional experience will also affect the semantic processing of concrete concept representations. This study used the emotion priming paradigm and semantic judgment task to explore whether emotion priming impacts the processing of animal concepts with different emotional experiences through two experiments. In Experiments 1a and 1b, pleasant or disgusted faces were used as emotional priming stimuli to explore whether the explicit processing of emotions would affect the semantic processing of animal concepts. Experiments 2a and 2b used positive or negative scenery pictures as emotional priming stimuli to explore whether the implicit processing of emotions would affect the semantic processing of animal concepts. The Experiment 1 results showed that the perception of faces promotes the processing of animal words, showing the "word-emotion congruence effect". Experiment 2a did not show the expected results, while Experiment 2b showed that the general negative perception of scenery pictures could significantly promote the processing of disgusted animal words. The results further proved the "word-emotion congruence effect" shown in the results of Experiment 1 from the perspective of implicit emotion processing. Combining the results of two experiments, it can be proven that emotional experience affects the semantic processing process of concrete concepts. Both Experiment 1 and Experiment 2b of this study show the "word-emotion congruence effect". PDP theory believes that conceptual representation is represented by the activity patterns of billions of neurons distributed in many areas of the brain, and related semantic processing and sensory processing will occur simultaneously. The results of this experiment well support PDP theory.


Unexpected improvement, decline, and stasis: a prediction confidence perspective on achievement success and failure.
The authors hypothesized that reactions to performance feedback depend on whether one's lay theory of intelligence is supported or violated. In Study 1, following improvement feedback, all participants generally exhibited positive affect, but entity theorists (who believe that intelligence is fixed) displayed more anxiety and more effort to restore prediction confidence than did incremental theorists (who believe that intelligence is malleable). Similarly, when performance declined, entity theorists displayed more anxiety and compensatory effort than incremental theorists. However, when performance remained rigidly static despite a learning opportunity, incremental theorists evinced more anxiety and compensatory effort than entity theorists. In Study 2, this pattern was replicated when the entity and incremental theories were experimentally manipulated. Study 3 demonstrated that for both groups, theory violation impairs subsequent task performance. Taken together, these studies provide evidence that lay theory violation and damaged prediction confidence have significant and measurable effects on emotion and motivation. The authors discuss the implications of these findings for the literature on achievement success and failure.


AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications.
Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O-methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation.


Raised intracranial pressure presenting with spontaneous periorbital bruising: two case reports.
The venous drainage of the orbit is known to be via the ophthalmic and vortex veins which communicate with the cavernous sinus. We describe two patients with raised intracranial pressure presenting with periorbital bruising. In one patient dural venous sinus thrombosis was demonstrated and it is suspected that the cause of the raised intracranial pressure may have been the same in the second. We suggest that the abrupt rise of pressure in the cerebral venous system was transmitted via the cavernous sinus to the orbital venous system.


HACA3: A unified approach for multi-site MR image harmonization.
The lack of standardization and consistency of acquisition is a prominent issue in magnetic resonance (MR) imaging. This often causes undesired contrast variations in the acquired images due to differences in hardware and acquisition parameters. In recent years, image synthesis-based MR harmonization with disentanglement has been proposed to compensate for the undesired contrast variations. The general idea is to disentangle anatomy and contrast information from MR images to achieve cross-site harmonization. Despite the success of existing methods, we argue that major improvements can be made from three aspects. First, most existing methods are built upon the assumption that multi-contrast MR images of the same subject share the same anatomy. This assumption is questionable, since different MR contrasts are specialized to highlight different anatomical features. Second, these methods often require a fixed set of MR contrasts for training (e.g., both T1-weighted and T2-weighted images), limiting their applicability. Lastly, existing methods are generally sensitive to imaging artifacts. In this paper, we present Harmonization with Attention-based Contrast, Anatomy, and Artifact Awareness (HACA3), a novel approach to address these three issues. HACA3 incorporates an anatomy fusion module that accounts for the inherent anatomical differences between MR contrasts. Furthermore, HACA3 can be trained and applied to any combination of MR contrasts and is robust to imaging artifacts. HACA3 is developed and evaluated on diverse MR datasets acquired from 21 sites with varying field strengths, scanner platforms, and acquisition protocols. Experiments show that HACA3 achieves state-of-the-art harmonization performance under multiple image quality metrics. We also demonstrate the versatility and potential clinical impact of HACA3 on downstream tasks including white matter lesion segmentation for people with multiple sclerosis and longitudinal volumetric analyses for normal aging subjects. Code is available at https://github.com/lianruizuo/haca3.


Structure, stability and elasticity of DNA nanotubes.
DNA nanotubes are tubular structures composed of DNA crossover molecules. We present a bottom up approach for the construction and characterization of these structures. Various possible topologies of nanotubes are constructed such as 6-helix, 8-helix and tri-tubes with different sequences and lengths. We have used fully atomistic molecular dynamics simulations to study the structure, stability and elasticity of these structures. Several nanosecond long MD simulations give the microscopic details about DNA nanotubes. Based on the structural analysis of simulation data, we show that 6-helix nanotubes are stable and maintain their tubular structure; while 8-helix nanotubes are flattened to stabilize themselves. We also comment on the sequence dependence and the effect of overhangs. These structures are approximately four times more rigid having a stretch modulus of ∼4000 pN compared to the stretch modulus of 1000 pN of a DNA double helix molecule of the same length and sequence. The stretch moduli of these nanotubes are also three times larger than those of PX/JX crossover DNA molecules which have stretch moduli in the range of 1500-2000 pN. The calculated persistence length is in the range of a few microns which is close to the reported experimental results on certain classes of DNA nanotubes.


Amiodarone-Induced Syndrome of Inappropriate Antidiuretic Hormone: A Case Report and Review of the Literature.
Amiodarone (Cordarone®, Pfizer Inc) is an antiarrhythmic medication with a well-known toxicity profile, including rare cases of hyponatremia as a result of syndrome of inappropriate antidiuretic hormone (SIADH). We report on such a case in which a patient was found to be hyponatremic after evaluation. An 88-year-old male who presented to the emergency department was found to be hyponatremic secondary to amiodarone-induced SIADH following a fall, with possible seizure and traumatic brain injury. He had a history of hypertension, paroxysmal atrial fibrillation, emphysema, myocardial infarction, benign prostatic hyperplasia, chronic kidney disease, Meniere's disease, anemia, and gastroesophageal reflux. Upon admission, his urine sodium level was elevated, and his serum sodium, urine osmolality, and anion gap were below normal. In the setting of hyponatremia, the patient's amiodarone was held: he had been taking amiodarone 200 mg once daily for nine months prior to admission. He was treated with intravenous (IV) normal saline over four days. He was fluid-restricted and his sodium levels were closely monitored every two hours. Within 19 hours, his serum sodium levels had improved. Amiodarone was restarted approximately three days later. Upon follow-up after discharge, the patient remained on amiodarone for the next two months. His serum sodium level ranged from 126 mEq/L to 131 mEq/L over a two-week period. He was supplemented with sodium chloride tablets and has been otherwise stable. Amiodarone may cause acute or chronic SIADH, with a wide range of symptoms. Seizures have not been reported in the literature but our patient had a witnessed seizure, although his electroencephalogram (EEG) was negative. Syndrome of inappropriate antidiuretic hormone can occur with any formulation of amiodarone in a dose-dependent fashion. Our patient's sodium levels stabilized within two weeks after amiodarone was resumed. The mechanism of amiodarone-induced SIADH remains unclear.


Cardiotonic agents. 1. Novel 8-aryl-substituted imidazo[1,2-a]- and -[1,5-a]pyridines and imidazo[1,5-a]pyridinones as potential positive inotropic agents.
Several 8-arylimidazo[1,2-a]pyridines, 8-arylimidazo[1,5-a]pyridines, and 8-arylimidazo[1,5-a]pyridinones were prepared and tested in vitro for potential cardiac inotropic and electrophysiological activity. Selected analogues were further tested in vivo in canine hemodynamic and cardiac electrophysiology models. Compounds having an imidazole substituent consistently showed activity. A pharmacophoric relationship between heterocycle-phenyl-imidazole and positive inotropic activity was noted. The significance of this relationship is discussed.


A 100,000-year periodicity in the accretion rate of interplanetary dust
Numerical modeling of the orbital evolution of interplanetary dust particles revealed that, over the past 1.2 million years, the rate of accretion of dust by Earth has varied by a factor of 2 to 3. These variations display a 100,000-year periodicity and are anticorrelated with Earth's changing orbital eccentricity. Extraterrestrial helium-3 concentrations in a deep-sea sediment core display a similar periodicity but are 50,000 years out of phase with the predicted variations. Also, because collisions between large bodies in the asteroid belt are inevitable, it is expected that large-amplitude stochastic variations on 10(7)- to 10(8)-year time scales would be superimposed on the 10(5)-year periodic variations.


Glutamate 107 in subunit I of cytochrome bd from Escherichia coli is part of a transmembrane intraprotein pathway conducting protons from the cytoplasm to the heme b595/heme d active site.
Cytochrome bd is a terminal quinol:O 2 oxidoreductase of the respiratory chain of Escherichia coli. The enzyme generates protonmotive force without proton pumping and contains three hemes, b 558, b 595, and d. A highly conserved glutamic acid residue of transmembrane helix III in subunit I, E107, was suggested to be part of a transmembrane pathway delivering protons from the cytoplasm to the oxygen-reducing site. When E107 is replaced with leucine, the hemes are retained but the ubiquinol-1-oxidase activity is lost. We compared wild-type and E107L mutant enzymes during single turnover using absorption and electrometric techniques with a microsecond time resolution. Both wild-type and E107L mutant cytochromes bd in the fully reduced state bind O 2 rapidly, but the formation of the oxoferryl species in the mutant is dramatically retarded as compared to the wild type. Intraprotein electron redistribution induced by the photolysis of CO bound to ferrous heme d in the one-electron-reduced wild-type enzyme is coupled to the membrane potential generation, whereas the mutant cytochrome bd shows no such potential generation. The E107L mutation also causes decrease of midpoint redox potentials of hemes b 595 and d by 25-30 mV and heme b 558 by approximately 70 mV. There are two protonatable groups redox-linked to hemes b 595 and d in the active site, one of which has been recently identified as E445, whereas the second group remains unknown. Here we propose that E107 is either the second group or a key residue of a proposed proton delivery pathway leading from the cytoplasm toward this second group.


EVOLUTION OF PUFFERFISH INFLATION BEHAVIOR.
The evolution of the extraordinary inflation mechanism of pufferfishes was studied in the light of an independently derived phylogenetic hypothesis of tetraodontiform fishes. Inflation behavior is found in all members of the puffer sister taxa Tetraodontidae and Diodontidae. However, most other tetraodontiform fishes exhibit two functionally similar behaviors. All taxa exhibit a "coughing" behavior and, with the exception of the sister-group to all other tetraodontiforms, represented by the Triacanthidae, all lineages "blow" strong jets of water out of their mouth to excavate prey. Functional specializations associated with the three behaviors were identified from anatomical analyses and electromyographic recordings of muscle activity in representatives of the major lineages of the order. The phylogenetic distribution of the three buccal compression behaviors and their functional bases indicates the following: (1) the evolution of inflation behavior involved major structural modifications of the head that function in a novel mechanism that links depression of the floor of the mouth to posterior expansion of the buccal cavity; (2) the contraction patterns of four key head muscles used in the three behaviors are generally similar both across behaviors and taxa; (3) however, the distribution of the two significant modifications of muscle activity are consistent with the hypothesis that the three behaviors represent a transformation series from coughing to water blowing to inflation. The motor pattern for water blowing is a slightly modified version of that seen in coughing, and the inflation motor pattern retains the blowing specialization and adds a single additional modification. The convergent evolution of a poorly developed inflation behavior in at least one genus of filefish provides evidence that tetraodontiform fishes are predisposed to the evolution of this unusual defensive behavior. The presence of a well developed water-blowing behavior in most tetraodontiform lineages may represent an intermediate functional specialization that increased the probability of the evolution of inflation.


Reliability and validity of the M. D. Anderson Symptom Inventory-Spine Tumor Module.
Tumors involving the spine have unique associated neurological symptoms. The occurrence of spine-related symptoms has been shown to predict treatment course and survival in several studies conducted in patients with solid tumors and consequent spinal cord dysfunction. Currently, no instrument that measures both neurological and cancer-related symptoms exists for patients with spine tumors. The objective of this study was to develop a reliable and valid self-reporting instrument for patients with spine tumors. Patients with diagnosed tumors involving the spine (both primary and metastatic) participated in this study. Data collection tools included a patient-completed demographic data sheet, an investigator-completed clinician checklist, and the core M. D. Anderson Symptom Inventory to which were added 16 neurological symptoms (M. D. Anderson Symptom Inventory-Spine Tumor Module [MDASI-SP]). The authors evaluated the reliability and validity of the MDASI-SP in patients with spine tumors. One hundred twenty-six patients participated in the study. Participants were primarily white (73%) males (53%) with metastatic spine tumors (76%). They ranged in age from 18-81 years (median 56 years). Cognitive debriefing of the MDASI-SP was conducted showing the instrument was clear, concise, and easily understood by patients. The most severe core symptoms were pain, fatigue, numbness, disturbed sleep, and distress. The most severe spine module symptoms were spine pain, numbness, weakness in the legs, neck stiffness, and changes in bowel or sexual function. The mean symptom severity of items as well as a cluster analysis was used to reduce the number of total items to 18 (5 spine module items). Regression analysis showed that 57.4% of the variability in symptom interference with daily function was explained by the final instrument. Factor analysis was performed to determine the underlying constructs being evaluated by the symptom items. The 18-item MDASI-SP measures 4 underlying constructs including a disease, an autonomic, a constitutional/treatment, and an emotional factor. The internal consistency (reliability) of the MDASI-SP was 0.946, and the instrument was sensitive to disease severity based on the Karnofsky Performance Scale (KPS). The mean symptom severity was 1.52 for those with good KPS scores (80-100) versus 2.46 for those with poor scores (p < 0.01). The instrument was also sensitive to neurological status according to the Frankel grade (p < 0.001) and inpatient status (p < 0.01). The 18-item MDASI-SP demonstrated validity and reliability in patients with spine tumors as a composite measure of disease-related symptoms. This instrument can be used to describe symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management.


Steroid-responsive renal insufficiency due to idiopathic granulomatous tubulointerstitial nephritis.
A 26-year-old male was admitted to our hospital having suffered from subfever, sterile pyuria and renal insufficiency for 1 year. There had been no apparent hematuria/proteinuria, and evidence of infection, allergy or intoxication was not demonstrated. Open renal biopsy revealed severe tubulointerstitial changes with granuloma accompanied by neither caseous necrosis nor giant cells. Infiltrating cells mostly consisted of CD4 and CD8 T cells, and some proximal tubular cells presented MHC class II antigen. Following the negative culture of biopsied specimen for acid-fast bacilli, diagnosis of idiopathic granulomatous tubulointerstitial nephritis was made, and steroid therapy was started. Two months later, pyuria disappeared and renal function improved significantly, proving the effectiveness of steroid on idiopathic granulomatous tubulointerstitial nephritis.


[Nephrocutaneous fistula revealing xanthogranulomatous pyelonephritis].
A patient presented with a reno-cutaneous fistula revealing a xanthogranulomatous pyelonephritis secondary to staghorn calculus. Total nephrectomy was necessary because of renal destruction. This treatment allowed closure of the fistula and a good clinical result.


Clinical outcomes and prognosis of recurrent thymoma management.
Clinical outcomes and prognosis of recurrent thymoma are not well known because of its rarity and indolent clinical course. This study was designed to determine the clinical outcomes and prognosis of recurrent thymoma. Between 1986 and 2009, 41 of 305 patients who underwent resection for thymoma had recurrence. We reviewed those patients retrospectively. Of 15 patients who underwent re-resection for recurrent thymoma, 13 patients (87%) achieved complete re-resection. Of 26 patients who did not undergo re-resection, 11 patients received chemotherapy, five received chemoradiotherapy, one received another treatment, and nine patients did not receive any treatment. World Health Organization histological types AB or B1 and complete re-resection were positive prognostic factors. The complete re-resection group had better survival after recurrence than the non/incomplete re-resection group (5-year survival rate: 90.9% versus 44.7%, p = 0.014). The complete re-resection group had comparable survival after initial resection of thymoma to the patients without recurrence (5-year, 10-year survival: 91.7%, 91.7% versus 90.7%, 86.5%, p = 0.618) and better survival compared with the non/incomplete re-resection group (5-year, 10-year survival: 91.7%, 91.7% versus 81.6%, 56.7%, p = 0.018). World Health Organization histologic types AB or B1 and complete re-resection are favorable prognostic factors of recurrent thymoma. In particular, complete re-resection of recurrent thymoma contributes to better survival than other management. Therefore, we suggest that long-term surveillance extended at least 20 years may be essential for early detection of recurrence to increase the chance of complete re-resection of recurrent thymoma.