Simulation and fabrication of a new novel 3D injectable biosensor for high throughput genomics and proteomics in a lab-on-a-chip device.
Biosensors are used for the detection of biochemical molecules such as proteins and nucleic acids. Traditional techniques, such as enzyme-linked immuno-sorbent assay (ELISA), are sensitive but require several hours to yield a result and usually require the attachment of a fluorophore molecule to the target molecule. Micromachined biosensors that employ electrical detection are now being developed. Here we describe one such device, which is ultrasensitive, real-time, label free and localized. It is called the nanoneedle biosensor and shows promise to overcome some of the current limitations of biosensors. The key element of this device is a 10 nm wide annular gap at the end of the needle, which is the sensitive part of the sensor. The total diameter of the sensor is about 100 nm. Any change in the population of molecules in this gap results in a change of impedance across the gap. Single molecule detection should be possible because the sensory part of the sensor is in the range of bio-molecules of interest. To increase throughput we can flow the solution containing the target molecules over an array of such structures, each with its own integrated read-out circuitry to allow 'real-time' detection (i.e. several minutes) of label free molecules without sacrificing sensitivity. To fabricate the arrays we used electron beam lithography together with associated pattern transfer techniques. Preliminary measurements on individual needle structures in water are consistent with the design. Since the proposed sensor has a rigid nano-structure, this technology, once fully developed, could ultimately be used to directly monitor protein quantities within a single living cell, an application that would have significant utility for drug screening and studying various intracellular signaling pathways.


Development and Usability of a Smartphone Application for Tracking Oncology Patients in Gaborone, Botswana.
The majority of new cancer cases are expected to be diagnosed in low- and middle-income countries (LMICs) by 2025, and 65% of cancer deaths currently occur in LMICs. Treatment adherence, patient monitoring, and follow-up are essential to cancer care but are often not possible in these settings. Out Patient (OP) Care, a smartphone application (app) developed to fill this gap, texts appointment reminders to patients and electronically stores medical records confidentially. This study aims to present the development of this app and evaluate its usability and feasibility as defined by provider and patient experiences in the context of a multidisciplinary cancer clinic in Gaborone, Botswana. OP Care was piloted at a multidisciplinary team gynecologic oncology clinic in Gaborone, Botswana. The app was developed through an iterative process with feedback from clinic staff and physicians. The usability was evaluated using a cross-sectional survey. All staff members in the gynecologic oncology clinic, which typically consists of one doctor and four nurses, as well as a portion of the staff in the (Princess Marina Hospital general) oncology ward used the app. All providers using the app were surveyed, along with all patients who attended the gynecologic oncology clinic during the 3-week survey period. Staff demographics, reactions, and opinions on usability, as well as patients' reactions to the appointment reminders were collected. Agreement to the ease-of-usability statements was recorded on a 1 (not at all) to 7 (extremely so) scale. Primary outcomes were the app's usability and the feasibility of text reminders from the patient's perspective. Nine staff and 15 patients were surveyed. Staff included three doctors and six nurses and encompassed all of the staff in the gynecologic oncology clinic as well as a portion of the general oncology ward. All surveyed staff owned a smartphone and used a computer at home. Most (78%) staff did not feel that OP Care would increase their work burden and were willing to use the app if implemented permanently (median: 6; interquartile range [IQR]: 1). Seventeen out of the nineteen usability questions, such as "I feel comfortable using this system," scored a median of 6, corresponding to "very much so." Patients reported that the reminder text messages were helpful (median: 6; IQR: 1) and preferred the text reminders to be in Setswana (median: 7; IQR: 1). High usability scores indicate that the app can be scaled up to usage in this clinic and others. Although patients appreciate OP Care, the option for call and text reminders in Setswana is indicated.


Evaluation of the setup accuracy of a stereotactic radiotherapy head immobilization mask system using kV on-board imaging.
The purpose of this study was to evaluate setup accuracy and quantify random and systematic errors of the BrainLAB stereotactic immobilization mask and localization system using kV on-board imaging. Nine patients were simulated and set up with the BrainLAB stereotactic head immobilization mask and localizer to be treated for brain lesions using single and hypofractions. Orthogonal pairs of projections were acquired using a kV on-board imager mounted on a Varian Trilogy machine. The kV projections were then registered with digitally-reconstructed radiographs (DRR) obtained from treatment planning. Shifts between the kV images and reference DRRs were calculated in the different directions: anterior-posterior (A-P), medial-lateral (R-L) and superior-inferior (S-I). If the shifts were larger than 2mm in any direction, the patient was reset within the immobilization mask until satisfying setup accuracy based on image guidance has been achieved. Shifts as large as 4.5 mm, 5.0 mm, 8.0 mm in the A-P, R-L and S-I directions, respectively, were measured from image registration of kV projections and DRRs. These shifts represent offsets between the treatment and simulation setup using immobilization mask. The mean offsets of 0.1 mm, 0.7 mm, and -1.6 mm represent systematic errors of the BrainLAB localizer in the A-P, R-L and S-I directions, respectively. The mean of the radial shifts is about 1.7 mm. The standard deviations of the shifts were 2.2 mm, 2.0 mm, and 2.6 mm in A-P, R-L and S-I directions, respectively, which represent random patient setup errors with the BrainLAB mask. The Brain-LAB mask provides a noninvasive, practical and flexible immobilization system that keeps the patients in place during treatment. Relying on this system for patient setup might be associated with significant setup errors. Image guidance with the kV on-board imager provides an independent verification technique to ensure accuracy of patient setup. Since the patient may relax or move during treatment, uncontrolled and undetected setup errors may be produced with patients that are not well-immobilized. Therefore, the combination of stereotactic immobilization and image guidance achieves more controlled and accurate patient setup within 2mm in A-P, R-L and S-I directions.


Regulation of glomerular cell number by apoptosis.
While commonly viewed as leading to glomerular scarring and end-stage renal failure, glomerular cell proliferation may be a beneficial response that promotes the injured glomerulus to return to its proper function. This brief review looks at the potentially counterbalancing influences that cause glomerular cells to survive, undergo mitosis, differentiate or die.


Plasma bovine pregnancy-associated glycoprotein concentrations throughout gestation in relationship to fetal number in the cow.
This study characterized the peripheral plasma bovine pregnancy-associated glycoprotein (bPAG) profile throughout gestation and examined the effect of stage of gestation and fetal number on this profile in Holstein cows after non-surgical embryo transfer. Cows (n = 12) were divided into three groups: group 1 = normal singleton pregnancies (n = 5); group 2 = normal twin pregnancies (n = 5); group 3 = abnormal twin pregnancies (n = 2). Blood was collected about every third day from day 0 (defined as the first day of standing estrus), then daily for the last 10 days of gestation, and sampling was stopped one day postpartum. The time-related changes in plasma bPAG concentrations were significantly (P < 0.01) affected by the stage of gestation and fetal number (P < 0.01), except during the last 10 days of gestation. In both normal pregnancy groups, bPAG concentration increased rapidly during the first trimester (0.5 +/- 0.1 to 14.6 +/- 1.7 ng/ml and 1.0 +/- 0.6 to 21.8 +/- 4.8 ng/ml, in singleton and twin-bearing groups respectively), then progressively between days 160 and 20 prepartum (31.6 +/- 6.2 to 114.3 +/- 31.3 ng/ml and 41.6 +/- 7.4 to 155.8 +/- 36.6 ng/ml in singleton and twin-bearing cows respectively). The mean concentration between days 20 and 10 prepartum approximately tripled (P < 0.001) in both these groups of cows (114.3 +/- 31.1 to 493.0 +/- 75.3 ng/ml and 155.8 +/- 36.6 to 409.3 +/- 114.7 ng/ml in singleton and twin-bearing cows respectively), but between days 10 prepartum and parturition the values increased about threefold (P < 0.01) in the singleton group (493.0 +/- 75.3 to 1352.8 +/- 286.5 ng/ml) and fivefold (P < 0.001) in the twin-bearing group (409.3 +/- 114.7 to 2154.0 +/- 505.7 ng/ml). The two cows in group 3 that gave birth prematurely to a stillborn calf or to a schistosomus reflexus calf exhibited an aberrant bPAG profile. Our results indicate that peripheral bPAG concentrations are correlated to the stage of gestation and fetal number, and that the profile of the peripheral plasma concentrations provides a useful indication of the feto-placental status.


HBCUs inform students and the community about cervical cancer.
In summary, HBCUs can no longer remain reactive, but must spearhead efforts to increase both the health of the student body, as well as the community at large. HBCUs should collaboratively initiate a "Call to Action", whereby policies and programs could be created to aid in the prevention of HPV and other STIs. To support this action, HBCUs could more actively pursue funding sources that support both universities and the communities in which they exist. Student orientation could be redefined to include short courses in STI awareness and prevention, and be communicated in a manner that is professional, yet engaging to students. Moreover, university departments which have an interest in the health of communities should supervise these efforts. The knowledge of university faculty members within departments of Nursing, Social Work, Public Health, Rehabilitation Counseling and Physical Education should extend beyond the classroom and into the community. Clark commented, "Perhaps course content across departments could be revised to encompass an increased focus on practice skills which support awareness and prevention efforts". Through employment, volunteerism and student internships, each of these disciplines have established relationships with the surrounding community and understand the associated critical needs. Such relationships provide the best environment for both the creation and implementation of services, and provide students with a model of how to "give back" to the community by utilizing their education. Campus health centers should be more prevention-driven beyond the distribution of condoms and pamphlets, to collaborate with local area high schools and community-based organizations to create an information network accessible to students and community residents. Additionally, health centers should promote the availability of HPV vaccination, which depending on state of residence and age, may be free or available at a discounted cost. According to Bynum, some HBCUs have already begun to promote and provide the vaccination, "South Carolina State University is one of the HBCUs which provides the HPV vaccination and promotes HPV prevention. There has been a great initiative by their health center to focus prevention efforts on incoming freshman". HBCU administrations must bear in mind that beyond the campus, students will undoubtedly carry the information learned during college into the communities in which they live after graduation and moreover, utilize this information as a basis for educating their children and families. Community activist and Columbia resident Linda "T'Zima" Brown, whose 16 year-old son is considering application to Delaware State University, believes that HBCUs bear a great responsibility to the well-being of the community, "We as residents should be able to take part in the events that our black colleges have. Black colleges used to operate from a more inclusive, family approach, and we need to get back to that; plus, many HBCUs are supported with our state dollars, so the community should be able to look to them for information aside from what our children relay to us".


PECAM-1-dependent neutrophil transmigration is independent of monolayer PECAM-1 signaling or localization.
Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), a tyrosine phosphoprotein highly expressed on endothelial cells and leukocytes, is an important component in the regulation of neutrophil transendothelial migration. Engagement of endothelial PECAM-1 activates tyrosine phosphorylation events and evokes prolonged calcium transients, while homophilic engagement of neutrophil PECAM-1 activates leukocyte beta-integrins. Although PECAM-1 modulates polymorphoneutrophil transmigration via homophilic PECAM-1-PECAM-1 interaction, the mechanisms underlying endothelial PECAM-1 function are unknown. Proposed mechanisms include (1) formation of a haptotactic gradient that "guides" neutrophils to the cell-cell border, (2) service as a "passive ligand" for neutrophil PECAM-1, ultimately mediating activation of neutrophil beta integrins, (3) regulation of endothelial calcium influx, and (4) mediation of SH2 protein association, and/or (5) catenin and non-SH2 protein interaction. Utilizing PECAM-1-null "model" endothelial cells (REN cells), we developed a neutrophil transmigration system to study PECAM-1 mutations that specifically disrupt PECAM-1-dependent signaling and/or PECAM-1 cell localization. We report that interleukin-1 beta (IL-1 beta) elicits PECAM-1-dependent transmigration that requires homophilic PECAM-PECAM-1 engagement, but not heterophilic neutrophil PECAM-1 interactions, and is intercellular adhesion molecule-1 dependent. Conversely, whereas IL-8 and leukotriene-B(4)-mediated transmigration is PECAM-1-independent, PECAM-1 and IL-8-dependent transmigration represent separable and additive components of cytokine-induced transmigration. Surprisingly, neither monolayer PECAM-1-regulated calcium signaling, cell border localization, nor the PECAM-1 cytoplasmic domain was required for monolayer PECAM-1 regulation of neutrophil transmigration. We conclude that monolayer (endothelial cell) PECAM-1 functions as a passive homophilic ligand for neutrophil PECAM-1, which after engagement leads to neutrophil signal transduction, integrin activation, and ultimately transmigration in a stimulus-specific manner.


One-Pot Three-Component Synthesis of 2-Imino-1,3-Thiazolines on Soluble Ionic Liquid Support.
An efficient one-pot, three-component synthesis of 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines using ionic liquid-tethered 2-aminobenzimidazoles was reported. The protocol includes reaction of ionic liquid attached 2-aminobenzimidazoles with isothiocyanates to afford isothioureas, followed by its base induced inter and intramolecular nucleophilic displacement reactions with 1,2-dichloroethane (EDC) which results in thiazolidine ring formation. In the next to the last step, the ionic liquid support was removed by methanolysis to deliver 2-imino-1,3-thiazolidines, which were sequentially oxidized with manganese(III) triacetate to yield 2-imino-1,3-thiazolines. The salient feature of this method is the use of 1,2-dichloroethane as a synthetic equivalent for α-haloketone to avoid the use of toxic halogenating reagents.


Do women with idiopathic sensory urgency have early interstitial cystitis?
Interstitial cystitis is rarely considered as a cause of urinary symptoms in referrals to gynaecology clinics. Recent concepts in the diagnosis of this condition mean that it is emerging as a much more common entity, with both early and late forms of the disease being described. Mast cell density in the detrusor muscle has been reported to be useful as a disease marker to substantiate the diagnosis of interstitial cystitis where no classical diagnostic features exist. We assessed mast cell counts in bladder biopsies from 27 women with idiopathic sensory urgency and 10 control patients about to undergo a colposuspension procedure for pure genuine stress incontinence; 30% of the study group had a clear increase in the detrusor muscle mast cell population (detrusor mastocytosis). No control patient showed such an increase. Early interstitial cystitis should be considered as a possible cause of lower urinary tract symptoms in patients with apparently idiopathic sensory urgency.


The Nager syndrome.
The Nager syndrome was identified in a newborn infant and in a subsequent sib by prenatal ultrasonography. This report documents an autosomal recessive pattern of inheritance for this disorder.


cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384----Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia.
cDNA clones for human R-type pyruvate kinase (PK) were isolated from a human reticulocyte cDNA library, constructed by PCR with a single gene-specific primer. The full-length cDNA was 2060 base pairs long, and the cDNA encoded 574 amino acids, the same number as that by rat R-type PK. Compared with human L-type PK, R-type PK was 31 amino acids longer at the amino terminus. We also cloned and characterized R-type PK cDNA clones from patients with hereditary hemolytic anemia from a PK deficiency, PK Tokyo. A single nucleotide substitution (ACG to ATG) was found at nucleotide 1151 of the coding sequence of the R-type PK, which caused an amino acid substitution, Thr384----Met. Dot blot hybridization of PCR-amplified genomic DNA from patients and their parents by allele-specific oligonucleotide probes showed that the parents, who were second cousins, were heterozygous. To confirm that the nucleotide change was responsible for the variant phenotype, we expressed the L-type PK with the single amino acid change in Escherichia coli and characterized the enzyme. The variant PK was thermolabile and moved slowly in the polyacrylamide gel buffered in 10 mM Tris.HCl, pH 8.3; these characteristics were fully compatible with data obtained from the patient's PK. From these results, we concluded that enzymatic stability of the variant was affected by the point mutation of the PK-encoding gene.


Purification and Characterization of the Nitrate Reductase from the Diatom Thalassiosira pseudonana.
THE ASSIMILATORY NITRATE REDUCTASE (NADH: nitrate oxidoreductase, E.C. 184.108.40.206.) from the marine diatom Thalassiosira pseudonana, Hasle and Heimdal, has been purified 200-fold and characterized. The regulation of nitrate reductase in response to various conditions of nitrogen nutrition has been investigated.Nitrate reductase activity is repressed by the presence of ammonium in vivo, and its synthesis is derepressed when ammonium is absent. The derepression process is sensitive to cycloheximide and apparently requires protein synthesis. Repression of enzyme activity by ammonium is neither inhibited nor delayed by the presence of cycloheximide. In vitro, ammonium does not inhibit enzyme activity.NADH is the physiological electron donor for the enzyme in a flavin-dependent reaction. Spectral studies have indicated the presence of a b-type cytochrome associated with the enzyme. It is possible to observe enzymatic oxidation-reduction reactions which represent partial functions of the over-all electron transport capacity of this enzyme. Nitrate reductase will accept electrons from artificial electron donors such as reduced methyl viologen in a flavin-independent reaction. Further, dithionitereduced flavin adenine dinucleotide can donate electrons to the enzyme to reduce nitrate to nitrite. Finally, the nitrate reductase will exhibit a diaphorase activity and reduce the artificial electron acceptor mammalian cytochrome c in flavin-adeninedinucleotide-dependent reaction.Inhibition studies with potassium cyanide, sodium azide, and o-phenanthroline have yielded indirect evidence for metal component (s) of the enzyme.The inhibition of the NADH-requiring enzyme activities by p-hydroxymercuribenzoate has shown that an essential sulfhydryl group is involved in the initial portion of the electron transport. Heat treatment exerts an effect similar to the p-hydroxymercuribenzoate inhibition; namely, the NADH-requiring activities are rapidly inactivated, whereas the terminal nitrate-reducing activities are relatively stable to heat.The T. pseudonana nitrate reductase molecule has the hydrodynamic properties of an ellipsoid with a frictional coefficient of 1.69 and a molecular weight of 330,000.


Successful Treatment of Suspected Cannabinoid Hyperemesis Syndrome Using Haloperidol in the Outpatient Setting.
Chronic use of cannabis can result in a syndrome of hyperemesis characterized by cyclical vomiting without any other identifiable causes. Cannabinoid hyperemesis syndrome (CHS) is seldom responsive to traditional antiemetic therapies. Despite frequent nausea and vomiting, patients may be reluctant to discontinue use of cannabis. We report a case of severe, refractory CHS with complete resolution of nausea and vomiting after treatment with haloperidol in the outpatient setting. After review of the literature, we believe this is the first reported successful outpatient treatment of CHS and suggests a potential treatment for refractory patients.


Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma.
Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T cell. However, this concept does not explain the key characteristics of MF, such as the debut with multiple, widespread skin lesions or inability of skin-directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here, we used a whole-exome sequencing approach to detect and quantify TCR-α, β, and γ clonotypes in tumor cell clusters microdissected from MF lesions. This method allowed us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I to IV proved the existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median, 11 clones; range, 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings, we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF, thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.


Recovery of upper limb function after cerebellar stroke: lesion symptom mapping and arm kinematics.
Loss of movement coordination is the main postacute symptom after cerebellar infarction. Although the course of motor recovery has been described previously, detailed kinematic descriptions of acute stage ataxia are rare and no attempt has been made to link improvements in motor function to measures of neural recovery and lesion location. This study provides a comprehensive assessment of how lesion site and arm dysfunction are associated in the acute stage and outlines the course of upper limb motor recovery for the first 4 months after the infarction. Sixteen adult patients with cerebellar stroke and 11 age-matched healthy controls participated. Kinematics of goal-directed and unconstrained finger-pointing movements were measured at the acute stage and in 2-week and 3-month follow-ups. MRI data were obtained for the acute and 3-month follow-up sessions. A voxel-based lesion map subtraction analysis was performed to examine the effect of ischemic lesion sites on kinematic performance. In the acute stage, nearly 70% of patients exhibited motor slowing with hand velocity and acceleration maxima below the range of the control group. MRI analysis revealed that in patients with impaired motor performance, lesions were more common in paravermal lobules IV/V and affected the deep cerebellar nuclei. Stroke affecting the superior cerebellar artery led to lower motor performance than infractions of the posterior cerebellar artery. By the 2-week-follow-up, hand kinematics had improved dramatically (gains in acceleration up to 86%). Improvements between the 2-week and the 3-month-follow-ups were less pronounced. In the acute stage, arm movements were mainly characterized by abnormal slowness (bradykinesia) and not dyscoordination (ataxia). The motor signs were associated with lesions in paravermal regions of lobules IV/V and the deep cerebellar nuclei. Motor recovery was fast, with the majority of gains in upper limb function occurring in the first 2 weeks after the acute phase.


Pleomorphic Pulmonary Manifestations of IgG4-Related Disease.
Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder which has been first reported in 2001 by Hamano and colleagues in a patient with autoimmune sclerosing pancreatitis. Almost every organ in the human body can be affected by IgG4-RD from infiltration with IgG4-positive plasma cells. Involvement of lungs with IgG4 is reported previously, but still, there is no clear picture of the pathophysiology behind lung involvement. Here, we are presenting a patient who has IgG4-RD presenting as pseudotumor of the lungs.


Self-concept and woman abuse: a rural and cultural perspective.
The prevalence of woman abuse has serious community health ramifications because of its associated psychological responses. Theoretical frameworks have described behaviors arising from interpersonal interactions as being affected by self-concept. Therefore, assessing self-concept is critical in research and practice for understanding the behavior of abused women and the effects of self-concept on the physical self. This research arose from clinical practice in a rural Mexican American and non-Hispanic white community. The practice focused on individual and group counseling for women and adolescents in abusive relationships. This study was conducted to refine the theoretical basis for interventions related to self-concept and woman abuse for rural Mexican American and non-Hispanic white women.


Neural Tree Indexers for Text Understanding.
Recurrent neural networks (RNNs) process input text sequentially and model the conditional transition between word tokens. In contrast, the advantages of recursive networks include that they explicitly model the compositionality and the recursive structure of natural language. However, the current recursive architecture is limited by its dependence on syntactic tree. In this paper, we introduce a robust syntactic parsing-independent tree structured model, Neural Tree Indexers (NTI) that provides a middle ground between the sequential RNNs and the syntactic tree-based recursive models. NTI constructs a full n-ary tree by processing the input text with its node function in a bottom-up fashion. Attention mechanism can then be applied to both structure and node function. We implemented and evaluated a binary-tree model of NTI, showing the model achieved the state-of-the-art performance on three different NLP tasks: natural language inference, answer sentence selection, and sentence classification, outperforming state-of-the-art recurrent and recursive neural networks .


Diagnosis and management of endocrine disorders of erectile dysfunction.
Organic causes of erectile dysfunction with androgen deficiency may be associated with aging, systemic illness, and a number of specific endocrine disorders stemming from pituitary, thyroid, and adrenal dysfunction. Central hypogonadism is the main mechanism in the majority. Erectile dysfunction in diabetes mellitus is caused by chronic complications due to poor metabolic control. Diagnosis and management of these disorders are discussed, as is the need for tight glycemic control in men with diabetes.


Non-equilibrium relaxation in a stochastic lattice Lotka-Volterra model.
We employ Monte Carlo simulations to study a stochastic Lotka-Volterra model on a two-dimensional square lattice with periodic boundary conditions. If the (local) prey carrying capacity is finite, there exists an extinction threshold for the predator population that separates a stable active two-species coexistence phase from an inactive state wherein only prey survive. Holding all other rates fixed, we investigate the non-equilibrium relaxation of the predator density in the vicinity of the critical predation rate. As expected, we observe critical slowing-down, i.e., a power law dependence of the relaxation time on the predation rate, and algebraic decay of the predator density at the extinction critical point. The numerically determined critical exponents are in accord with the established values of the directed percolation universality class. Following a sudden predation rate change to its critical value, one finds critical aging for the predator density autocorrelation function that is also governed by universal scaling exponents. This aging scaling signature of the active-to-absorbing state phase transition emerges at significantly earlier times than the stationary critical power laws, and could thus serve as an advanced indicator of the (predator) population's proximity to its extinction threshold.


Simulating the kinetics and thermodynamics of transitions via forward flux/umbrella sampling.
First, a technique is introduced for computing equilibrium probability distributions for transitional rare-event simulations by combining the ensemble of trajectories generated by forward flux sampling (FFS) and by umbrella sampling (US) in multiple windows along an order parameter of interest; this method is denoted FFS-US. Second, the FFS algorithm is extended to obtain rate constants of partial transitions involving intermediate states from a single simulation; this is denoted "multiple state" FFS. For the FFS-US method, a FFS algorithm (preoptimized for order parameter and staging) is used to take advantage of its zero potential bias of phase-space sampling to gather histogram data with which to jump start the US and get the equilibrium distributions. In this way, kinetic data (like the rate constants and the transition path ensemble) and the underlying free-energy landscape (or probability distribution) of the system are obtained efficiently and concurrently. The applicability of these techniques is illustrated by studying several test systems, including two that involve potential energy surfaces having multiple metastable states and transition pathways, representative of complex kinetic behavior.


What smokers believe about light and ultralight cigarettes.
To assess the knowledge of smokers and ex-smokers about light cigarettes and nicotine yields and their perception of the risk of lung cancer, and to identify the characteristics of smokers of light cigarettes. Mail survey in a population sample of 494 smokers and exsmokers in Geneva, Switzerland, in 1999. Participants were on average 40 years old, and 49% were men. They estimated that one would have to smoke two light cigarettes or four ultralight cigarettes in order to inhale the same amount of nicotine as that in one regular cigarette. Most participants (60%) answered that the risk of lung cancer was the same, but 27% answered that this risk was lower in smokers of light cigarettes than in smokers of regular cigarettes. The most frequent answer (41% of answers) to an open-ended question on the meaning of the number of milligrams of nicotine printed on cigarette packs was that this number indicated the nicotine content in cigarettes, rather than a machine-determined yield in smoke. In a multivariate model, smoking mild, light, or ultralight (vs regular) cigarettes was associated with females, a lower Fagerström dependence score, an intention to quit smoking, and an intention to decrease cigarette consumption. Many smokers choose light cigarettes because they think that such cigarettes are safer or less addictive. The public should be further informed of the meaning and purpose of cigarette labels.


[Thin-needle aspiration biopsy in thoracic lesions. Analysis of 60 cases in a General Zone Hospital].
The intention of the study was to confirm the usefulness of the transthoracic fine needle biopsy aspiration (FNBA) procedure, in a second level hospital that did not have technologically advanced equipment to locate thoracic diseases, such as computerized tomography, fluoroscopy or ultrasonography. Employing a vertical and horizontal coordinate design and posteroanterior as well as lateral radiological studies, specimens were taken from 77 patients. Of this total only 60 (77.9%) were in proper conditions to be examined; in seven (11.6%) patients a second aspiration was required. Of the total suitable specimens, malignant neoplasms were found in 46 (76.7%), and inflammatory diseases were detected in 14 (23.3%). The most frequent diagnoses were squamous cell carcinoma in 20 (33.3%), undifferentiated carcinoma in seven (11.6%), and bronchoalveolar carcinoma in another seven (11.6%). In 12 patients, it was possible to obtain tissue samples and in two patients, autopsy was performed; in all of them, the FNBA diagnoses were confirmed. Four (6.6%) patients suffered complications like pneumothorax, three were cured spontaneously, and one was treated with tube drainage. FNBA demonstrated its usefulness in a hospital with limited technological resources; 77.9% of the patients were property diagnosed with reduced cost, minimal morbidity, and without mortality.


[Materializing interdisciplinary outpatient management of complex situations].
Patient management is becoming increasingly complex, particularly because of the growing prevalence ofchronic diseases and ageing populations. The Swiss health care system is fragmented and struggles to coordinate care provided by professionals from multiple disciplines or working for different institutions. Models to improve health care of complex situations are available that particularly advocate a coordinated team approach. This article presents an action-research designed to empower health professionals to manage complex situations in outpatient settings by means of this type of approach. Health professionals - good practice leaders in the medical and nursing fields in the Geneva Canton (Switzerland) - explored complex management situations, as well as facilitating components and obstacles. A team approach is essential to manage all of the patient's issues, to take the patient's priorities into account, and to work on a joint care plan. The legitimate role of each member of this team is highlighted, together with new roles for existing practices: informing and motivating the patient, highlighting and supporting care givers, coordination by nurses. The creation of such teams, and implementation of these roles involve new processes, which require financing of coordination as well as development of new methods of interdisciplinary management, particularly novel information technology tools.


[Comparative histologic study of implants (magnets) in orbits of female rabbits].
To evaluate microscopically the signs of inflammatory reaction due to the fixation of an orbitary implant (magnet, covered by gold). An experimental study was performed in 54 adult female rabbits, divided into 3 groups of eighteen with 3 subgroups of 6; an evaluation at 1, 3 and 6 postoperative weeks was performed. An implant (magnet, covered by gold) was fixed in the inferior orbital rim using biologic glue, screw or unabsorbable suture (Mersilene 5.0). The opposite orbits (without implants) represented the control group. Microscopic signs of inflammatory reaction due to orbitary fixation of the implant were observed with the use of the three methods (biologic glue, screw or unabsorbable suture) (Mersilene 5.0), until six weeks of the postoperatory period. Histopathological signs of inflammatory reaction to the implant and to its orbital fixation were observed up to the sixth week, with cyanoacrylate, screw, or unabsorbable suture (Mersilene 5.0), with prevalence of the chronic inflammatory process and cicatricial fibrosis, without statistically significant difference in most of the cases.


A Comprehensive, Evidence-Based Literature Review of the Surgical Treatment of Rectus Diastasis.
Rectus diastasis is a common condition that can result in a protruding abdomen, causing cosmetic and functional disability. Although it is usually repaired during abdominoplasty or herniorrhaphy, there is a lack of consensus with regard to the repair indications and optimal surgical techniques. The goal of this study is to provide an updated review of the surgical techniques used for rectus diastasis repair and their comparative efficacy. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Embase, and Cochrane databases were searched for articles that discussed the surgical management of rectus diastasis and reported on either outcomes, complications, or recurrence rates. Data detailing surgical techniques were extracted, and pooled analyses of complication and recurrence rates were performed, controlling for surgical approach, common variations in technique, and an associated herniorrhaphy. Thirty-seven studies describing 45 techniques were included. An open rectus diastasis repair was performed in 24 of the studies. After controlling for an associated herniorrhaphy, there was no statistically significant difference in surgical complication and recurrence rates between open and laparoscopic approaches (p = 0.165 and p = 0.133, respectively). Although a double-layer suture closure was associated with a significantly lower rate of complications (p = 0.002), no significant difference was found for suture type absorbability. Surgical repair of rectus diastasis is safe and effective through both open and laparoscopic approaches. Although suture type absorbability does not affect complication or recurrence rates, a double-layer suture closure can decrease surgical complications. The pooled analysis of complication and recurrence rates can help improve informed consent and patient education.


The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes.
Ellagic acid (EA), a naturally occurring plant polyphenol possesses broad chemoprotective properties. Dietary EA has been shown to reduce the incidence of N-2-fluorenylacetamide-induced hepatocarcinogenesis in rats and N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumors. In this study changes in the expression and activities of specific rat hepatic and esophageal mucosal cytochromes P450 (P450) and phase II enzymes following dietary EA treatment were investigated. Liver and esophageal mucosal microsomes and cytosol were prepared from three groups of Fisher 344 rats which were fed an AIN-76 diet containing no EA or 0.4 or 4.0 g/kg EA for 23 days. In the liver total P450 content decreased by up to 25% and P450 2E1-catalyzed p-nitrophenol hydroxylation decreased by 15%. No changes were observed in P450 1A1, 2B1 or 3A1/2 expression or activities or cytochrome b5 activity. P450 reductase activity decreased by up to 28%. Microsomal epoxide hydrolase (mEH) expression decreased by up to 85% after EA treatment, but mEH activities did not change. The hepatic phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone reductase [NAD-(P)H:QR] and UDP glucuronosyltransferase (UDPGT) activities increased by up to 26, 17 and 75% respectively. Assays for specific forms of GST indicated marked increases in the activities of isozymes 2-2 (190%), 4-4 (150%) and 5-5 (82%). In the rat esophageal mucosa only P450 1A1 could be detected by Western blot analysis and androstendione was the only P450 metabolite of testosterone detectable. However, there were no differences in the expression of P450 1A1, the formation of androstendione or NAD(P)H:QR activities between control and EA-fed rats in the esophagus. Although there was no significant decrease in overall GST activity, as measured with 1-chloro-2,4-dinitrobenzene (CDNB), there was a significant decrease in the activity of the 2-2 isozyme (66% of control). In vitro incubations showed that EA at a concentration of 100 microM inhibited P450 2E1, 1A1 and 2B1 activities by 87, 55 and 18% respectively, but did not affect 3A1/2 activity. Using standard steady-state kinetic analyses, EA was shown to be a potent non-competitive inhibitor of both liver microsomal ethoxyresorufin O-deethylase and p-nitrophenol hydroxylase activities, with apparent Ki values of approximately 55 and 14 microM respectively. In conclusion, these results demonstrate that EA causes a decrease in total hepatic P450 with a significant effect on hepatic P450 2E1, increases some hepatic phase II enzyme activities [GST, NAD-(P)H:QR and UDPGT] and decreases hepatic mEH expression. It also inhibits the catalytic activity of some P450 isozymes in vitro. Thus the chemoprotective effect of EA against various chemically induced cancers may involve decreases in the rates of metabolism of these carcinogens by phase I enzymes, due to both direct inhibition of catalytic activity and modulation of gene expression, in addition to effects on the expression of phase II enzymes, thereby enhancing the ability of the target tissues to detoxify the reactive intermediates.


Transgenic mouse models of venous thrombosis: fulfilling the expectations?
During the last 15 years, transgenic mice have been generated that carry defective and/or mutant alleles of the natural anticoagulant pathways and display a spontaneous thrombotic phenotype. With the generation of these mouse lines, better opportunities became available for investigating both existing and novel risk factors for venous thrombosis. In addition, these models could serve as a tool for evaluating novel antithrombotic strategies. This review summarizes these mouse models and evaluates whether they have fulfilled the expectations.


The psychological effects of working in the NHS during a pandemic on final-year students: part 2.
This study explored the psychological experience of a small cohort of nursing and midwifery students who had been deployed to work in the NHS during the COVID-19 pandemic. The students were employed on band 4 contracts within an acute NHS Trust in the South of England. Overall, students found the experience of being deployed into clinical practice during a major public health emergency a valuable and unique experience that strengthened their resilience. However, students reported a significant level of personal obligation to opt-in to deployment. Working within clinical areas caused heightened anxiety and uncertainty, which was alleviated by managerial support.


Photosystem electron-transport capacity and light-harvesting antenna size in maize chloroplasts.
Spectrophotometric and kinetic measurements were applied to yield photosystem (PS) stoichiometries and the functional antenna size of PSI, PSII(alpha), and PSII(beta) in Zea mays chloroplasts in situ. Concentrations of PSII and PSI reaction centers were determined from the amplitude of the light-induced absorbance change at 320 and 700 nm, which reflect the photoreduction of the primary electron acceptor Q of PSII and the photooxidation of the reaction center P700 of PSI, respectively. Determination of the functional chlorophyll antenna size (N) for each photosystem was obtained from the measurement of the rate of light absorption by the respective reaction center. Under the experimental conditions employed, the rate of light absorption by each reaction center was directly proportional to the number of light-harvesting chlorophyll molecules associated with the respective photosystem. We determined N(P700) = 195, N(alpha) = 230, N(beta) = 50 for the number of chlorophyll molecules in the light-harvesting antenna of PSI, PSII(alpha), and PSII(beta), respectively. The above values were used to estimate the PSII/PSI electron-transport capacity ratio (C) in maize chloroplasts. In mesophyll chloroplasts C > 1.4, indicating that, under green actinic excitation when Chl a and Chl b molecules absorb nearly equal amounts of excitation, PSII has a capacity to turn over electrons faster than PSI. In bundle sheath chloroplasts C < 1, suggesting that such chloroplasts are not optimally poised for linear electron transport and reductant generation.


Impact of breast pumping on lactogenesis stage II after cesarean delivery: a randomized clinical trial.
Women at risk for delayed onset of lactation are often advised to pump their breasts before lactogenesis stage II to hasten the timing of this process. The effectiveness of this clinical practice has not been previously evaluated. This study investigates the effects of breast pumping before the onset of lactation on early milk transfer and subsequent breastfeeding duration among women giving birth by cesarean delivery. Sixty women were randomly assigned to either the pumping group (n = 30), which used a double electric breast pump for six 10- to 15-minute sessions from 24 to 72 hours postpartum, or to the control group (n = 30), which held the pump to their breasts without suction for the same amount of time. Milk transfer was assessed by test weighing infants before and after 3 breastfeeding sessions daily. Test weight data were fitted to a second-order polynomial curve, to predict milk transfer over time. Breast pumping between 24 and 72 hours after cesarean delivery did not improve milk transfer. Participants in the pumping group tended to have lower milk transfer than did controls. Primiparae in the pumping group breastfed for ~5 months less than their counterparts in the control group; however, this difference was not statistically significant. Breast pumping did not improve milk transfer during the first 72 hours postpartum and may negatively affect breastfeeding duration among primiparous women. lactation, lactogenesis, breast milk, breast pumping, milk expression, breastfeeding, cesarean delivery.


Agonist-selective, receptor-specific interaction of human P2Y receptors with beta-arrestin-1 and -2.
Interaction of G-protein-coupled receptors with beta-arrestins is an important step in receptor desensitization and in triggering "alternative" signals. By means of confocal microscopy and fluorescence resonance energy transfer, we have investigated the internalization of the human P2Y receptors 1, 2, 4, 6, 11, and 12 and their interaction with beta-arrestin-1 and -2. Co-transfection of each individual P2Y receptor with beta-arrestin-1-GFP or beta-arrestin-2-YFP into HEK-293 cells and stimulation with the corresponding agonists resulted in a receptor-specific interaction pattern. The P2Y(1) receptor stimulated with ADP strongly translocated beta-arrestin-2-YFP, whereas only a slight translocation was observed for beta-arrestin-1-GFP. The P2Y(4) receptor exhibited equally strong translocation for beta-arrestin-1-GFP and beta-arrestin-2-YFP when stimulated with UTP. The P2Y(6), P2Y(11), and P2Y(12) receptor internalized only when GRK2 was additionally co-transfected, but beta-arrestin translocation was only visible for the P2Y(6) and P2Y(11) receptor. The P2Y(2) receptor showed a beta-arrestin translocation pattern that was dependent on the agonist used for stimulation. UTP translocated beta-arrestin-1-GFP and beta-arrestin-2-YFP equally well, whereas ATP translocated beta-arrestin-1-GFP to a much lower extent than beta-arrestin-2-YFP. The same agonist-dependent pattern was seen in fluorescence resonance energy transfer experiments between the fluorescently labeled P2Y(2) receptor and beta-arrestins. Thus, the P2Y(2) receptor would be classified as a class A receptor when stimulated with ATP or as a class B receptor when stimulated with UTP. The ligand-specific recruitment of beta-arrestins by ATP and UTP stimulation of P2Y(2) receptors was further found to result in differential stimulation of ERK phosphorylation. This suggests that the two different agonists induce distinct active states of this receptor that show differential interactions with beta-arrestins.


Pre-operative quadriceps activation is related to post-operative activation, not strength, in patients post-ACL reconstruction.
Quadriceps activation failure is considered to contribute to the weakness that lingers following anterior cruciate ligament (ACL) reconstruction. Importantly, the impact of pre-operative quadriceps activation on post-operative quadriceps function is unknown. Understanding this relationship is clinically important; as the counteractive approach clinicians should employ pre-operatively to mitigate post-operative quadriceps weakness is unclear. Accordingly, the primary purpose of this study was to investigate the relationship between pre-operative quadriceps activation and post-operative quadriceps strength and activation. Fifty-four individuals post-ACL injury reported for testing on two occasions: prior to surgery and post-surgery once they returned to activity. Quadriceps activation was assessed using the burst superimposition technique and quantified using the central activation ratio. Quadriceps strength was assessed using isometric contractions that were performed at 90° of knee flexion. Multiple linear regressions were utilized to detect the relationships between pre-operative activation and strength and post-operative activation and strength. Pre-operative activation was not associated with post-operative strength (R(2) = 0.064, P = 0.186). Pre-operative quadriceps activation and strength were associated with post-operative activation (R(2) = 0.383, P ≤ 0.001) and strength (R(2) = 0.465, P ≤ 0.001), respectively. Individuals with better pre-operative quadriceps activation demonstrated greater post-operative activation. Similarly, individuals with better pre-operative strength demonstrated better post-operative strength. Pre-operative quadriceps activation was not a predictor of post-operative strength. From a clinical perspective, our work indicates that clinicians should utilize therapies targeting both quadriceps activation and strength prior to ACL reconstruction in order to maximize these factors post-ACL reconstruction, as pre-operative activation and strength are related to post-operative activation and strength, respectively at return-to-activity.


Application of a DSS colitis model in toxicologically assessing norisoboldine.
In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.


A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo.
Sonic hedgehog (Shh) is a key signal in the specification of ventral cell identities along the length of the developing vertebrate neural tube. In the presumptive hindbrain and spinal cord, dorsal development is largely Shh independent. By contrast, we show that Shh is required for cyclin D1 expression and the subsequent growth of both ventral and dorsal regions of the diencephalon and midbrain in early somite-stage mouse embryos. We propose that a Shh-dependent signaling relay regulates proliferation and survival of dorsal cell populations in the diencephalon and midbrain. We present evidence that Fgf15 shows Shh-dependent expression in the diencephalon and may participate in this interaction, at least in part, by regulating the ability of dorsal neural precursors to respond to dorsally secreted Wnt mitogens.


IL-4 induces IL-13-independent allergic airway inflammation.
The related T(H)2 cytokines IL-4 and IL-13 are produced during allergic responses, signal through receptors that contain IL-4 receptor (IL-4R) alpha, and promote allergic inflammation by activating signal transducer and activator of transcription 6. IL-4 promotes T(H)2 response induction, and IL-13 is necessary and sufficient to induce airways hyperresponsiveness (AHR) and goblet cell hyperplasia in some mouse models of asthma. The nonredundant role of IL-13 could reflect unique IL-13 activation of a signaling pathway, inhibitory effects induced by IL-4 but not IL-13, or greater production-potency of IL-13 than IL-4. We sought to distinguish among these possibilities by determining whether IL-4 inhalation can induce acute allergic airways disease in the absence of IL-13. Mice were inoculated intratracheally with IL-13 or a long-acting formulation of IL-4. Responses of IL-13-deficient and IL-13-sufficient mice were compared, as were responses in mice treated with a potent IL-13 antagonist, anti-IL-4Ralpha antibody, or control reagents. IL-4 inhalation stimulated bronchoalveolar lavage fluid eosinophilia, AHR, and goblet cell hyperplasia. These responses were similar in IL-13-deficient and IL-13-sufficient mice and were not inhibited by an IL-13 antagonist but were blocked by anti-IL-4Ralpha antibody. IL-4 can induce IL-13-independent AHR and goblet cell hyperplasia. Thus the greater role for IL-13 than IL-4 in the induction of these acute allergy-related changes reflects increased production, potency, or both of IL-13 relative to IL-4 rather than a unique IL-13-signaling pathway or a suppressive effect of IL-4. Dual IL-4/IL-13 inhibition might be more effective than selective IL-13 inhibition at suppressing allergic inflammation in some circumstances.


Tuning the physicochemical properties of reticular covalent organic frameworks (COFs) for biomedical applications.
Since the first report by Yaghi's group in 2005, research enthusiasm has been increasingly raised to synthesize diverse crystalline porous materials as -B-O-, -C-N-, -C-C-, and -C-O- linkage-based COFs. Recently, the biomedical applications of COFs have become more and more attractive in biomedical applications, including drug delivery, bioimaging, biosensing, antimicrobial, and therapeutic applications, as these materials bear well-defined crystalline porous structures and well-customized functionalities. However, the clinical translation of these research findings is challenging due to the formidable hindrances for in vivo use, such as low biocompatibility, poor selectivity, and long bio-persistence. Some attempts have raised a promising solution towards these obstacles by tailored engineering the functionalities of COFs. To speed up the clinical translations of COFs, a short review of principles and strategies to tune the physicochemical properties of COFs is timely and necessary. In this review, we summarized the biomedical utilities of COFs and discussed the related key physicochemical properties. To improve the performances of COFs in biomedical uses, we propose approaches for the tailored functionalization of COFs, including large-scale manufacture, standardization in nanomedicines, enhancing targeting efficacy, maintaining predesigned functions upon transformations, and manipulation of multifunctional COFs. We expect that this minireview strengthens the fundamental understandings of property-bioactivity relationships of COFs and provides insights for the rational design of their high-order reticular structures.


Development and validation of chemical and biological analyses to determine the antiestrogenic potency of resin acids in paper mill effluents.
This study combined chemical analysis and bioassays of paper mill effluents and their components in order to determine their antiestrogenic activity. The bioassay comprised a yeast two-hybrid assay incorporating the estrogen receptor alpha (hERalpha) and an hERalpha competitive enzyme-linked immunosorbent assay (ELISA). Samples were fractionated by solid phase extraction (SPE) with a C18 disk and a Florisil cartridge to obtain four fractions. The final fraction, eluted with methanol from the Florisil cartridge after pre-extraction by the C18 disk, was the most active in the two-hybrid assay, and its antiestrogenic potency, expressed as the equivalent concentration to 4-hydroxytamoxifen (OHT), was 277 nM. Seven resin acids had antiestrogenic activity in the active fraction as determined by gas chromatography/mass spectrometry (GC/MS), and their concentration levels ranged from 0.11 to 12 microg/L. All the resin acids exhibited greater activity than OHT; their activity relative to OHT ranged from 2.8- to 4.0-fold in the yeast two-hybrid assay. Based on the chemical analysis data and relative potency of resin acids from the yeast two-hybrid assay, the contribution ratio of resin acids accounted for 72% of the observed antiestrogenic activity of the extract. Furthermore, no resin acid showed any affinity for the estrogen receptor in the ELISA. This study showed that analysis combining the SPE method and the yeast two-hybrid assay is likely to be effective for the comprehensive monitoring of resin acids in paper mill industrial discharge areas.


Metallointercalators-DNA Tetrahedron Supramolecular Self-Assemblies with Increased Serum Stability.
Self-assembly of metallointercalators into DNA nanocages is a rapid and facile approach to synthesize discrete bioinorganic host/guest structures with a high load of metal complexes. Turberfield's DNA tetrahedron can accommodate one intercalator for every two base pairs, which corresponds to 48 metallointercalators per DNA tetrahedron. The affinity of the metallointercalator for the DNA tetrahedron is a function of both the structure of the intercalating ligand and the overall charge of the complex, with a trend in affinity [Ru(bpy)2(dppz)]2+ > [Tb-DOTAm-Phen]3+ ≫ Tb-DOTA-Phen. Intercalation of the metal complex stabilizes the DNA tetrahedron, resulting in an increase of its melting temperature and, importantly, a significant increase in its stability in the presence of serum. [Ru(bpy)2(dppz)]2+, which has a greater affinity for DNA than [Tb-DOTAm-Phen]3+, increases the melting point and decreases degradation in serum to a greater extent than the TbIII complex. In the presence of Lipofectamine, the metallointercalator@DNA nanocage assemblies substantially increase the cell uptake of their respective metal complex. Altogether, the facile incorporation of a large number of metal complexes per assembly, the higher stability in serum, and the increased cell penetration of metallointercalator@DNA make these self-assemblies well-suited as metallodrugs.


Lack of perceived social support among immigrants after a disaster: comparative study.
Disaster research suggests that immigrant groups who are affected by a disaster receive less emotional support than their native counterparts. However, it is unclear to what extent these differences can be attributed to post-disaster mental health problems or whether they were present before the event. To examine the association between lack of social support, immigration status and victim status, as well as differences in support between immigrants and Dutch natives with disaster-related post-traumatic stress disorder (PTSD). Social support and psychological distress were assessed among immigrants and Dutch natives, among affected and non-affected individuals 4 years post disaster. Post-traumatic stress disorder was examined in the affected groups. Affected immigrants more often lacked various kinds of perceived social support compared with affected Dutch natives. Remarkably, we found no differences in support between affected immigrants and non-affected immigrants. Immigrants with PTSD differ on only two out of six aspects of support from the Dutch natives with PTSD. Results clearly indicate that differences in support between immigrants and Dutch natives are not so much a consequence of the disaster but were largely present before the disaster.


[The genetic aspects of occupational hearing impairment].
This article was designed to be the overview of the current literature publications concerning the identification of the genetic markers of susceptibility to the noise-induced loss of hearing. The analysis of these data has demonstrated that the major gene polymorphisms associated with the development of this pathological condition are localized in the genes encoding for the antioxidant systems, potassium homeostasis, and adhesion molecules as well as in the genes involved in intercellular coupling, the mechanisms underlying the cellular response to stress, activation and regulation of heat shock proteins, and signaling function of the immune system. It is concluded that the further investigations into the genetic aspects of the full-genome sequencing techniques and the search for genomic associations could greatly contribute to the development of personalized medicine and the reduction of risks of occupational noise-induced sensorineural impairment of hearing.


Attitudes of physicians towards the care of critically ill elderly patients - a European survey.
Very elderly patients are one of the fastest growing population in ICUs worldwide. There are lots of controversies regarding admission, discharge of critically ill elderly patients, and also on treatment intensity during the ICU stay. As a consequence, practices vary considerably from one ICU to another. In that perspective, we collected opinions of experienced ICU physicians across Europe on statements focusing on patients older than 80. We sent an online questionnaire to the coordinator ICU physician of all participating ICUs of an recent European, observational study of Very old critically Ill Patients (VIP1 study). This questionnaire contained 12 statements about admission, triage, treatment and discharge of patients older than 80. We received answers from 162 ICUs (52% of VIP1-study) spanning 20 different European countries. There were major disagreements between ICUs. Responders disagree that: there is clear evidence that ICU admission is beneficial (37%); seeking relatives' opinion is mandatory (17%); written triage guidelines must be available either at the hospital or ICU level (20%); level of care should be reduced (25%); a consultation of a geriatrician should be sought (34%) and a geriatrician should be part of the post-ICU trail (11%). The percentage of disagreement varies between statements and European regions. There are major differences in the attitude of European ICU physicians on the admission, triage and treatment policies of patients older than 80 emphasizing the lack of consensus and poor level of evidence for most of the statements and outlining the need for future interventional studies.


Two effects of electrical fields on chloroplasts.
An electrical field across a suspension of Chenopodium chloroplasts stimulates the emission of delayed light during the time the field is on. This stimulation can be used to calculate the distance over which the electron moves in the untrapping process that gives the delayed light. An electrical field applied at the time of illumination gives a polarization to the suspension of chloroplasts that lasts for some seconds. This polarization is a new way to study delayed light and fluorescence from chloroplasts.


13. New biological therapies for breast cancer.
The exploitation of biological differences between normal and malignant cells is a logical approach to novel treatments for breast cancer. The potential targets for such therapy include the products of proto-oncogenes and oncogenes, inhibition of growth factor receptor signalling and the immunological exploitation of antigenic differences between normal and malignant cells. Monoclonal antibody technology was heralded as a potential 'magic bullet' for cancer therapy following its discovery in the mid-1970s, but it is only in the past few years that such technology has entered mainstream clinical practice. The humanised murine monoclonal antibody to HER2 (trastuzumab) has significant anti-tumour activity but with minimal toxicity, and has been licensed for use in patients with advanced breast cancer. A different approach has been the use of enzyme inhibitors to interfere with the signalling pathways downstream of growth factor receptors (e.g. farnesyl transferase inhibitors). It is likely that effective targets for such therapies will be identified in the next few years. There have been significant advances in our understanding of human immunology which have coincided with the identification of so-called tumour-associated antigens (TAA). These developments have resulted in a resurgence of interest in tumour immunotherapy. Peptides derived from these TAAs have been used to generate tumour-specific immune responses. An alternative strategy has been to immunise patients using viral vectors and plasmid cDNA encoding the TAA. In some studies, notably those in patients with advanced melanoma, significant clinical responses have been observed. Cell-based strategies including autologous tumour cell vaccines, allogeneic tumour cell vaccines and dendritic cell vaccines have been used, and significant responses have been reported in several studies. Few of these methods have so far been applied to breast cancer, but the possible benefits and drawbacks of such an approach will be discussed.


Fully automated quantification of cardiac chamber and function assessment in 2-D echocardiography: clinical feasibility of deep learning-based algorithms.
We aimed to compare the segmentation performance of the current prominent deep learning (DL) algorithms with ground-truth segmentations and to validate the reproducibility of the manually created 2D echocardiographic four cardiac chamber ground-truth annotation. Recently emerged DL based fully-automated chamber segmentation and function assessment methods have shown great potential for future application in aiding image acquisition, quantification, and suggestion for diagnosis. However, the performance of current DL algorithms have not previously been compared with each other. In addition, the reproducibility of ground-truth annotations which are the basis of these algorithms have not yet been fully validated. We retrospectively enrolled 500 consecutive patients who underwent transthoracic echocardiogram (TTE) from December 2019 to December 2020. Simple U-net, Res-U-net, and Dense-U-net algorithms were compared for the segmentation performances and clinical indices such as left atrial volume (LAV), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), LV mass, and ejection fraction (EF) were evaluated. The inter- and intra-observer variability analysis was performed by two expert sonographers for a randomly selected echocardiographic view in 100 patients (apical 2-chamber, apical 4-chamber, and parasternal short axis views). The overall performance of all DL methods was excellent [average dice similarity coefficient (DSC) 0.91 to 0.95 and average Intersection over union (IOU) 0.83 to 0.90], with the exception of LV wall area on PSAX view (average DSC of 0.83, IOU 0.72). In addition, there were no significant difference in clinical indices between ground truth and automated DL measurements. For inter- and intra-observer variability analysis, the overall intra observer reproducibility was excellent: LAV (ICC = 0.995), LVEDV (ICC = 0.996), LVESV (ICC = 0.997), LV mass (ICC = 0.991) and EF (ICC = 0.984). The inter-observer reproducibility was slightly lower as compared to intraobserver agreement: LAV (ICC = 0.976), LVEDV (ICC = 0.982), LVESV (ICC = 0.970), LV mass (ICC = 0.971), and EF (ICC = 0.899). The three current prominent DL-based fully automated methods are able to reliably perform four-chamber segmentation and quantification of clinical indices. Furthermore, we were able to validate the four cardiac chamber ground-truth annotation and demonstrate an overall excellent reproducibility, but still with some degree of inter-observer variability.


Skeletal age, dental age, and the maturation of KNM-WT 15000.
The skeleton of the Homo erectus boy from West Lake Turkana, Kenya (KNM-WT 15000), is remarkably complete, and this individual has thus provided a case study for several researchers examining Homo erectus growth. Using data from a longitudinal study of Montreal French-Canadian children, it is shown that while dental and skeletal ages match reasonably well at the level of a sample of children, individuals can display differences between skeletal and dental ages of 2 years or more. Furthermore, the relationship between these two markers may change over time in individual children. It is also possible to find children with patterns of dental maturation similar to KNM-WT 15000's pattern in the Montreal sample. Therefore, neither the discrepancy between skeletal age and dental age alone nor the pattern of dental maturation as assessed by dental stages precludes a human-like pattern of growth, including an adolescent growth spurt, for this individual. Some indicators (e.g., estimated body size for predicted age, and enamel formation) do suggest possible growth-patterning differences from modern humans, and therefore earlier maturation is a reasonable hypothesis, but caution is warranted, given the large degree of modern human variation in developmental markers and the inherent uncertainty in precise estimation of KNM-WT 15000's maturational parameters.


Hyperpolarized (13)C spectroscopy detects early changes in tumor vasculature and metabolism after VEGF neutralization.
No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent-enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, (13)C flux between hyperpolarized [1-(13)C]pyruvate and [1-(13)C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in (13)C flux from hyperpolarized [1-(13)C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-(13)C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized (13)C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death.


A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus.
Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection. The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials. Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered. The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA(1c)) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA(1c) goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved beta-cell function, as measured by homeostasis model assessment for beta-cell function analysis (20%-44%) and by ratios of pro-insulin to insulin (-0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient. Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.


Re-evaluation and re-construction of water purification system using soil. II. Removal of pollutants from infiltrating water.
Presented in this paper are the results of a series of column experiments and a pilot scale test conducted to develop the treatment system of freshwater and wastewater by their percolation through soil and the other materials at the rate of a few metres per day. Materials that had high ability to sorb fulvic acid (FA hereafter) and phosphate ion were selected based on the results of the batch sorption tests and were processed into beads before subjecting them to the column test. The results of the column experiment suggested that the reagents added to increase the strength of the beads reduced the sorption of FA, thus causing the early breakthrough of the FA injected into the column. Less effect from the bead processing was observed for the removal of phosphate ion. Pilot scale test showed that the removal of particulate fraction of phosphorus differed among the materials used. The bead processing technique that can ensure the high water permeability while maintaining the sorption capacity of the material was required for further development of the treatment system.


Divalent metal cation requirement and possible classification of cGMP-inhibited phosphodiesterase as a metallohydrolase.
cGMP-inhibited phosphodiesterase (cGI-PDE) has been found to require a divalent metal cation for cAMP hydrolysis. The cGI-PDE isolated from human platelets exhibited significantly higher enzymatic activity when incubated with Mn2+, Mg2+, and Co2+. The addition of Zn2+, Cd2+, Ca2+, K+, or Na+ to the enzyme did not enhance the activity and, when present in high concentration (> 1.0 microM), Zn2+ and Cd2+ inhibited the enzymatic activity of cGI-PDE. The inhibition by Zn2+ (and Cd2+) was partially prevented by preincubation of the enzyme with Mn2+. The enzyme was also inhibited by metal chelators EDTA and 1,10-phenanthroline and not by their non-metal-chelating analogs. The partial protection against chelation (and inhibition) was afforded by AMP (the product of cAMP hydrolysis).


Determining the angles of incidence in a LEED experiment.
A new method for determining the angles of incidence in a back-reflection, post-acceleration, fluorescent display LEED apparatus is presented which uses the angles between the diffraction spots on a photograph of the LEED pattern. Absolute accuracies better than 0.1 degrees for both incidence angles should be routinely available.


Dendrimer-based organic/inorganic hybrid nanoparticles in biomedical applications.
This review reports some recent advances on the synthesis, self-assembly, and biofunctionalization of various dendrimer-based organic/inorganic hybrid nanoparticles (NPs) for various biomedical applications, including but not limited to protein immobilization, gene delivery, and molecular diagnosis. In particular, targeted molecular imaging of cancer using dendrimer-based organic/inorganic hybrid NPs will be introduced in detail.


A Novel Injectable Hydrogel Matrix Loaded With 90Y Microspheres for the Treatment of Solid Tumors.
The need to concentrate the anti-tumoral activity of 90Y only to the targeted tumor, while minimizing its off-target effects, led to the development of an innovative device (BAT-90) composed of a hydrogel matrix and 90Y microspheres. This in vivo randomized study was planned to assess the efficacy, safety, and biodistribution of BAT-90 in 46 rabbits implanted with a VX2 tumor. The effects of BAT-90 were compared to those of 90Y microspheres and the hydrogel matrix. BAT-90 localized effectively the 90Y radiation in the injection site, minimizing dispersion of the microspheres in the target and distant organs of the treated animals. BAT-90 can be administered as an adjuvant treatment to clear surgical margins from any potential minimal residual disease, or as an alternative to other loco-regional treatments for non-resectable tumors.


Review of "Implications of Hormesis for Industrial Hygiene".
Hormesis is an appealing concept when considered from the evolutionary viewpoint. It may provide a new approach to deriving the "no observed adverse effect level" for occupational exposures to chemicals. An over-reliance on mathematical modeling without a clear understanding of exposures and health outcomes stymies current scientific decision-making. Care must be taken, however, as not all endpoints will exhibit a hormetic response.


Fiber tract-oriented statistics for quantitative diffusion tensor MRI analysis.
Diffusion tensor imaging (DTI) has become the major modality to study properties of white matter and the geometry of fiber tracts of the human brain. Clinical studies mostly focus on regional statistics of fractional anisotropy (FA) and mean diffusivity (MD) derived from tensors. Existing analysis techniques do not sufficiently take into account that the measurements are tensors, and thus require proper interpolation and statistics based on tensors, and that regions of interest are fiber tracts with complex spatial geometry. We propose a new framework for quantitative tract-oriented DTI analysis that includes tensor interpolation and averaging, using nonlinear Riemannian symmetric space. As a result, tracts of interest are represented by the geometry of the medial spine attributed with tensor statistics calculated within cross-sections. Examples from a clinical neuroimaging study of the early developing brain illustrate the potential of this new method to assess white matter fiber maturation and integrity.


Patients' Acceptance of COVID-19 Vaccine: Implications for Patients with Chronic Disease in Low-Resource Settings.
Coronavirus disease 2019 (COVID-19) has become a major global health challenge, with high morbidity and mortality. Despite different vaccines being produced around the globe, the spread of the virus is still uncontrolled. In particular, the shortage of vaccines in low-income countries is one of the key factors hindering efforts to reduce the spread of the virus. Even though evidence has been provided by different responsible bodies, there are still multiple beliefs and misconceptions about COVID-19 vaccination that have not yet been addressed. Nowadays, vaccine hesitancy is one of the top ten threats to global health, arising from the unwillingness of chronic patients to receive the vaccine. Chronic disease patients in low-resource settings are fearful of taking the vaccine because of a shortage of information about the COVID-19 vaccine. Therefore, the acceptance of the COVID-19 vaccine among chronic disease patients should be studied more widely in low-resource settings.


Ultralarge Area Sub-10 nm Plasmonic Nanogap Array by Block Copolymer Self-Assembly for Reliable High-Sensitivity SERS.
Effective surface enhancement of Raman scattering (SERS) requires strong near-field enhancement as well as effective light collection of plasmonic structures. To this end, plasmonic nanoparticle (NP) arrays with narrow gaps or sharp tips have been suggested as desirable structures. We present a highly dense and uniform Au nanoscale gap array enabled by the customized design of NP shape and arrangement employing block copolymer self-assembly. Block copolymer self-assembly in thin films offers uniform hexagonally packed nanopost template arrays over the entire surface of a 2 in. wafer. Conventional evaporative metal deposition over the nanotemplate surface allows precise geometric control and positional arrangement of metal NPs, constituting tunable, strong plasmonic near-field enhancement particularly at the "hot spots" near interparticular nanoscale gaps. Underlying field distribution has been investigated by a finite-difference time-domain simulation. In the detection of thiophenol, our Au nanogap array shows a remarkable enhancement of Raman intensity greater than ∼104, a standard deviation as small as 12.3% compared to that of the planar Au thin film. In addition, adenine biomolecules can be detected with a detection limit as low as 100 nM. Our approach proposes highly sensitive and reliable SERS on the basis of a scalable, low-cost bottom-up strategy.


Mineralization, biodegradation, and drug release behavior of gelatin/apatite composite microspheres for bone regeneration.
Gelatin microspheres are well-known for their capacity to release growth factors in a controlled manner, but gelatin microspheres do not calcify in the absence of so-called bioactive substances that induce deposition of calcium phosphate (CaP) bone mineral. This study has investigated if CaP nanocrystals can be incorporated into gelatin microspheres to render these inert microspheres bioactive without compromising the drug releasing properties of gelatin microspheres. Incorporation of CaP nanocrystals into gelatin microspheres resulted into reduced biodegradation and drug release rates, whereas their calcifying capacity increased strongly compared to inert gelatin microspheres. The reduced drug release rate was correlated to the reduced degradation rate as caused by a physical cross-linking effect of CaP nanocrystals dispersed in the gelatin matrix. Consequently, these composite microspheres combine beneficial drug-releasing properties of organic gelatin with the calcifying capacity of a dispersed CaP phase.


Alagille syndrome: an unusual presentation of an uncommon disease.
Alagille syndrome is a rare genetic disorder that results in intrahepatic cholestasis. Cardiac involvement mainly involves stenosis of branches of the pulmonary arteries. Aortic valve involvement is less common. To our knowledge, this is the first case of Alagille syndrome associated with severe aortic stenosis due to a bicuspid aortic valve.


[In vitro metabolic interaction between diphenytriazol and steroid hormone drugs].
To observe the metabolic interaction between diphenytriazol and steroid hormone drugs, and provide some useful information for clinical medication. The steroid hormone drugs which may be co-administrated with diphenytriazol were selected, such as mifepriston, estradiol, medroxyprogesterone acetate, progesterone, norethisterone and so on. Diphenytriazol was incubated with each drug in rat liver microsome. The residual concentration of diphenytriazol or steroid hormone drugs in the microsomal incubates was determined by reversed-phase high-performance liquid chromatography, separately. The inhibition constants (K(i)) for each of them were calculated. The inhibition constant K(is) of diphenytriazol for the metabolism of mifepristone, estradiol, medroxyprogesterone acetate, progesterone and norethisterone were (201.3 +/- 1.0), (94 +/- 4), (128.7 +/- 2.2), (64 +/- 5) and (80 +/- 4) micromol x L(-1), respectively. The inhibition constants K(i) of steroid hormone drugs for the metabolism of diphenytriazol was (66.9 +/- 2.2) micromol x L(-1) for estradiol, (60.0 +/- 2.3) micromol x L(-1) for medroxyprogesterone acetate, (163 +/- 10) micromol x L(-1) for progesterone and (88 +/- 5) micromol x L(-1) for norethisterone, respectively. Diphenytriazol shows metabolism interaction with steroid hormone drugs such as estradiol, medroxyprogesterone acetate, progesterone and norethisterone.


G-quadruplex occurrence and conservation: more than just a question of guanine-cytosine content.
G-quadruplexes are motifs found in DNA and RNA that can fold into tertiary structures. Until now, they have been studied experimentally mainly in humans and a few other species. Recently, predictions have been made with bacterial and archaeal genomes. Nevertheless, a global comparison of predicted G4s (pG4s) across and within the three living kingdoms has not been addressed. In this study, we aimed to predict G4s in genes and transcripts of all kingdoms of living organisms and investigated the differences in their distributions. The relation of the predictions with GC content was studied. It appears that GC content is not the only parameter impacting G4 predictions and abundance. The distribution of pG4 densities varies depending on the class of transcripts and the group of species. Indeed, we have observed that, in coding transcripts, there are more predicted G4s than expected for eukaryotes but not for archaea and bacteria, while in noncoding transcripts, there are as many or fewer predicted G4s in all species groups. We even noticed that some species with the same GC content presented different pG4 profiles. For instance, Leishmania major and Chlamydomonas reinhardtii both have 60% of GC content, but the former has a pG4 density of 0.07 and the latter 1.16.


Transition Probabilities of Co ii Weak Lines to the Ground and Low Metastable Levels.
New branching fraction (BF) measurements based primarily on data from a cross-dispersed echelle spectrometer are reported for 84 lines of Co ii. The BFs for 82 lines are converted to absolute atomic transition probabilities using radiative lifetimes from laser-induced fluorescence (LIF) measurements on 19 upper levels of the lines. A lifetime of 3.3(2) ns for the z5D0 level is used based on LIF measurements for lifetimes of the four other levels in the z5D term. Twelve of the eighty-four lines are weak transitions connecting to the ground and low metastable levels of Co+. Another 46 lines are strong transitions connecting to the ground and low metastable levels of Co+. For these lines, log(gf) values were measured in earlier studies and, with a few exceptions, are confirmed in this study. Such lines, if unblended in stellar spectra, have the potential to yield Co abundance values unaffected by any breakdown of the local thermodynamic equilibrium approximation in stellar photospheres because the ground and low metastable levels of Co+ are the primary population reservoirs of Co in the photospheres of interest. Weak lines, if unblended, are useful in photospheres with high Co abundance, and strong lines are useful in metal-poor photospheres. New hyperfine structure A constants for 28 levels of ionized Co from least-squares fits to Fourier transform spectra line profiles are reported. These laboratory data are applied to re-determine the Co abundance in the metal-poor halo star HD 84937. BFs and transition probabilities for 19 lines are reported for the first time.


Intraoral anastomosis of a prelaminated radial forearm flap in reconstruction of a large persistent cleft palate.
In this report, we present a case of a prelaminated radial forearm flap in reconstruction of a large persistent cleft palate with transoral single arterial and three venous anastomoses. A 17-years-old female patient presented a large cleft palate defect and complete dentition, dysmelia of both arms and bilateral thumb aplasia. A radial flap was prelaminated using oral mucosa 5 days prior to transplantation. Five days after flap prelamination, the facial artery and vein, submandibular vein, and a venous branch to the masseter muscle behind the buccinator muscle fibers were exposed through an intraoral incision lateral to the inferior right mucogingival junction. The radial artery, its bilateral accompanying veins, and the cephalic vein of transplanted flap were anastomosed transorally to the facial vessels, submandibular vein, and masseter branch. The vessel pedicle ran through the palatoglossal arch dorsal to the second upper molar. Good flow and flap perfusion were evinced, and further-on successful healing was achieved. The case encourages similar treatment in comparable situations avoiding facial nerve hazard and extraoral scars.


Effectiveness of CKD Exacerbation Countermeasures in Izumo City.
To diagnose chronic kidney disease (CKD) at an early stage, it is important to promote appropriate health guidance and consultation recommendations through regular medical examinations and implementation of continuous high-quality and appropriate treatment. From fiscal year (FY) 2018, Izumo City has initiated the "Izumo City CKD Exacerbation Countermeasures" program. In this study, we aimed to report on the methods undertaken and the effects of this program. Residents aged 40-74 years who underwent specific health checkups from the Izumo City National Health Insurance in FY2018 and FY2019 were included. The rates of CKD re-examination candidates, re-examinations implementation, nephrologist referrals, and health guidance referrals between FY2018 and FY2019 were compared. The rate of CKD re-examination candidates in both years remained unchanged at approximately 7%. The rate of re-examination implementation in FY2019 significantly increased relative to that in FY2018 (p < 0.001). Subsequent re-examination candidate trends showed that the rate of nephrologist referrals did not increase. However, the rate of city health guidance referrals significantly increased (p < 0.001). Increase in the re-examination and health guidance examination rates indicate improved awareness of CKD among the public and family doctors, and it is expected to prevent CKD exacerbation in the future.


Role of decreased levels of Fis histone-like protein in Crohn's disease-associated adherent invasive Escherichia coli LF82 bacteria interacting with intestinal epithelial cells.
The interaction of Crohn's disease (CD)-associated adherent-invasive Escherichia coli (AIEC) strain LF82 with intestinal epithelial cells depends on surface appendages, such as type 1 pili and flagella. Histone-like proteins operate as global regulators to control the expression of these virulence factors. We evaluated the role of histone-like proteins in AIEC reference strain LF82 during infection of intestinal epithelial cells, Intestine-407, and observed that the fis mRNA level was decreased. The role of Fis in AIEC LF82 was determined by studying the phenotype of an LF82 fis::Km mutant. This was the first mutant of strain LF82 that has been described thus far that is unable to express flagellin but still able to produce type 1 pili. The cyclic-di-GMP pathway linking flagella and type 1 pilus expression is not involved in Fis-mediated regulation, and we identified in the present study Fis-binding sites located upstream of the fimE gene and in the intergenic region between fimB and nanC of the fim operon encoding type 1 pili. The major consequence of decreased Fis expression in AIEC bacteria in contact with host cells is a direct downregulation of fimE expression, leading to the preferential ON phase of the fimS element. Thus, by maintaining type 1 pilus expression, AIEC bacteria, which interact with the gut mucosa, have greater ability to colonize and to induce inflammation in CD patients.


Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist.
Glomerular injury is characterized by mesangial cell (MC) proliferation and matrix formation. We sought to determine if reducing the activity of cyclin-dependent kinase 2 (CDK2) with the purine analogue, Roscovitine, decreased MC proliferation in vitro and in vivo. Roscovitine (25 microM) inhibited FCS-induced proliferation (P < 0.0001) in cultured MC. Rats with experimental mesangial proliferative glomerulonephritis (Thy1 model) were divided into two groups. A prevention group received daily intraperitoneal injections of Roscovitine in DMSO (2.8 mg/kg) starting at day 1. A treatment group received daily Roscovitine starting at day 3, when MC proliferation was established. Control Thy1 rats received DMSO alone. MC proliferation (PCNA +/OX7 + double immunostaining) was reduced by > 50% at days 5 and 10 in the Roscovitine prevention group, and at day 5 in the treatment group (P < 0.0001). Early administration of Roscovitine reduced immunostaining for collagen type IV, laminin, and fibronectin at days 5 and 10 (r = 0.984; P < 0.001), which was associated with improved renal function (urinary protein/creatinine, blood urea nitrogen, P < 0.05). We conclude that reducing the activity of CDK2 with Roscovitine in experimental glomerulonephritis decreases cell proliferation and matrix production, resulting in improved renal function, and may be a useful therapeutic intervention in disease characterized by proliferation.


"Normal" prevertebral soft tissue swelling following elective anterior cervical decompression and fusion.
Prevertebral soft tissue swelling (PSTS) has been evaluated in the setting of traumatic cervical spine injuries. However, no study to date has quantified the PSTS following elective anterior cervical decompression and fusion or the time course to resolution of that swelling. From May 2002 to May 2005 the senior author performed 193 elective 1- or 2-level anterior cervical decompression and fusions. Patients who underwent corpectomies and anterior cervical fusions for trauma or tumor were excluded. Preoperative, 2-week postoperative and 6-week postoperative radiographs were available on 100 patients. The prevertebral soft tissue stripe was measured on the neutral lateral radiographs for the 3 time points. The mean swelling (mm) for each time point was calculated and stratified by cervical level. Repeated measures analysis of variance with the Tukey-Kramer multiple comparisons test was used to compare the measured swelling at the various time points. The average PSTS was calculated for each cervical level, for each of the 3 time points, preoperative, 2- and 6-week postoperative. There was a significant increase in PSTS between the preoperative and 2-week postoperative measurements at all levels. There is a significant decrease in PSTS between 2- and 6-week postoperatively at all cervical levels. There is no significant change in PSTS at C2, C3, and C5, when comparing the preoperative and 6-week postoperative measurements. There is significant PSTS at C4, C6, and C7, when comparing preoperative and 6-week postoperative measurements. The "normal" range for PSTS at 2 weeks and at 6 weeks after elective 1- and 2- level anterior cervical decompression and fusions is described. Our data demonstrates that edema persists at the 2-week follow-up. By 6 weeks postoperative, the increased PSTS has greatly dissipated.


Clinical or Imaging Diagnosis of the Current Medical Practice for Superior Vena Cava Syndrome?
Most cases of superior vena cava syndrome are easily diagnosed bya clinical examination alone, but several diagnostic tests and procedures can be helpful. When a patient presentswith a suspected diagnosis of superior vena cava syndrome, the first step is to obtain an imaging study that confirms the diagnosis and aids treatment decisions. Magnetic resonance imaging, contrast-enhanced CT scanning, radionuclide flow studies and traditional venography are all appropriate techniques. Still, the CT scan is the most readily available technology in most centers. The CT scan and magnetic resonance imaging also provide information on possible etiologies and can therefore direct the approach towards a tissue diagnosis.