Contrast agent-free sonoporation: The use of an ultrasonic standing wave microfluidic system for the delivery of pharmaceutical agents.
Sonoporation is a useful biophysical mechanism for facilitating the transmembrane delivery of therapeutic agents from the extracellular to the intracellular milieu. Conventionally, sonoporation is carried out in the presence of ultrasound contrast agents, which are known to greatly enhance transient poration of biological cell membranes. However, in vivo contrast agents have been observed to induce capillary rupture and haemorrhage due to endothelial cell damage and to greatly increase the potential for cell lysis in vitro. Here, we demonstrate sonoporation of cardiac myoblasts in the absence of contrast agent (CA-free sonoporation) using a low-cost ultrasound-microfluidic device. Within this device an ultrasonic standing wave was generated, allowing control over the position of the cells and the strength of the acoustic radiation forces. Real-time single-cell analysis and retrospective post-sonication analysis of insonated cardiac myoblasts showed that CA-free sonoporation induced transmembrane transfer of fluorescent probes (CMFDA and FITC-dextran) and that different mechanisms potentially contribute to membrane poration in the presence of an ultrasonic wave. Additionally, to the best of our knowledge, we have shown for the first time that sonoporation induces increased cell cytotoxicity as a consequence of CA-free ultrasound-facilitated uptake of pharmaceutical agents (doxorubicin, luteolin, and apigenin). The US-microfluidic device designed here provides an in vitro alternative to expensive and controversial in vivo models used for early stage drug discovery, and drug delivery programs and toxicity measurements.


Anopheles prachongae, a new species of the Gigas Complex of subgenus Anopheles (Diptera: Culicidae) in Thailand, contrasted with known forms of the complex.
Anopheles (Anopheles) prachongae, a new species of the Gigas Complex from northern Thailand, is described and illustrated in the adult, pupal and larval stages, and bionomics and chaetotaxy tables are provided for the immature stages. The species is distinguished from Anopheles baileyi, the only other species of the complex known to occur in Thailand, and contrasted with other taxa of the complex that occur in the Oriental Region. Available morphological data indicate that An. gigas sumatrana is unique and is therefore formally afforded species status. The three other Sumatran subspecies may be conspecific. The taxonomic status of the non-Sumatran subspecies, i.e. crockeri (Borneo), formosus (Philippines), refutans (Sri Lanka) and simlensis (south-central Asia), is questioned but their status is unchanged pending further study.


Association Between Future Orientation and Anxiety in University Students During COVID-19 Outbreak: The Chain Mediating Role of Optimization in Primary-Secondary Control and Resilience.
The unfamiliar and menacing epidemic has undoubtedly increased the anxiety of students. Therefore, the strategies to reduce anxiety are urgently required. The present study principally investigated a protective mechanism of future orientation in anxiety during the low-risk period of COVID-19 outbreak. The study was conducted in 528 non-infected students (range = 16-24 years) recruited from five universities in China. The participants completed questionnaires between January 22, 2021, and January 24, 2021. Chain intermediary analyses were performed after controlling for gender and age. Results indicated that future orientation lowers anxiety through (a) optimization in primary and secondary control, (b) resilience, and (c) chain mediating path of optimization in primary and secondary control coupled with resilience. We investigated how individuals deal with risk factors after encountering adversity and how their psychological flexibility stimulates and promotes them to achieve a well-adapted developmental state. This study provided reference suggestions on reducing anxiety levels during an emergency.


Preparation of a neural electrode implantation device for in-vivo surgical use.
An instrument designed for the implantation of neural electrode array devices has been refined in preparation for use in cortical implantation procedures in non-human primates. This instrument has undergone extensive testing to ensure its successful first use in a live surgical setting. This work describes the modifications made to the instrument and the testing performed on it during that preparatory period as well as planned future modifications and augmentations.


Urinary-free cortisol excretion in relation to age in acutely stressed persons with depressive symptoms.
We examined the relationship between age and urinary excretion of free cortisol in acutely stressed middle-aged and elderly persons. We observed that elderly persons under stress excreted larger amounts of urinary-free cortisol than did middle-aged persons; Pearson's r between age and cortisol = 0.38, p less than 0.05. When the sample was stratified by severity of depressive symptoms, the relationship between age and cortisol excretion was strongly accentuated among those with severe depressive symptoms (r = 0.62, p = 0.01) and diminished among those with milder symptoms (r = 0.25, N.S.). Potentially confounding factors such as diet, use of medications, and physical stature were controlled and did not explain the observations. The high depression scores in this acutely stressed sample were indicative of a higher severity of stress response and also a higher risk of occurrence of depressive syndromes. The depressive syndromes did not resemble depressive disorder of an endogenous nature.


Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia.
See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive individuals. Increased baseline cerebrovascular resistance index also predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Finally, increased cerebrovascular resistance index predicted greater regional atrophy among non-demented older adults who were amyloid-negative. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.


MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation.
Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, PAX5, RhoH/TTF, and c-MYC in 17 MALT lymphomas and 17 extranodal diffuse large B-cell lymphomas (DLBCLs) still exhibiting a low-grade MALT lymphoma component (transformed MALT lymphoma). Mutations in one or more genes were detected in 13 (76.5%) of 17 cases of MALT lymphomas and in all of 17 (100%) cases of extranodal DLBCL. A total of 100 sequence variants were found in 30 of 34 cases, 28 in the MALT lymphomas and 72 in extranodal DLBCL. Further, in PIM1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. Expression levels of activation-induced cytidine deaminase (AID), an enzyme essential for somatic hypermutation (SHM), was associated with the mutational load. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes, ASHM may represent a major contributor to their pathogenesis.


Time-resolved ARPES Determination of a Quasi-Particle Band Gap and Hot Electron Dynamics in Monolayer MoS2.
The electronic structure and dynamics of 2D transition metal dichalcogenide (TMD) monolayers provide important underpinnings both for understanding the many-body physics of electronic quasi-particles and for applications in advanced optoelectronic devices. However, extensive experimental investigations of semiconducting monolayer TMDs have yielded inconsistent results for a key parameter, the quasi-particle band gap (QBG), even for measurements carried out on the same layer and substrate combination. Here, we employ sensitive time- and angle-resolved photoelectron spectroscopy (trARPES) for a high-quality large-area MoS2 monolayer to capture its momentum-resolved equilibrium and excited-state electronic structure in the weak-excitation limit. For monolayer MoS2 on graphite, we obtain QBG values of ≈2.10 eV at 80 K and of ≈2.03 eV at 300 K, results well-corroborated by the scanning tunneling spectroscopy (STS) measurements on the same material.


A Dysprosium Metallocene Single-Molecule Magnet Functioning at the Axial Limit.
Abstraction of a chloride ligand from the dysprosium metallocene [(Cpttt )2 DyCl] (1Dy Cpttt =1,2,4-tri(tert-butyl)cyclopentadienide) by the triethylsilylium cation produces the first base-free rare-earth metallocenium cation [(Cpttt )2 Dy]+ (2Dy ) as a salt of the non-coordinating [B(C6 F5 )4 ]- anion. Magnetic measurements reveal that [2Dy ][B(C6 F5 )4 ] is an SMM with a record anisotropy barrier up to 1277 cm-1 (1837 K) in zero field and a record magnetic blocking temperature of 60 K, including hysteresis with coercivity. The exceptional magnetic axiality of 2Dy is further highlighted by computational studies, which reveal this system to be the first lanthanide SMM in which all low-lying Kramers doublets correspond to a well-defined MJ value, with no significant mixing even in the higher doublets.


Identifying Risk Factors of Complications following Total Gastrectomy for Gastric Cancer: Comparison between Splenectomy and Spleen-Preserving Surgery - A Supplementary Analysis of JCOG0110.
Splenectomy for proximal gastric cancer was found to offer no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). Although many studies have explored risk factors for morbidities following total gastrectomy, none have assessed the risk factors for postoperative complications in spleen-preserving total gastrectomy. Using data from 505 patients enrolled in a previous randomized trial, risk factors for postoperative complications were identified by multivariable logistic regression analysis. Then, the risk factors were assessed separately between splenectomy and spleen-preserving total gastrectomy. Postoperative complications were identified in 119 patients (23.6%) and were more common following splenectomy than following spleen-preserving surgery (30.7% and 16.1%, respectively, p < 0.01). Multivariable analysis revealed that age ≥65 years (p = 0.032), body mass index ≥25 (p = 0.003), and blood loss ≥350 (p = 0.019) were independent risk factors for postoperative complications in the entire cohort. Among them, only body mass index was a significant independent risk factor for complications in both spleen preservation (p = 0.047) and splenectomy groups (p = 0.017). Risk factors for postoperative complications were essentially the same between splenectomy and spleen preservation. Being overweight increased the risk of postoperative complications.


[Fingolimod treatment in multiple sclerosis].
Multiple sclerosis (MS), an inflammatory disorder of the central nervous system, is characterized by relapsing-remitting (RR) clinical course. Fingolimod was the first oral therapy to prevent relapses in patients with RRMS, approved in Japan in 2011. In lymph node, fingolimod acts as functional antagonist, leading to internalization of sphingosine-1-phosphate 1(S1P1) receptors of lymphocytes. Lymphocytes in lymph nodes bearing S1P1 receptors cannot egress from lymph nodes. As a result, lymphocyte count in the circulation is reduced. Fingolimod showed reduced relapses, and suppressed the number of enhancing lesion and the progression of brain atrophy of brain MRI, however, it also showed some adverse effects such as bradycardia, herpes zoster infection, macular edema, liver dysfunction, and teratogenic properties. We proposed indications of fingolimod therapy, and reduced dosage therapy of fingolimod for patients with a lymphocyte count below 0.2 x 10(9) cells/L.


Cerebral Infarction Observed on Brain MRI in Unconscious Out-of-Hospital Cardiac Arrest Survivors: A Pilot Study.
Cumulative evidence regarding the use of brain magnetic resonance imaging (MRI) for predicting prognosis of unconscious out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM) is available. Theoretically, these patients are at a high risk of developing cerebral infarction. However, there is a paucity of reports regarding the characteristics of cerebral infarction in this population. Thus, we performed a pilot study to identify the characteristics and risk factors of cerebral infarction and to evaluate whether this infarction is associated with clinical outcomes. A single-center, retrospective, registry-based cohort study was conducted at Severance Hospital, a tertiary center. Unconscious OHCA survivors were registered and treated with TTM between September 2011 and December 2015. We included patients who underwent brain MRI in the first week after the return of spontaneous circulation. We excluded patients who underwent any endovascular interventions to focus on "procedure-unrelated" cerebral infarctions. We assessed hypoxic-ischemic encephalopathy (HIE) and procedure-unrelated cerebral infarction separately on MRI. Patients were categorized into the following groups based on MRI findings: HIE (-)/infarction (-), infarction-only, and HIE (+) groups. Conventional vascular risk factors showing p < 0.05 in univariate analyses were entered into multivariate logistic regression. We also evaluated if the presence of this procedure-unrelated cerebral infarction lesion or HIE was associated with a poor clinical outcome at discharge, defined as a cerebral performance category of 3-5. Among 71 unconscious OHCA survivors who completed TTM, underwent MRI, and who did not undergo endovascular interventions, 14 (19.7%) patients had procedure-unrelated cerebral infarction based on MRI. Advancing age [odds ratio (OR) 1.11] and atrial fibrillation (OR 5.78) were independently associated with the occurrence of procedure-unrelated cerebral infarction (both p < 0.05). There were more patients with poor clinical outcomes at discharge in the HIE (+) group (88.1%) than in the infarction-only (30.0%) or HIE (-)/infarction (-) group (15.8%) (p < 0.001). HIE (+) (OR 38.69, p < 0.001) was independently associated with poor clinical outcomes at discharge, whereas infarction-only was not (p > 0.05), compared to HIE (-)/infarction (-). In this pilot study, procedure-unrelated cerebral infarction was noted in approximately one-fifth of unconscious OHCA survivors who were treated with TTM and underwent MRI. Older age and atrial fibrillation might be associated with the occurrence of procedure-unrelated cerebral infarction, and cerebral infarction was not considered to be associated with clinical outcomes at discharge. Considering that the strict exclusion criteria in this pilot study resulted in a highly selected sample with a relatively small size, further work is needed to verify our findings.


Hyperactivity of human DNase I variants. Dependence on the number of positively charged residues and concentration, length, and environment of DNA.
Human DNase I, an enzyme used to treat cystic fibrosis patients, has been engineered to more effectively degrade double-stranded DNA to lower molecular weight forms by introducing positively charged amino acids at positions that can interact favorably with the proximal negatively charged phosphate groups of the DNA. A series of combination mutants having from one to six additional basic residues compared with the wild type has been constructed, expressed in human 293 cells, and characterized. The degree of hyperactivity for the mutants was highly dependent upon the conditions in various assays, including the concentration and length of the DNA substrate and the salt and divalent metal ion concentrations. The level of hyperactivity was inversely proportional to both DNA concentration and DNA length, consistent with the processive nicking mechanism for the hyperactive variants. Salt was inhibitory for wild type DNase I but actually enhanced the activity of the hyperactive variants. Under optimal conditions for wild type, variants with one additional positive charge possessed the highest activity, which was only severalfold greater than that for wild type. However, in the presence of low DNA concentrations and molecular weights, no Ca2+, and 150 mM NaCl, the variant with six engineered basic residues was most active, having >10,000-fold higher activity than the wild type enzyme. Therefore, any potential increase in potency for the hyperactive variants in vivo will be determined by the concentration, length, and environment of the DNA.


[Risk factors for recurrent hospitalizations of patients with atrial fibrillation].
Objective: To determine the predictors of recurrent hospitalizations among atrial fibrillation (AF) patients. Methods: We analyzed data from the Chinese Atrial Fibrillation Registry (CAFR), a prospective cohort study involving non-valvular atrial fibrillation (NVAF) patients from Augest 2011 to December 2017. A total of 5 349 NVAF patients with a minimum of 48 months follow-up were included for analysis. Data including patient demographics, complications, medical and ablation history were collected. The maximum number of all-cause hospitalizations within one-year for each patient served as the primary endpoint. Patients hospitalized less than twice within one-year were defined as non-recurrent hospitalizations group, those hospitalized at least twice within one-year were definned as recurrent hospitalizations group. Logistic regression model was used to identify associated risk factors for recurrent hospitalizations. Results: Of 5 349 NVAF patients, those hospitalized for 0, 1, 2, 3, 4 and at least 5 times within one-year was 2 703 (50.5%), 1 776 (33.2%), 642 (12.0%), 161(3.0), 52 (1.0%), 15 (0.3%), respectively. Eight hundred and seventy (16.3%) patients were included in recurrent hospitalizations group, 4 479 (83.7%) patients were included in non-recurrent hospitalizations group. Compare with non-recurrent hospitalizations group, patients in recurrent hospitalizations group was more likely to be older and female, more frequently had a history of hypertension, heart failure, coronary heart disesase, ischaemic stroke/transient ischaemic attack, diabetes mellitus, peptic ulcer, a AF duration for more than 1 year, medication including drugs for ventricular rate control, statin, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB) and higher CHA(2)DS(2)-VASc scores (P<0.05), but less frequently had higher education, a history of drinking, smoking and ablation (P<0.05). Multivariable analysis showed that age 50-64 (OR=1.47, 95%CI 1.20-1.80), age≥65 (OR=1.89, 95%CI 1.50-2.38), female (OR=1.21, 95%CI 1.01-1.46), hypertension history (OR=1.42, 95%CI 1.16-1.74), heart failure history (OR=1.73, 95%CI 1.37-2.18), coronary heart disease history (OR=1.63, 95%CI 1.31-2.03), peptic ulcer history (OR=2.00, 95%CI 1.18-3.39) were independent risk factors for recurrent hospitalizations, while higher education (college or above) (OR=0.82, 95%CI 0.69-0.99) was the protective factor for recurrent hospitalizations. Conclusions: Nearly 1 in 6 of AF patients were admitted to hospital more than once within one year in this NVAF cohort. Age≥50, female, hypertension history, heart failure history, coronary heart disease history, peptic ulcer history are associated with an increased risk of recurrent hospitalizations.


Agarose gel electrophoresis of cerebrospinal fluid proteins and analysis of the pherogram profiles by analog computer.
A micro-method of agarose gel electrophoresis requiring 1--3 ml of cerebrospinal fluid for quantitative analysis of cerebrospinal fluid proteins is described. After concentration of CSF to about 50 microliter by ultrafiltration and refractometric determination of protein, approximately 20--40 microgram of total protein are used for electrophoresis. Photometric scanning of the electrophoretic pattern at two different wavelengths permits quantitative evaluation. The pherograms are analysed by means of a modified DU-PONT analog computer. Factors which influence quantitative electrophoresis are examined. In cerebrospinal fluid of normal children 15 protein fractions are demonstrated: 2 prealbumins, albumin, 5 alpha-, 3 beta- and 4 gamma-globulins.


Rheological and structural properties of enzyme-induced gelation of milk proteins by ficin and Polyporus badius.
The rheological and microstructural characteristics of ewes' milk curd obtained by coagulating with milk-clotting enzymes, including ficin extract and Polyporus badius were evaluated. The gelation of milk was examined by small amplitude oscillatory shear measurements (SAOS). Different concentrations of ficin and P. badius extracts (1, 3, and 5%) were utilized to coagulate milk proteins. The ewes' samples containing ficin and mushroom enzymes were heated from 25 to 45°C at a heating rate 1°C/min and kept for 30 min. Then, the curds were cooled down to 25°C with the same heating rate. The ficin extract could induce stronger gels at 45°C and 5% ficin. Similar results were also found for 5% P. badius extract and incubation at 45°C. However, P.badius gels achieved a network with more viscous characteristics and had a softer texture than ficin gels. Therefore, it may be concluded the induced gels with mushroom had higher moisture and lower protein contents, which related to the high proteolytic activity of P. badius. The microstructure survey showed that the mushroom-induced gel had a more compact structure. By increasing enzyme concentration, both gels showed a coarser and more compact protein network. Whereas, the P. badius gels had more fusions and folds which indicate the greater proteolysis occurred during gelation and there was greater breakdown of protein. Our findings suggest the application of ficin and P. badius enzymes to develop a novel procedure to coagulate milk proteins and providing new structures in food systems.


WWOX, the common chromosomal fragile site, FRA16D, cancer gene.
Gross chromosomal rearrangements and aneuploidy are among the most common somatic genomic abnormalities that occur during cancer initiation and progression, in particular in human solid tumor carcinogenesis. The loss of large chromosomal regions as consequence of gross rearrangements (e.g. deletions, monosomies, unbalanced translocations and mitotic recombination) have been traditionally associated with the existence of tumor suppressor genes within the areas affected by the loss of genetic material. The long arm of chromosome 16 was identified as being frequently associated with structural abnormalities in multiple neoplasias, that led us to focus attention on the detailed genetic dissection of this region resulting in the cloning of the putative tumor suppressor gene, WWOX (WW domain containing Oxidoreductase). Interestingly, the WWOX gene resides in the very same region as that of the common chromosomal fragile site 16D (FRA16D). The WWOX gene encodes a protein that contains two WW domains, involved in protein-protein interactions, and a short chain dehydrogenase (SDR) domain, possibly involved in sex-steroid metabolism. We have identified the WWOX WW domain ligand as the PPXY motif confirming the biochemical activity of this domain. WWOX normally resides in the Golgi and we will demonstrate that Golgi localization requires an intact SDR. Inactivation of the WWOX gene during tumorigenesis can occur by homozygous deletions and possibly mutation, however, aberrantly spliced forms of WWOX mRNA have been observed even when one allele is still intact. The aberrantly spliced mRNAs have deletions of the exons that encode the SDR and these WWOX protein isoforms display abnormal intracellular localization to the nucleus possibly functioning as dominant negative inhibitors of full length WWOX. Thus, generation of aberrant transcripts of WWOX may represent a novel mechanism to functionally inactivate WWOX without genomic alteration of the remaining allele. In this article we will review the cloning and identification of WWOX as the target of FRA16D. In addition, we will discuss the possible biochemical functions of WWOX and present evidence that ectopic WWOX expression inhibits tumor growth.


A new method for measuring oxidative stress in claudicants during strenuous exercise using free radical derivatives of antipyrine as indicators: a pilot study.
Patients with intermittent claudication disease suffer from temporary lack of oxygen in the legs, caused by narrowing of arteries, resulting in ischemia and followed by reperfusion. The degree of oxidative stress present in 16 patients during strenuous exercise was determined using several indicators. Two derivatives of an exogenous marker, antipyrine (AP), (ie, p-hydroxyantipyrine, p-APOH, and o-hydroxyantipyrine, o-APOH), were assayed in plasma using HPLC-tandem-MS. Plasma malondialdehyde (assayed as thiobarbituric acid reactive species, TBARS) was also determined. The branchial/ankle blood pressure index (b-a index) was used to assess the severity of intermittent claudication disease, and plasma lactate concentration was also measured as an indicator of the ischemic situation. Plasma TBARS level did not change significantly after exercise. During the ischemic situation as well as during reperfusion, both free radical derivatives of antipyrine increased significantly in plasma (p < 0.01). Because p-APOH is also formed enzymatically in humans, the plasma ratio of o-APOH to AP appeared to be the most specific marker for oxidative stress in patients with intermittent claudication.


User-Information-Aware D2D Multicast File Distribution Mechanism.
There are a large number of redundant transmissions in current D2D multicast content delivery systems, which seriously reduces the utilization efficiency of resources. This paper designs a novel user-information-aware D2D video distribution mechanism. More specifically, by predicting users' video requests, the video can be pushed to potential service requesters while distributing video for service requesters. Firstly, the willingness of potential requesters to accept the pushed video is estimated based on the users' interests, the popularity of the videos and the residual-energy of the users' devices, and the user-demand-aware clustering algorithm is proposed. Secondly, considering social and interference information, the utility metric of D2D multicast is proposed to measure the value of content distribution service. Finally, this paper proposes a D2D video distribution mechanism to optimize the utility value. Simulation results show that the proposed mechanism significantly improves throughput, energy and spectrum efficiency compared to the traditional distribution mechanism.


Automatic Detection of Atrial Fibrillation from Single-Lead ECG Using Deep Learning of the Cardiac Cycle.
Objective and Impact Statement. Atrial fibrillation (AF) is a serious medical condition that requires effective and timely treatment to prevent stroke. We explore deep neural networks (DNNs) for learning cardiac cycles and reliably detecting AF from single-lead electrocardiogram (ECG) signals. Introduction. Electrocardiograms are widely used for diagnosis of various cardiac dysfunctions including AF. The huge amount of collected ECGs and recent algorithmic advances to process time-series data with DNNs substantially improve the accuracy of the AF diagnosis. DNNs, however, are often designed as general purpose black-box models and lack interpretability of their decisions. Methods. We design a three-step pipeline for AF detection from ECGs. First, a recording is split into a sequence of individual heartbeats based on R-peak detection. Individual heartbeats are then encoded using a DNN that extracts interpretable features of a heartbeat by disentangling the duration of a heartbeat from its shape. Second, the sequence of heartbeat codes is passed to a DNN to combine a signal-level representation capturing heart rhythm. Third, the signal representations are passed to a DNN for detecting AF. Results. Our approach demonstrates a superior performance to existing ECG analysis methods on AF detection. Additionally, the method provides interpretations of the features extracted from heartbeats by DNNs and enables cardiologists to study ECGs in terms of the shapes of individual heartbeats and rhythm of the whole signals. Conclusion. By considering ECGs on two levels and employing DNNs for modelling of cardiac cycles, this work presents a method for reliable detection of AF from single-lead ECGs.


Hepatopleural Fistula with Empyema Thoracis: A Rare Complication of Autosomal Dominant Polycystic Kidney Disease.
We report a 70-year-old man with autosomal dominant polycystic kidney disease (ADPKD) who presented with right-sided extended-spectrum beta-lactamases Escherichia coli empyema thoracis. Chest and abdominal computed tomography showed hepatopleural fistula. The patient refused a surgical operation and was treated with tube thoracotomy, percutaneous drainage of dominant liver cyst, and intravenous antibiotics. His symptoms improved after 2 months of nonsurgical treatment.


Pseudoseizures and dissociative disorders: a common mechanism involving traumatic experiences.
Patients with psychogenic non-epileptic seizures (pseudoseizures) have been diagnosed as having conversion disorder or dissociative disorder. Pseudoseizure patients frequently report a history of physical and sexual abuse, and traumatic experience is considered part of the mechanism for producing dissociation. Pseudoseizures may be a manifestation of dissociative disorder, especially when a history of sexual or physical abuse is documented. A common mechanism involving traumatic experience may be present in both pseudoseizures and dissociative disorders. A complete neurodiagnostic evaluation along with an awareness of this relationship is needed to provide appropriate care for this patient population.


Evaluation of Vitamin D Levels and Response to Therapy of Childhood Migraine.
Vitamin D deficiency and insufficiency are related with many neurological diseases such as migraine. The aim of this study was to investigate whether pediatric migraine is associated with vitamin D deficiency and the effect of vitamin D therapy on the frequency, duration, severity of migraine attacks, and Pediatric Migraine Disability Assessment (PedMIDAS). We retrospectively examined the patients' levels of calcium, phosphorus, parathyroid hormone, alkaline phosphatase, and 25-OH vitamin D of 92 pediatric migraine patients. The patients were divided into two groups: Group 1, which had low vitamin D levels and received vitamin D therapy, and group 2, which had normal vitamin D levels and did not receive vitamin D therapy. Migraine severity measured by the visual analog scale (VAS), migraine frequency, and duration as well as scores on the PedMIDAS questionnaire were compared with regard to the 25-OH vitamin D levels. In addition, pre- and posttreatment pedMIDAS scores, VAS, migraine frequency, and duration were compared with baseline values. A total of 34.7% patients had vitamin D insufficiency (vitamin D levels between 10 and 20 ng/mL), whereas 10.8% had vitamin D deficiency (vitamin D levels < 10 ng/mL). Migraine frequency, migraine duration, and PedMIDAS scores were significantly higher in the group 1 than group 2 (p = 0.004, p = 0.008, and p = 0.001). After vitamin D therapy at sixth months of supplementation, migraine duration was reported statistically significant shorter (p < 0.001) and the migraine frequency, VAS scores, and pedMIDAS scores were statistically significant lower compared with baseline values in group 1 (p < 0.001). We found a marked correlation between pediatric migraine and vitamin D levels. Vitamin D therapy was beneficial in migraine pediatric patients.


Chronic Autoimmune Meningoencephalitis and Periodic Fever Syndrome Treated with Anakinra.
We report the case of a 63-year-old male diagnosed with chronic autoimmune mediated meningoencephalitis and periodic cyclical fever syndrome. After 2 years of failed conventional treatment and recurrent hospitalizations, anakinra treatment (an interleukin-1 [IL-1] receptor antagonist) was trialed which resulted in full recovery. As evidenced by this case, anakinra can be used to treat chronic autoimmune meningitis, which can often be refractory to treatment.


Targeting of NF-κB to Dendritic Spines Is Required for Synaptic Signaling and Spine Development.
Long-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor κB (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine enrichment (p65ΔSE) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or p65ΔSE both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not p65ΔSE, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses.SIGNIFICANCE STATEMENT Extensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus specificity to gene regulation, ensuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.


The lived experiences of a male survivor of intimate partner violence: a qualitative case study.
The purpose of this phenomenological qualitative case study, analyzed using Colaizzi's (1978) method, was to gain a holistic understanding of the lived-experience of a male victim of intimate partner violence and the real-life context in which the violence emerged.


Multi-Scale Comparison of Physicochemical Properties, Refined Structures, and Gel Characteristics of a Novel Native Wild Pea Starch with Commercial Pea and Mung Bean Starch.
In the present study, the morphology, refined structure, thermal properties, and dynamic rheological, texture, and digestive properties of common vetch starch, a potential new type of legume starch, were systematically investigated, and compared with commercially available pea and mung bean starch. The results showed that the composition and chemical structure of common vetch starch were similar to the pea and mung bean starch. However, the amylose content (35.69), A-chain proportion (37.62), and relative crystallinity (34.16) of common vetch starch were higher, and the particle size and molecular weight (44,042 kDa) were larger. The value of pasting properties and enthalpy change (ΔH) of gelatinization of common vetch starch was lower and higher than mung bean and pea starch, respectively, and a lower swelling power and pasting index indicate that common vetch starch had higher hot-paste and cold-paste stability. In addition, common vetch starch gel exhibited good rheology, cohesiveness, and anti-digestive properties. These results provide new insights into the broader application of common vetch starch.


Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.
Paget disease of bone (PDB) is a common disorder characterized by focal and disorganized increases of bone turnover. Genetic factors are important in the pathogenesis of PDB. We and others recently mapped the third locus associated with the disorder, PDB3, at 5q35-qter. In the present study, by use of 24 French Canadian families and 112 unrelated subjects with PDB, the PDB3 locus was confined to approximately 300 kb. Within this interval, two disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the ubiquitin-binding protein sequestosome 1 (SQSTM1/p62), which is a candidate gene for PDB because of its association with the NF-kappaB pathway. Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals. Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients.


In vivo measurement method of ovarian dose during barium enema examinations.
Barium enema is currently the most commonly performed fluoroscopic procedure. In general, it is not possible to measure directly gonadal dose in women during this procedure. A measurement method to allow an estimate of radiation dose to the ovaries is described. The method uses thermoluminescent dosimeters attached to the tip of the rectal tube to measure radiation dose during procedures. A series of measurements was made at a university hospital equipped with an image-intensified, camera-based X-ray system and at a private clinic with a mirror-optics X-ray system. Measurements were made on both single contrast and double contrast barium enema examinations. On the image-intensified, camera-based X-ray system, the average results of dose measurements for single and double contrast barium enema were 3.11 mGy and 6.50 mGy and the results for the mirror optics system were 1.57 mGy and 3.64 mGy, respectively.


Impact of locoregional treatment on the early-stage breast cancer patients: a retrospective analysis.
Although adequate locoregional treatment improves local and regional control in early-stage breast cancer, uncertainty still exists about the role of locoregional therapy with respect to survival. To study the impact of surgery and radiotherapy on locoregional control and survival, we combined the data of three European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group trials including early-stage breast cancer patients with long-term follow-up. Risk ratios (RR) were estimated for locoregional recurrence and overall survival using Cox regression models. All analyses were adjusted for tumour size, nodal status, age, adjuvant radiotherapy, adjuvant chemotherapy and trial. The combined data-set consisted of 3648 patients. The median follow-up period was 11 years. 5.9% of the patients who underwent mastectomy and 10.8% of the patients who underwent breast-conserving therapy had a locoregional recurrence (P<0.0001). The risk of death after breast-conserving therapy was similar compared with mastectomy (RR 1.07, P=0.37). Adjuvant radiotherapy after mastectomy was associated with a lower risk for locoregional recurrence (RR 0.43, P<0.001) and death (RR 0.73, P=0.001). Patients with 1-3 positive nodes benefited the most from radiotherapy after mastectomy. Breast-conserving therapy was associated with an impaired locoregional control. However, breast-conserving therapy was not associated with a worse overall survival. Adjuvant radiotherapy in mastectomised patients was associated with both a significantly superior locoregional control and overall survival. The effect of adjuvant radiotherapy was most profound in patients who had 1-3 positive nodes.


Bisphosphonates and the dental patient: part 1.
This 2-part article is intended to educate readers on the current recommendations with regard to specific treatment for dental patients who will be starting or are currently taking the different types of bisphosphonate medications. The first article deals with the basic science and medicine surrounding the use of bisphosphonate medications. The second article will be clinically orientated, dealing with possible treatment options for dental patients who are on or will be starting bisphosphonate medications. These treatment options will be based on the most current literature available and the authors' experiences. However, readers should note that the newness of the subject matter and the research that is sure to follow will make some of these recommendations obsolete within a few years. Readers are invited to view this article not as the "final word" on this subject but rather as a foundation.


The Src family kinase inhibitors PP2 and PP1 effectively block TGF-beta1-induced cell migration and invasion in both established and primary carcinoma cells.
We have previously demonstrated that in pancreatic ductal adenocarcinoma (PDAC)-derived cell lines, the common Src family kinase inhibitors PP2 and PP1 effectively inhibited morphologic alterations associated with TGFβ1-mediated epithelial-to-mesenchymal transition (EMT) by blocking the kinase activity of the TGF-β type I receptor ALK5 rather than Src (Ungefroren et al. in Curr Cancer Drug Targets 11:524, 2011). In this report, the ability of PP2 and PP1, the more specific Src inhibitor SU6656, and the ALK5 inhibitor SB431542 to functionally block TGF-β1-dependent EMT and cell motility in established PDAC (Panc-1, Colo 357) and primary NSCLC (Tu459) cell lines were investigated. The effects of PP2, PP1, SU6656, and SB431542 on TGF-β1-dependent cell scattering/EMT, cell migration/invasion, and expression of invasion-associated genes were measured by using the real-time cell analysis assay on the xCELLigence system and quantitative real-time RT-PCR, respectively. In all three cell lines tested, PP1, PP2, and SB431542 effectively blocked TGF-β1-induced cell scattering/EMT, migration, and invasion and in Colo 357 cells inhibited the induction of the invasion-associated MMP2 and MMP9 genes. In contrast, SU6656 only blocked TGF-β1-induced invasion in Panc-1 and Tu459 but not Colo 357 cells. PP1, and to a greater extent PP2, also inhibited the high spontaneous migratory activity of Panc-1 cells expressing a kinase-active ALK5 mutant. These data provide evidence that PP2 and PP1 are powerful inhibitors of TGF-β-induced cell migration and invasion in vitro and directly target ALK5. Both agents may be useful as dual TGF-β/Src inhibitors in experimental therapeutics to prevent metastatic spread in late-stage PDAC and NSCLC.


Microarray analysis of the Escherichia coli response to CdTe-GSH Quantum Dots: understanding the bacterial toxicity of semiconductor nanoparticles.
Most semiconductor nanoparticles used in biomedical applications are made of heavy metals and involve synthetic methods that require organic solvents and high temperatures. This issue makes the development of water-soluble nanoparticles with lower toxicity a major topic of interest. In a previous work our group described a biomimetic method for the aqueous synthesis of CdTe-GSH Quantum Dots (QDs) using biomolecules present in cells as reducing and stabilizing agents. This protocol produces nanoparticles with good fluorescent properties and less toxicity than those synthesized by regular chemical methods. Nevertheless, biomimetic CdTe-GSH nanoparticles still display some toxicity, so it is important to know in detail the effects of these semiconductor nanoparticles on cells, their levels of toxicity and the strategies that cells develop to overcome it. In this work, the response of E. coli exposed to different sized-CdTe-GSH QDs synthesized by a biomimetic protocol was evaluated through transcriptomic, biochemical, microbiological and genetic approaches. It was determined that: i) red QDs (5 nm) display higher toxicity than green (3 nm), ii) QDs mainly induce expression of genes involved with Cd+2 stress (zntA and znuA) and tellurium does not contribute significantly to QDs-mediated toxicity since cells incorporate low levels of Te, iii) red QDs also induce genes related to oxidative stress response and membrane proteins, iv) Cd2+ release is higher in red QDs, and v) QDs render the cells more sensitive to polymyxin B. Based on the results obtained in this work, a general model of CdTe-GSH QDs toxicity in E. coli is proposed. Results indicate that bacterial toxicity of QDs is mainly associated with cadmium release, oxidative stress and loss of membrane integrity. The higher toxicity of red QDs is most probably due to higher cadmium content and release from the nanoparticle as compared to green QDs. Moreover, QDs-treated cells become more sensitive to polymyxin B making these biomimetic QDs candidates for adjuvant therapies against bacterial infections.


Conical intersection between the lowest spin-aligned Li3(4A') potential-energy surfaces.
We have calculated new potential-energy surfaces for the lowest two spin-aligned (4)A(') states of the Li(3) trimer. This calculation shows a seam of conical intersections between these states resulting from the extra symmetry of the system when the atoms are in a collinear arrangement. This seam is especially important because of its proximity to the three-body dissociation limit of the system; ultracold scattering calculations and the bound-state energies of the system will be affected by the presence of this conical intersection. In this paper we discuss the calculation of the potential-energy surface and the location of the conical intersection seam.


Generic antiepileptic drugs.
Generic antiepileptic drugs (AEDs) generally provide safe, effective, lower-cost alternatives to brand-name drugs. To be approved by the US Food and Drug Administration (FDA), manufacturers must show that generic drugs are comparable to brand-name formulations, meeting bioequivalence, dissolution, and manufacturing quality standards. Bioequivalence for most generic formulations is evaluated by measuring blood pharmacokinetic values in a small, crossover study of adult volunteers taking single doses of brand-name and generic AEDs. Bioequivalence standards require that ratios of average peak drug concentrations (C(max)) and total extent of absorption (area under the curve, AUC) for a test drug be within 80% to 125% of the reference brand-name drug, with a confidence interval of 90%. Bioequivalence of most generic AEDs, however, has not been evaluated in patients with epilepsy or in other special populations such as elderly patients or patients taking multiple AEDs and prodrugs. Moreover, evidence is limited regarding the adequacy of FDA generic standards for AEDs, particularly for "narrow therapeutic ratio" medications such as oxcarbazepine, although two carbamazepine studies are supportive. Most patients can successfully initiate therapy with generic AEDs and can safely switch from brand-name to generic AEDs (and sometimes back again). The FDA, however, has not shown safety in generic-to-generic switches, which could potentially cause drug concentration changes of up to 40%. Less expensive generic formulations will soon be available for most of the "second generation" AEDs--onisamide, for example, recently had 17 generic formulations approved in the United States--providing substantial savings in health care costs. In summary, although generic AEDs are generally safe and effective for most patients, the current bioequivalence standards may not be sufficient for certain patient populations and for certain drugs, requiring vulnerable patients to be monitored very carefully when converting to generic AEDs. The adequacy or inadequacy of FDA bioequivalence standards for AEDs has not yet been well evaluated with large, well-controlled studies.


m7G tRNA modification reveals new secrets in the translational regulation of cancer development.
Orellana et al. (2021) and Dai et al. (2021) demonstrate that increased m7G modification of a subset of tRNAs by the METTL1/WDR4 complex stabilizes these mRNAs against decay, increases translation efficiency, reduces ribosome pausing, is associated with poor survival in human cancers, and is directly transforming.


Distortion of anterior airway anatomy during laryngoscopy with the GlideScope videolaryngoscope.
A non-line-of-sight view is expected to cause less movement of the anterior airway anatomy and cervical spine during laryngeal visualization. Reduced distortion of anterior airway anatomy during laryngoscopy with the GlideScope videolaryngoscope (GVL), compared with the Macintosh laryngoscope, could explain the relatively easier nasotracheal intubation with the GVL. The purpose of this radiographic study was to compare the degree of anterior airway distortion and cervical spine movement during laryngoscopy with the GVL and the conventional Macintosh laryngoscope. Twenty patients requiring general anesthesia and tracheal intubation were studied. Each patient underwent laryngoscopy using the first-generation GVL and a direct laryngoscope with a Macintosh blade. During each laryngoscopy, a radiograph was taken when the best view of the larynx was obtained. Independent radiologists with subspeciality training in musculoskeletal imaging evaluated anterior airway distortion and cervical spine movement. The distance between the epiglottis and the posterior pharyngeal wall during the GlideScope procedure was 21% less than that during the Macintosh laryngoscopy (P < 0.05). Anterior deviations of the vertebral bodies from baseline were 27, 32, 36, and 39% less at the atlas, C2, C3, and C4 vertebrae, respectively, during the GlideScope procedure than those measured during Macintosh laryngoscopy (P < 0.01). Cervical extension between the occiput and C4 during the GlideScope procedure was 23% less than that during Macintosh laryngoscopy (P < 0.05). Both anterior airway distortion and cervical spine movement during laryngeal visualization were less with the GVL than with the Macintosh laryngoscope.


An evaluation of systemic reforms of public hospitals: the Sanming model in China.
Low- and middle-income countries (LMICs) have been searching for effective strategies to reform their inefficient and wasteful public hospitals. Recently, China developed a model of systemic reforms called the Sanming model to address the inefficiency and waste at public hospitals. In this article, we explain and evaluate how the Sanming model reformed its 22 public hospitals in 2013 by simultaneously restructuring the hospital governance structure, altering the payment system to hospitals, and realigning physicians' incentives. By employing the difference-in-difference (DID) method and using the hospital-level data from 187 public hospitals in Fujian province, we find that the Sanming model has reduced medical costs significantly without measurably sacrificing clinical quality and productive efficiency. The systemic reform, on average, has reduced the medical care cost per outpatient visit and per inpatient admission by 6.1% (P-value = 0.0445) and 15.4% (P-value < 0.001), respectively. It is largely accomplished through a decrease in drug expenditures per outpatient visit and per inpatient admission of about 29% (P-value < 0.001) and 53% (P-value < 0.001). These results show that the Sanming model has achieved at least a short-term success in improving the performance of the public hospitals. These findings suggest that such a systemic transformation of public hospitals, where the governance structure, payment system and physician compensation methods are aligned, are crucial to improving their performance; it holds critical lessons for China and other LMICs.


Impact of different levels of low-fat dried distillers grains on performance of young Nellore bulls during the finishing phase.
This study evaluated the effect of including low-fat dried distillers grains (DDG) on young Nellore bulls performance, nutritional parameters, and nitrogen metabolism. Thirty-five Nellore cattle were randomly divided into four diets: without dried distillers grains (D0) or with the inclusion of DDG at 150 g/kg (D150), 300 g/kg (D300), or 450 g/kg (D450). The evaluation period lasted 126 days, and three periods of collection of feces and urine were carried out. Final body weight (P = 0.099) and average daily gain (P = 0.097) tended to decrease linearly; the digestibility of dry matter (P < 0.001), organic matter (P < 0.001), ether extract (P < 0.001) and nonfiber carbohydrates (P < 0.001), and intakes of total digestible nutrients (TDN, P < 0.001) decreased linearly. The increase in crude protein intake (P < 0.001) did not result in an increase in the amount of nitrogen retained (P = 0.540). We concluded that the inclusion of low-fat DDG in finishing diets up to the level of 450 g/kg tends to reduce animal performance and the intake of TDN.


Between stigmatisation and regulation: prostitution in colonial Northern Vietnam.
Colonisation was a masculine adventure which took place in a distorted world full of 'welcoming' native women. The colonial encounter therefore was both racial and gendered: boundaries between European men and Vietnamese women were obvious. On the other hand the intimacy that resulted from this encounter blurred the racial boundaries that were the foundation of the colonial order. These boundaries had to be redrawn or sharpened. Focusing on French colonial northern Vietnam (Tonkin) this paper examines how the whole colonial encounter was embodied in the sexual encounter between European men and native women and how prostitution was an integral part of the colonial order. This analysis of the regulation of prostitution and its ambivalence reveals that the definition of prostitution and its treatment by the French colonial authorities was political, racial and therefore connected to a specific period. The political definition of prostitution in today's Vietnam is different from the colonial one. This shift reveals that prostitution is a pertinent vantage point from which one can study how a society apprehends itself and its own future.


[Urinary biomarkers of kidney injury in patients treated with anti-VEGF drugs].
Antiangiogenic drugs are widely used in oncological practice and are aimed at inhibiting angiogenesis. Despite the high antitumor efficacy, their use may be limited by nephrotoxicity, and therefore the search for early biomarkers of kidney damage remains relevant, which will preserve a favorable safety profile of therapy. To determine urinary biomarkers of tubular and podocyte damage in patients receiving treatment with antiangiogenic drugs. The study included patients (n=50) who received intravenous anti-VEGF drugs (aflibercept, bevacizumab, ramucirumab) in various chemotherapy regimens. Concentrations of tubular damage markers KIM-1 (Kidney Injury Molecule-1) and NGAL (Neutrophil Gelatinase-Associated Lipocalin), hypoxia marker HIF-1 (Hypoxia-Inducible Factor 1-alpha) in urine samples were determined by enzyme-linked immunosorbent assay (ELISA) before treatment, and during 8 weeks of treatment. To assess the risk factors for kidney damage, a logistic regression analysis was performed with the inclusion of the main clinical and laboratory parameters. A decrease in the calculated GFR of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Formula) of less than 60 ml/min per 1.73 m2 at week 8 of treatment was noted in 42% of patients. An increase in NGAL, KIM-1, HIF-1 and nephrin in urine during the first two weeks of therapy predicted the development of renal damage by the 8th week of follow-up. When constructing ROC-curves, the high sensitivity and specificity of these urinary indicators as prognostic markers were established. Among the clinical and laboratory indicators, independent unfavorable prognostic factors of nephrotoxicity were an initial decrease in eGFR, a history of hypertension, an increase in the concentration of KIM-1 and HIF-1 in urine during the first two weeks of therapy. The predictors of renal damage in the treatment with antiangiogenic drugs were previously an increase in NGAL, KIM-1 and HIF-1 in urine during the first two weeks after the start of therapy.


Lysophosphatidylcholine Acyltransferase-3 Expression Is Associated with Atherosclerosis Progression.
Free arachidonic acid (AA) is an important precursor of lipid mediators such as leukotrienes and prostaglandins that induces inflammation and is associated with atherosclerosis progression. Recent studies have shown that lysophosphatidylcholine acyltransferase-3 (LPCAT3) converts lysophosphatidylcholine (LPC) and free AA into phosphatidylcholine (PC)-containing AA (arachidonyl-PC) and thereby can regulate intracellular free-AA levels. However, the association between LPCAT3 and atherosclerosis remains to be established. In this study, we analyzed human and mouse atherosclerotic tissues to gain insight into the arachidonyl-PC metabolism involving LPCAT3 using imaging mass spectrometry. The data revealed a complementary distribution of arachidonyl-PC and LPC in human atherosclerotic tissues with arachidonyl-PC decreasing and LPC increasing as atherosclerosis progressed. Furthermore, we found a homologous distribution of LPCAT3 expression and arachidonyl-PC based on atherosclerotic progression. In contrast, in ApoE-deficient mice, atherosclerosis increased both arachidonyl-PC accumulation and LPCAT3 expression. Taken together, these findings suggest that the regulation of LPCAT3 expression might be associated with atherosclerotic progression in humans.


Split liver transplantation: What's unique?
The intraoperative management of split liver transplantation (SLT) has some unique features as compared to routine whole liver transplantations. Only the liver has this special ability to regenerate that confers benefits in survival and quality of life for two instead of one by splitting livers. Primary graft dysfunction may result from small for size syndrome. Graft weight to recipient body weight ratio is significant for both trisegmental and hemiliver grafts. Intraoperative surgical techniques aim to reduce portal hyperperfusion and decrease venous portal pressure. Ischemic preconditioning can be instituted to protect against ischemic reperfusion injury which impacts graft regeneration. Advancement of the technique of SLT is essential as use of split cadaveric grafts expands the donor pool and potentially has an excellent future.


Primary care of the premature infant discharged from the neonatal intensive care unit.
Premature infants require varying degrees of newborn intensive care and have a wide range of physical and developmental outcomes. Subsequent ambulatory care for these infants is often complex. Although tertiary hospitals often provide multidisciplinary follow-up clinics, the pediatric nurse practitioner (PNP) responsible for primary care has a unique opportunity to influence the lives of these special babies and their families. While the basic principles of well child care and health maintenance apply to this special population, there are several inherent challenges. The transition from neonatal intensive care unit (NICU) to home can be stressful for families. Infants born prematurely often have unpredictable behavior and present with cues that are vague and unclear to caregivers. Growth must be monitored adjusting for prematurity, and nutrition must be tailored to the physical and developmental level of the infant. Assessments of development, vision, and hearing must also be adjusted for prematurity. Fortunately, the majority of premature infants discharged from the NICU thrive and develop normally. However, some will experience medical problems and developmental delay. Knowledge of complications common to premature infants will be helpful to the PNP providing primary care. These include difficulties of growth and feeding, gastroesophageal reflux, apnea and bradycardia, chronic lung disease, fine and gross motor abnormalities, and other learning problems. Providing care to the NICU graduate is one of the challenges faced by PNPs in primary care, but one that is both rewarding and enjoyable.


Work-related stress and blood pressure: current theoretical models and considerations from a behavioral medicine perspective.
There is extensive evidence that the prevalence of human hypertension is related to psychosocial factors, possibly including chronic exposure to stress. A tripartite model, consistent with the literature on stress and health, may help to define this relationship better. Its 3 components are environmental stressors, individual factors affecting the perception of stress, and the individual's physiological susceptibility. To date, researchers have looked at individual parts of this model, but rarely at all 3. Some models of work stress (e.g., the job strain, effort-reward, and person-environment fit models) focus on work-related stressors alone or in conjunction with individual characteristics. Other models (e.g., the defense-defeat, John Henryism, and reactivity models) focus on individual differences in response, with little attention paid to the nature of the stressors. The authors suggest that it is timely to integrate these approaches and to look for physiological mechanisms.


Safety and effectiveness of the Bonebridge transcutaneous active direct-drive bone-conduction hearing implant at 1-year device use.
The objective of this study is to evaluate the safety and efficacy of a new transcutaneous bone-conduction implant (BCI BB) in patients with conductive and mixed hearing loss or with single-sided deafness (SSD), 1 year after surgical implantation. The study design is multicentric prospective, intra-subject measurements. Each subject is his/her own control. The setting is nine university hospitals: 7 French and 2 Belgian. Sixteen subjects with conductive or mixed hearing loss with bone-conduction hearing thresholds under the upper limit of 45 dB HL for each frequency from 500 to 4000 Hz, and 12 subjects with SSD (contralateral hearing within normal range) were enrolled in the study. All subjects were older than 18 years. The intervention is rehabilitative. The main outcome measure is the evaluation of skin safety, audiological measurements, benefit, and satisfaction questionnaires with a 1-year follow up. Skin safety was rated as good or very good. For the mixed or conductive hearing loss groups, the average functional gain (at 500 Hz, 1, 2, 4 kHz) was 26.1 dB HL (SD 13.7), and mean percentage of speech recognition in quiet at 65 dB was 95 % (vs 74 % unaided). In 5/6 SSD subjects, values of SRT in noise were lower with BB. Questionnaires revealed patient benefit and satisfaction. The transcutaneous BCI is very well tolerated at 1-year follow up, improves audiometric thresholds and intelligibility for speech in quiet and noise, and gives satisfaction to both patients with mixed and conductive hearing loss and patients with SSD.


Understanding the Microscopic Behavior of the Mixture of Ionic Liquid/Ethylene Glycol/Lithium Salt through Time-Resolved Fluorescence, Nuclear Magnetic Resonance (NMR), and Electron Paramagnetic Resonance (EPR) Studies.
The present study has been undertaken with an aim to find out the suitability of a binary solvent system, comprising an anionic liquid, 1-(2-hydroxyethyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([OHEMIM][NTf2]) and ethylene glycol (EG), toward lithium ion battery applications. For this purpose, the behavior in terms of structure, intermolecular interaction, and dynamics of several solvent systems, [OHEMIM][NTf2], [OHEMIM][NTf2]-LiNTf2(lithium bis(trifluorimethylsulfonyl)imide), [OHEMIM][NTf2]-EG, and [OHEMIM][NTf2]-EG-LiNTf2, is investigated by carrying out steady state and time-resolved fluorescence, nuclear magnetic resonance (NMR), and electron paramagnetic resonance (EPR) measurements. Both steady-state fluorescence and EPR studies have pointed out that the micropolarities of [OHEMIM][NTf2]-EG-LiNTf2 are close to those of neat RTIL. However, studies on rotational dynamics have revealed that the structural organization of [OHEMIM][NTf2]-LiNTf2 is significantly influenced upon addition of EG. Interestingly, the average solvation time is observed to be relatively faster in [OHEMIM][NTf2]-EG-LiNTf2 than those in other solvent systems. Since average solvation time and conductivity are inversely related to each other, the present observation indicates that the introduction of EG is helpful in increasing the electrical conductivity of [OHEMIM][NTf2]-EG-LiNTf2. Translational diffusion coefficient measurements in [OHEMIM][NTf2]-EG-LiNTf2 and [OHEMIM][NTf2]-LiNTf2 through NMR spectroscopy have also indicated the suitability of [OHEMIM][NTf2]-EG-LiNTf2 as a potential electrolytic medium for battery applications.


An Epitope-Specific Respiratory Syncytial Virus Vaccine Based on an Antibody Scaffold.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children. We have generated an epitope-specific RSV vaccine by grafting a neutralizing epitope (F-epitope) in its native conformation into an immunoglobulin scaffold. The resulting antibody fusion exhibited strong binding affinity to Motavizumab, an RSV neutralizing antibody, and effectively induced potent neutralizing antibodies in mice. This work illustrates the potential of the immunoglobulin molecule as a scaffold to present conformationally constrained B-cell epitopes.


Cut turnover costs with five rights of hiring.
Effective nurse leaders recruit, place, and retain staff. Here's how to educate your managers to perform the five rights of hiring just as nurses use the five rights of medication administration.


Ischemia alters the electrical activity of pacemaker cells isolated from the rabbit sinoatrial node.
The purpose of this study was to investigate the mechanisms responsible for ischemia-induced changes in spontaneous electrical activity. An ischemic-like Tyrode solution (pH 6.6) reversibly depolarized the maximum diastolic potential (MDP) and reduced the action potential (AP) overshoot (OS). We used SNARF-1, which is an indicator of intracellular pH (pH(i)), and perforated-patch techniques to test the hypothesis that acidosis caused these effects. Acidic but otherwise normal Tyrode solution (pH 6.8) produced similar effects. Basic Tyrode solution (pH 8.5) hyperpolarized the MDP, shortened the AP, and slowed the firing rate. In the presence of "ischemic" Tyrode solution, hyperpolarizing current restored the MDP and OS to control values. HOE-642, an inhibitor of Na/H exchange, did not alter pH(i) or electrical activity and did not prevent the effects of ischemic Tyrode solution or recovery after washout. Time-independent net inward current but not hyperpolarization-activated inward current was enhanced by ischemic Tyrode solution or by 30 microM BaCl(2), a selective blocker of inward-rectifying K currents at this concentration. The results suggest that 1) acidosis was responsible for the ischemia-induced effects but Na/H exchange was not involved, 2) the OS was reduced because of depolarization-induced inactivation of inward currents that generate the AP upstroke, and 3) reduction of an inward-rectifying outward K current contributed to the depolarization.


Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.


Acute hypertensive emergencies in pregnancy.
Obstetrical hypertensive emergencies are life-threatening conditions involving significant risk to both the mother and fetus. Aggressive treatment of the maternal hypertensive state requires an initial consideration of the effect of treatment on the fetus, via changes to the uteroplacental circulation with treatment. The challenge then is to correct blood pressure using appropriate, safe pharmacologic agents to prevent catastrophic maternal consequences, while minimizing acute changes to placental perfusion and any corresponding fetal ill effects. Hypertension in pregnancy may be one manifestation of a multiple-system pathologic process, as is the case in preeclampsia. Blood pressure control, along with delivery, will be the first step in treating the renal, hematologic, hepatic, and cardiac dysfunction that can be seen in preeclampsia. A review of medications most commonly used for hypertensive emergencies in pregnancy. Hypertensive emergencies in pregnancy require prompt evaluation and treatment in an intensive care setting to prevent untoward effects to both the fetus and mother.


Simultaneous study of gastric and pancreatic secretion in a preparation perfused ex vivo.
A canine gastroduodenopancreatic block was isolated and perfused ex vivo with homologous blood. This preparation allowed a simultaneous collection of gastric and pancreatic secretion under various conditions of stimulation. To stimulate gastric secretion, pentagastrin, bethanechol chloride or histamine was infused intra-arterially during a six to eight hour period, or both vagi were electrically stimulated. To stimulate pancreatic secretion, secretin was infused by the same method. Secretin infusion inhibited gastric juice volume and acid output by stimulated stomachs and induced an increase in pepsin concentration. Secretin infusion also resulted in a significant increase of flow of pancreatic juice and in both concentration and output of pancreatic secretion of bicarbonate. Arterial perfusion pressure and peripheral vascular resistance of this ex vivo preparation were significantly reduced by secretin. The method described permits the simultaneous study of the secretory function of the stomach and pancreas as well as the evaluation of biochemical changes of perfusion blood and hemodynamic changes in the circuit. Easy accessibility of the vessels and vagus branches also allows direct infusion of drugs and placement of stimulation electrodes.


Animal models of drug-resistant epilepsy.
It is not known why and how epilepsy becomes drug resistant in 20-30% of patients, while other patients with seemingly identical seizure types can achieve control of seizures with medication. An animal model of epilepsy allowing selection of pharmacoresistant and pharmacosensitive subgroups of animals would be a valuable tool to study mechanisms of pharmacoresistance and to develop more effective treatment strategies. Only a few models are available which mimic patterns of drug resistance in humans with epilepsy. One model seems to be particularly interesting: amygdala-kindled rats. In this model in Wistar rats, animals which do not respond to repeated or chronic administration of anti-epileptic drugs (non-responders) can be separated from animals in whom anti-epileptics are effective (responders). Hence, pharmacoresistant subgroups of kindled rats provide a unique tool to study why seizures become intractable, particularly because pathophysiological processes in these resistant rats can be directly compared with those of kindled rats that respond to treatment. By using this model, we have recently shown that both the individual genetic background and kindling-induced processes determine whether a rat becomes a responder or a non-responder to anticonvulsant treatment after kindling. We are currently studying the cellular mechanisms underlying the development of drug-resistant kindled seizures.


[Systemic enzyme therapy for treatment of women with chronic recurrent bacterial cystitis].
In most cases, treatment of infectious and inflammatory diseases, including lower urinary tract infections, includes antibacterial drugs. However, their efficiency decreases every year. The absence of new groups of antibiotics makes it necessary to develop alternative treatment schemes and methods for improving efficiency of existing drugs. Systemic enzyme therapy is one of the promising directions in the treatment of lower urinary tract infections, which was shown to be effective for treating a number of diseases. to evaluate the results of complex treatment of women with chronic recurrent bacterial cystitis using a drug for systemic enzyme therapy. The examination and treatment of 60 women aged 19 to 45 years with an exacerbation of chronic recurrent bacterial cystitis, who were randomly divided into two groups of 30 patients, was performed. In the group 1, patients received standard antibiotic therapy. In the group 2, women additionally received Phlogenzym. An evaluation of the efficiency was carried out on the 1st, 7th and 14th day and included analysis of lower urinary tract symptoms, according to bladder diaries, assessment of pain intensity and laboratory tests (C-reactive protein [CRP], IL-6, IL-1, TNF. During long-term follow-up (6 months after completion of treatment), the relapse rate was evaluated in both groups. At admission, all women had clinical and laboratory signs of cystitis. By the 14th day, there was normalization of evaluated parameters in both groups. However, in patients receiving systemic enzyme therapy a more rapid relief of the inflammatory process (a decrease in the frequency of urination, urgency, nocturia, severity of inflammatory changes in the blood and urine) by the 7th day of treatment was observed. During a further 6-month follow-up, relapses were detected in 9 (30%) and 4 (13.3%) patients in group 1 and 2, respectively. The results of the study demonstrated the high efficiency of systemic enzyme therapy. Its use for complex treatment provides more rapid relief of lower urinary tract symptoms and pain, as well as reduces the number of relapses in women with chronic recurrent bacterial cystitis.


Novel models for Parkinson's disease and their impact on future drug discovery.
Parkinson's disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson's Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times. Areas covered: The authors provide an outline of the various traditional models of Parkinson´s disease and address those that have been recently generated. They also discuss the utility of these models for the identification of drugs of potential therapeutic value for Parkinson´s Disease patients. From the cell based models and the well-known toxin-based animal models, to the recent genetic models and the increasingly used non-mammalian models, every model is worthwhile in the search for a better Parkinson´s Disease therapy. Expert opinion: Almost 60 years after its discovery, levodopa is still the gold standard treatment for Parkinson's Disease patients. It seems unlikely that a single model can fully recapitulate the complexity of Parkinson's Disease in the same way it appears improbable that a unique treatment could relieve both the motor and non-motor symptoms of Parkinson's Disease altogether. Therefore treatment will probably require a combination of therapies.


Air Pollution and Prosocial Behavior in Chinese Adolescents: The Role of Resilience and Interpersonal Relations.
Past studies have indicated that air pollution is a major environmental factor that negatively affects prosocial behavior in adolescents. However, the mechanism underlying this negative relationship has not been fully explored. This study postulated that this impact may occur through individual resilience, a major psychological capital for adolescents. In addition, we studied interpersonal relations, namely, adolescents' perceived family and teacher support, which may moderate the proposed relationship. This study combined the three-year tracking survey data of 11-to-15 old adolescents (N=1301; approximately 48% female) in China with objective data from the air quality index (AQI) to measure the level of air pollution. Findings from ordinary least squares analysis indicated that air pollution negatively influences adolescents' prosocial behavior, and their resilience mediates this negative relationship. In addition, the results showed that the negative effect of air pollution on adolescent resilience is attenuated by higher family income, whereas it is accentuated by the absence of teacher support. Our study provides insight into how the negative effect of air pollution on adolescents' prosocial behavior is mediated by their psychological resilience, and highlights the moderating role of adolescents' interpersonal relations in the association between air pollution and their psychological resilience. Our research also provides practical advice on how families, teachers, and psychologists can mitigate this negative impact.


SCOTCH: subtype A coreceptor tropism classification in HIV-1.
The V3 loop of the gp120 glycoprotein of the Human Immunodeficiency Virus 1 (HIV-1) is considered to be responsible for viral coreceptor tropism. gp120 interacts with the CD4 receptor of the host cell and subsequently V3 binds either CCR5 or CXCR4. Due to the fact that the CCR5 coreceptor is targeted by entry inhibitors, a reliable prediction of the coreceptor usage of HIV-1 is of great interest for antiretroviral therapy. Although several methods for the prediction of coreceptor tropism are available, almost all of them have been developed based on only subtype B sequences, and it has been shown in several studies that the prediction of non-B sequences, in particular subtype A sequences, are less reliable. Thus, the aim of the current study was to develop a reliable prediction model for subtype A viruses. Our new model SCOTCH is based on a stacking approach of classifier ensembles and shows a significantly better performance for subtype A sequences compared to other available models. In particular for low false positive rates (between 0.05 and 0.2, i.e. recommendation in the German and European Guidelines for tropism prediction), SCOTCH shows significantly better prediction performances in terms of partial area under the curves and diagnostic odds ratios compared to existing tools, and thus can be used to reliably predict coreceptor tropism for subtype A sequences. SCOTCH can be downloaded/accessed at http://www.heiderlab.de.


Expression feature of CD3, FcεRIγ, and Zap-70 in patients with chronic lymphocytic leukemia.
In leukemia patients, T-cell function has been suppressed with the disease progress. Patients with chronic lymphocytic leukemia (CLL) are all to a degree immunodeficient. In order to elucidate the feature of T-cell receptor signal transduction in CLL, the expression levels of CD3γ, δ, ε, and ζ chain, FcεRIγ, and Zap-70 genes in peripheral blood mononuclear cells (PBMCs) were analyzed. Real-time polymerase chain reaction with SYBR Green technique was used for detecting the gene expression level in PBMCs from 13 patients with CLL, 13 healthy individuals, and 10 B-cell acute lymphocytic leukemia (B-ALL) served as control. The β2-microglobulin gene was used as an endogenous reference. Relative mRNA expression level of genes was analyzed by using the 2(-ΔCt) × 100% method. Significant lower expression levels of CD3γ, ε, and ζ chain genes, as well as FcεRIγ gene were found in CLL samples. Moreover, there was lost the negative correlation of the expression levels between CD3ζ and FcεRIγ genes. The expression level of Zap-70 in CLL was lower than those from healthy controls, while higher than those from B-ALL group. There was no significant correlation between the expression levels of CD3ζ and Zap-70 genes neither in the healthy group nor in the CLL group. In conclusion, the results provide a global gene expression profile of CD3γ, δ, ε, and ζ chains, and the CD3ζ-related genes FcεRIγ and Zap-70 in CLL. Deficiency of these gene expression levels might represent the feature related to T-cell immunodeficiency. The study might contribute to better understand the cellular immune features in CLL patients.


Influence of Pilocarpine Eyedrops on the Ocular Biometric Parameters and Intraocular Lens Power Calculation.
To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power calculation in patients with primary angle-closure glaucoma (PACG). Twenty-two PACG patients and fifteen normal subjects were enrolled. Ocular biometric parameters including the axial length (AL), anterior chamber depth (ACD), lens thickness (LT), mean keratometry (Km), and white-to-white distance (WTW) were measured by using a Lenstar LS 900 device before and at least 30 minutes after instillation of 2% pilocarpine eyedrops. Lens position (LP) was calculated, and the IOL power prediction based on the ocular biometric parameters was performed using the Barrett Universal II, Haigis, Hoffer Q, Holladay I, or SRK/T formulas before and after pilocarpine application. In both PACG and normal groups, pilocarpine eyedrops induced a slight but statistically significant increase in the mean AL (0.01 mm for both groups) and mean LT (0.02 mm and 0.03 mm, respectively) but a significant decrease in the mean ACD (0.03 mm and 0.05 mm, respectively) and mean LP (0.02 mm and 0.04 mm, respectively). No significant changes in the mean Km and WTW were noticed in both groups. In addition, the IOL power calculation revealed insignificant changes before and after the pilocarpine instillation in both groups, regardless of the formula used. Pilocarpine eyedrops can induce slight changes in the ocular biometric parameters including the AL, ACD, LT, and LP. However, these parameter changes will not result in a significant difference in IOL power estimation.


Krüppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer.
Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that functions as an oncogene or tumor suppressor in a highly tissue-specific cell-dependent manner. However, its precise role in breast cancer and metastasis remains unclear. Here, we show that transient adenoviral expression of KLF4 in the 4T1 orthotopic mammary cancer model significantly attenuated primary tumor growth as well as micrometastases to the lungs and liver. These results can be attributed, in part, to decreased proliferation and increased apoptosis. Further supporting a tumor-suppressive role for KLF4 in the breast, we found that KLF4 expression is lost in a mouse model of HER2/NEU/ERBB2-positive breast cancer. To determine whether enforced KLF4 expression could alter tumor latency in these mice, we used a doxycycline-inducible expression model in the context of the MMTV-Neu transgene. Surprisingly, tumors that developed in this model also lost KLF4 expression, suggesting negative selection for sustained expression. We have previously reported that KLF4 inhibits epithelial-to-mesenchymal transition (EMT), a preliminary step in metastatic progression. Overexpression of KLF4 in 4T1 cells led to a significant reduction in the expression of Snail, a key mediator of EMT and metastasis. Conversely, KLF4 silencing increased Snail expression in the nontransformed MCF-10A cell line. Collectively, these data demonstrate the first functional, in vivo evidence for KLF4 as a tumor suppressor in breast cancer cells. Furthermore, our findings suggest an inhibitory role for KLF4 during breast cancer metastases that functions, in part, through repression of Snail.


Toward single-cell analysis by plume collimation in laser ablation electrospray ionization mass spectrometry.
Ambient ionization methods for mass spectrometry have enabled the in situ and in vivo analysis of biological tissues and cells. When an etched optical fiber is used to deliver laser energy to a sample in laser ablation electrospray ionization (LAESI) mass spectrometry, the analysis of large single cells becomes possible. However, because in this arrangement the ablation plume expands in three dimensions, only a small portion of it is ionized by the electrospray. Here we show that sample ablation within a capillary helps to confine the radial expansion of the plume. Plume collimation, due to the altered expansion dynamics, leads to greater interaction with the electrospray plume resulting in increased ionization efficiency, reduced limit of detection (by a factor of ~13, reaching 600 amol for verapamil), and extended dynamic range (6 orders of magnitude) compared to conventional LAESI. This enhanced sensitivity enables the analysis of a range of metabolites from small cell populations and single cells in the ambient environment. This technique has the potential to be integrated with flow cytometry for high-throughput metabolite analysis of sorted cells.


Pseudomonas aeruginosa infection among cystic fibrosis and ICU patients in the referral children medical hospital in Tehran, Iran.
Pseudomonas aeruginosa is one of the important causes of hospital-acquired infections in Intensive Care Unit (ICU) and considered as a major determinant of morbidity and mortality in patients affected by cystic fibrosis (CF). The aim of this study was to investigate clonal diversity among randomly picked P. aeruginosa isolates of CF and the other hospitalized patients in ICU. Cultivation, identification, and antimicrobial susceptibility testing of P. aeruginosa isolates were performed using standard techniques. The genetic similarity of the strains was investigated by amplification of the Enterobacterial Repetitive Intergenic Consensus-polymerase chain reaction (ERIC-PCR) sequence. Among 49 isolates, sixteen were isolated from 11 patients affected by CF and 33 came from an epidemiological investigation of 25 P. aeruginosa infected patients of ICU. Five clusters were generated for all isolates analyzed through ERIC-PCR genotyping. Two major clusters (B and C) were discovered in P. aeruginosa isolates of ICU and CF patients during the whole period of this study. Fifteen unique antibiogram patterns obtained from all isolates and multi-resistant P. aeruginosa (MRPA) were identified in 23 isolates (47%). MRPA isolates were detected in all clusters (except A) while pan-resistant isolates were recovered only in cluster C. The high prevalence of related or identical isolates in CF and non-CF patients can be due to transmission of particular dominant clones in ICU ward. Therefore, enhanced infection-control may become necessary to prevent further spread of clonal strains.


Postnatal Cardiac Autonomic Nervous Control in Pediatric Congenital Heart Disease.
Congenital heart disease is the most common congenital defect. During childhood, survival is generally good but, in adulthood, late complications are not uncommon. Abnormal autonomic control in children with congenital heart disease may contribute considerably to the pathophysiology of these long term sequelae. This narrative review of 34 studies aims to summarize current knowledge on function of the autonomic nervous system in children with a congenital heart defect. Large scale studies that measure both branches of the nervous system for prolonged periods of time in well-defined patient cohorts in various phases of childhood and adolescence are currently lacking. Pending such studies, there is not yet a good grasp on the extent and direction of sympathetic and parasympathetic autonomic function in pediatric congenital heart disease. Longitudinal studies in homogenous patient groups linking autonomic nervous system function and clinical outcome are warranted.


Bifunctional penicillin-binding proteins: focus on the glycosyltransferase domain and its specific inhibitor moenomycin.
Beta-lactams and glycopeptides antibiotics directed against enzymes involved in bacterial cell wall synthesis have generated bacterial resistance. Search for new antibiotic molecules is widely focused on bifunctional Penicillin-Binding Proteins (PBPs), with particular emphasis on their glycosyltransferase activity. This function catalyzes glycan chain polymerization of the cell wall peptidoglycan. This review summarizes recent results about biochemical characterization of bifunctional PBPs and enzymatic properties of the glycosyltransferase domain. Moenomycin, a well studied glycosyltransferase activity inhibitor has provided useful informations about lipid binding properties and about cellular role of bifunctional PBPs. These enzymes were shown to be a part of the multienzymatic complex involved in peptidoglycan biosynthesis. Furthermore, bifunctional PBPs are also present in the protein complex located at the site of septation during cell division. The glycosyltransferase domain of bifunctional PBPs remains unsufficently characterized: the structural analysis may lead to the development of novel antibacterials and to the understanding of the enzymatic properties, while genetic and cellular studies focused on bifunctional PBPs will provide a wealth of knowledge regarding cell growth and division.


Mechanism of fibroblast inflammatory responses to Pseudomonas aeruginosa elastase.
Receptor tyrosine kinases, including the epidermal growth factor receptors (EGFR), are able to activate the mitogen-activated protein kinases (MAPK) via several adaptor proteins and protein kinases such as Raf. EGFR can be activated by a variety of extracellular stimuli including neutrophil elastase, but we are aware of no report as to whether Pseudomonas aeruginosa produced elastase (PE) could elicit such signalling through EGFR activation. We sought to test the inference that PE modulates inflammatory responses in human lung fibroblasts and that the process occurs by activation of the EGFR/MAPK pathways. We utilized IL-8 cytokine expression as a pathway-specific end point measure of the fibroblast inflammatory response to PE. Western blot analysis was performed to detect phosphorylation of EGFR and signal transduction intermediates. Northern blot, real-time PCR, and ELISA methods were utilized to determine cytokine gene expression levels. We found that PE induces phosphorylation of the EGFR and the extracellular signal-regulated proteins (ERK1/2) of the MAPK pathway, and nuclear translocation of NF-κB. Furthermore, enzymically active PE enhances IL-8 mRNA and protein secretion. Pretreatment of the cells with specific inhibitors of EGFR, MAPK kinase and NF-κB markedly attenuated the PE-induced signal proteins phosphorylation and IL-8 gene expression and protein secretion. Collectively, the data show that PE produced by Pseudomonas aeruginosa can modulate lung inflammation by exploiting the EGFR/ERK signalling cascades and enhancing IL-8 production in the lungs via NF-κB activation.


The fraction of breast cancer attributable to smoking: The Norwegian women and cancer study 1991-2012.
Results from several recent cohort studies on smoking and breast cancer incidence and mortality suggest that the burden of smoking on society is underestimated. We estimated the fraction of breast cancer attributable to smoking in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study. We followed 130 053 women, aged 34-70 years, who completed a baseline questionnaire between 1991 and 2007, through linkages to national registries through December 2012. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), while adjusting for confounders. Never smokers, excluding passive smokers, were used as the reference group in all main analyses. We estimated attributable fractions (AFs) % in smokers and in the population (PAFs) % with 95% CIs. Altogether, 4293 women developed invasive breast cancer, confirmed by histology. Compared with never active, never passive smokers, ever (former and current) smokers had an overall risk of breast cancer that was 21% higher (HR=1.21; 95% CI=1.08-1.34). For ever smokers, the AF was 17.3% (95% CI =7.4-25.4) and for the population the PAF of breast cancer was 11.9% (95% CI=5.3-18.1). For passive smokers, the PAF of breast cancer was 3.2% (95% CI=1.0-5.4). When we applied PAF estimates for ever smoking on the 2907 new breast cancer cases among Norwegian women aged 35+ at diagnosis in 2012, this yielded 345 (95% CI=154-526) breast cancer cases that could have been avoided in the absence of active smoking that year. In smokers, one in six and in the population, one in nine breast cancer cases could have been avoided in the absence of active smoking. Our findings support the notion that the global cancer burden due to smoking is substantially underestimated.