Prevalence of urinary frequency in Taiwanese women aged 20-59 years.
To evaluate the prevalence of daytime urinary frequency among Taiwanese women aged 20-59 years. In 1998, there were an estimated 5.9 million female residents aged 20-59 years in Taiwan. A random sample of 4,549 women was chosen by multistage sampling. Face-to-face visits with 3,537 women were completed by trained professional interviewers within 3 months of the subjects' selection. Questions about lower urinary tract symptoms, sociodemographics, reproduction, and medical and surgical histories were recorded. The factors were assessed by frequency and logistic regression analyses using a significance level of less than 0.05. The prevalence of urinary frequency in Taiwanese women aged 20-59 years was 5.2% (182/3,519); 18 interviewees did not answer the question about frequency and were excluded. For those who complained of frequency, 47.2% voided 8-15 times a day, 37.4% voided 16-23 times a day, 1.1% voided 24-31 times a day and 14.3% voided more than 31 times a day. The prevalence of urinary frequency was not linked to age (p = 0.326). Urinary frequency is a common symptom in women of all ages and is not significantly related to age. More than half of the women interviewed admitted that less than an hour occurred between visits to the restroom during the daytime.


Wear of the Primary WaveOne single file when shaping vestibular root canals of first maxillary molar.
It is very important for a clinician to know the increased wear of mechanized files when establishing endodontic therapy. The aim of this study was to check the wear of the Primary WaveOne file upon shaping two, four and six maxillary molar vestibular canals. The deterioration of 40 files, divided into four groups, was evaluated microscopically: group 1, control (unused); group 2, two canals; group 3, four canals; and group 4, six canals. After instrumentation, the files were embedded in resin and sectioned at their apical third into three equal parts. To analyze the wear of edges in the different sections, AutoCAD software was used and analysis of variance (ANOVA) was then performed to compare the mean rake angles. The files with two and four uses showed slight wear, whereas those with six applications showed significant wear (p<0.05). Primary WaveOne files can be used in up to four root canals without their edges losing effectiveness. Key words:Files wear, reciprocating motion, shaping capacity, WaveOne.


The risk of acute kidney injury following transapical versus transfemoral transcatheter aortic valve replacement: a systematic review and meta-analysis.
The aim of this systematic review is to examine the literature for the risk of acute kidney injury (AKI) in patients who underwent transcatheter aortic valve replacement (TAVR) based on transapical (TA) versus transfemoral (TF) approaches. A literature search was conducted utilizing Embase, Medline, Cochrane Database of Systematic Reviews and ClinicalTrials.gov from inception through December 2015. Studies that reported relative risk, odds ratio or hazard ratio comparing the AKI risk in patients who underwent TA-TAVR versus TF-TAVR were included. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated using a random effect, generic inverse variance method. Seventeen cohort studies with 5085 patients were enrolled in the analysis to assess the risk of AKI in patients undergoing TA-TAVR versus TF-TAVR. The pooled RR of AKI in patients who underwent TA-TAVR was 2.26 (95% CI 1.79-2.86) when compared with TF-TAVR. When meta-analysis was confined to the studies with adjusted analysis for confounders evaluating the risk of AKI following TAVR, the pooled RR of TA-TAVR was 2.89 (95% CI 2.12-3.94). The risk for moderate to severe AKI [RR 1.02 (95% CI 0.57-1.80)] in patients who underwent TA-TAVR compared with TF-TAVR was not significantly higher. Our meta-analysis demonstrates an association between TA-TAVR and a higher risk of AKI. Future studies are required to assess the risks of moderate to severe AKI and mortality following TA-TAVR versus TF-TAVR.


Using a practical approach for determining the most effective stretching strategy in female college division I volleyball players.
The purpose of this investigation was to quantify the effects that a practical bout of static stretching (SS) and dynamic stretching (DS) has on maximal countermovement jump (CMJ) height across a time spectrum of 25 minutes in National Collegiate Athletic Association Division I varsity volleyball players. Eleven female varsity volleyball players (mean ± SD; age 20.00 ± 1.55 years; height 1.78 ± 0.08 m; mass 74.55 ± 12.18 kg) volunteered for this investigation. Three days of randomized experimental testing (SS, DS, control) were completed. The SS protocol consisted of stretching 7 muscle groups. The DS protocol consisted of the volleyball team's actual DS routine of equal duration (30 seconds) to SS. Poststretch performance measures of CMJ were determined at 1, 5, 15, and 25 minutes poststretch. Countermovement jump had an acute significant trial-by-time interaction, indicating that DS was found to produce significantly higher scores than the SS and control session at 1 and 5 minutes poststretch, but not at 15 and 25 minutes poststretch. Additionally, there was a timing interaction within trials where SS scores were significantly lower at 1 minute poststretch compared with 5 and 25 minutes poststretch, and DS scores were significantly higher at 1 and 5 minutes poststretch compared with 15 and 25 minutes poststretch. Athletes engaging in competitive power sports should continue to utilize their DS routine but may need to do so within 5 minutes before activity.


Deep Pathway Analysis V2.0: A Pathway Analysis Framework Incorporating Multi-Dimensional Omics Data.
Pathway analysis is essential in cancer research particularly when scientists attempt to derive interpretation from genome-wide high-throughput experimental data. If pathway information is organized into a network topology, its use in interpreting omics data can become very powerful. In this paper, we propose a topology-based pathway analysis method, called DPA V2.0, which can combine multiple heterogeneous omics data types in its analysis. In this method, each pathway route is encoded as a Bayesian network which is initialized with a sequence of conditional probabilities specifically designed to encode directionality of regulatory relationships defined in the pathway. Unlike other topology-based pathway tools, DPA is capable of identifying pathway routes as representatives of perturbed regulatory signals. We demonstrate the effectiveness of our model by applying it to two well-established TCGA data sets, namely, breast cancer study (BRCA) and ovarian cancer study (OV). The analysis combines mRNA-seq, mutation, copy number variation, and phosphorylation data publicly available for both TCGA data sets. We performed survival analysis and patient subtype analysis and the analysis outcomes revealed the anticipated strengths of our model. We hope that the availability of our model encourages wet lab scientists to generate extra data sets to reap the benefits of using multiple data types in pathway analysis. The majority of pathways distinguished can be confirmed by biological literature. Moreover, the proportion of correctly indentified pathways is 10 percent higher than previous work where only mRNA-seq and mutation data is incorporated for breast cancer patients. Consequently, such an in-depth pathway analysis incorporating more diverse data can give rise to the accuracy of perturbed pathway detection.


Does bone mineral density affect hip fracture severity?
The association between hip fracture and reduced bone mineral density is well documented, with reduced bone mineral density predisposing to fracture. However, it is unknown whether an association exists between the magnitude of bone density lost and the severity of the hip fracture sustained. One hundred forty-two patients (96 women, 46 men) with a mean age of 74 years (range, 49-92 years) who sustained a hip fracture following a simple ground-level fall and were treated for this injury were reviewed. All patients had undergone dual-energy x-ray absorptiometry bone scanning of the contralateral hip and lumbar spine. Fractures were classified as intra- or extracapsular or subtrochanteric and then subclassified by degree of severity as simple (stable) or multifragmentary (unstable) fracture patterns.Although a low hip bone mineral density (T- or Z score <2.5) was associated with an increased risk of extracapsular fracture (P=.025) compared with other fracture types, no association existed between bone mineral density and the severity of the resultant hip fracture. Although an association exists between bone mineral density and the risk of fragility fractures, the results of the current study suggest that the severity of hip fractures does not follow this correlation. Therefore, no assumption can be made about bone mineral density of the proximal femur based on the severity of the fracture observed on plain radiographs.


Calcium transients in infant human atrial myocytes.
Isolated infant human atrial cells have a slower early repolarization than adult human atrial cells. In addition, from room temperature voltage-clamp studies, infant cells have lower basal L-type calcium currents than adult cells. We hypothesized that the slower repolarization increases the calcium transient of infant human atrial cells. Atrial myocytes were enzymatically dissociated from biopsies of human right atrial appendages of infant (3-8 mo) patients who were undergoing open-heart surgery. Intracellular calcium transients were measured with fluorescence microscopy with application of either square waves or action potential waveforms at physiologic temperature. After repetitive application (1 Hz) of 100-ms duration conditioning depolarizations to 10 mV (from -80 mV), a test pulse of varying duration (DeltaT; 2-100 ms) produced smaller transients (expressed as percentage of the last conditioning pulse) at shorter durations (33 +/- 7% for DeltaT = 2 ms, 80 +/- 4% for DeltaT = 25 ms). With repetitive application of either adult or infant prerecorded action potentials to infant cells, the cells had a decreased calcium transient with the adult action potential (F/F(0) 2.2 +/- 0.4 for infant action potential versus 1.6 +/- 0.2 for adult action potential; n = 7; p < 0.05). The delayed early repolarization of infant cells alters the Ca(2+) transient, which may compensate for the lower availability of basal calcium current in infant cells. The steep relationship that we have demonstrated between test-pulse duration and the calcium transient suggests that modulation of the early repolarization phase of the action potential may be of great significance in modulating excitation-contraction coupling.


Comparative Assessment of Cytokine Pattern in Early and Late Onset of Neonatal Sepsis.
Neonatal sepsis is a significant health issue associated with high mortality. Immune responses associated with neonatal sepsis, such as proinflammatory cytokine production, are believed to play a central role in the pathogenesis of this disease. In the present study, serum levels of the proinflammatory cytokines TNF-α, IL1-β, and IL-6 and the anti-inflammatory cytokines IL-4 and IL-10 were evaluated for 25 subjects with neonatal sepsis. We observed that subjects with late onset of sepsis (LOS), as well as those with early onset of sepsis (EOS), had a substantial increase in serum TNF-α. In contrast to EOS, subjects with LOS demonstrated a significant increase in serum levels IL-6 and IL-10. Additionally, we observed a significant difference in cytokine profiles between acute and postacute cases of neonatal sepsis. For instance, the level of proinflammatory cytokines, such as TNF-α and IL-6, was elevated in the acute phase, whereas the production of anti-inflammatory cytokines, such as IL-10, became substantially upregulated during the postacute phase. Additionally, no correlation was observed between cytokine levels and CRP levels or lymphocyte counts. Thus, in contrast to CRP levels and lymphocyte counts, examination of the cytokine profile can provide valuable information when determining the most effective therapy for treating neonatal sepsis. This information may be useful to physicians when determining if anti-inflammatory or immune stimulatory therapy is warranted.


Maintenance of an undifferentiated state of human-induced pluripotent stem cells through botulinum hemagglutinin-mediated regulation of cell behavior.
Applications of human induced pluripotent stem cell (hiPSC) culture are impaired by problems with long term maintenance of pluripotency. In this study, we report that exposure to botulinum hemagglutinin (HA), an E-cadherin function-blocking agent, suppressed deviation from an undifferentiated state in hiPSC colonies. Time-lapse imaging of live cells revealed that cells in central regions of colonies moved slowly and underwent a morphological change to a cobblestone-like shape via interaction between contacting cells, forming dense, multiple layers. Staining and migration analysis showed that actin stress fibers and paxillin spots were diminished in colony central regions, and this was associated with alteration of cellular morphology and migratory behavior. However, in culture with HA exposure, cells in the central and peripheral regions of hiPSC colonies were migratory and arranged in loose monolayers, resulting in relatively uniform dispersion of cells in colonies. We also found that a well-organized network of actin stress fibers was of significance in the central and peripheral regions of a colony, resulting in activation of paxillin and E-cadherin expression in hiPSCs. After routine application of HA for serial passages, hiPSCs remained pluripotent and capable of differentiating into all three germ layers. These observations indicate that relaxation of cell-cell junctions by HA induced rearrangements of the cytoskeleton and cell adhesion in hiPSC colonies by promoting migratory behaviors. These results suggest that this simple and readily reproducible culture strategy is a potentially useful tool for improving the robust and scalable maintenance of undifferentiated hiPSC cultures.


Chromatin-Remodeling Genes Promote Immunotherapy Resistance.
Two studies show that genes that encode a chromatin-remodeling complex foster resistance to checkpoint inhibitors. One study identified the proteins by using CRISPR/Cas9 to knock out genes in mouse melanoma cells. The other study converged on the same result by identifying mutations in patients with clear cell renal cell carcinoma who responded to PD-1 inhibitors.


New techniques to understand chromosome dosage: mouse models of aneuploidy.
Aberrations in human chromosome copy number and structure are common and extremely deleterious. Their downstream effects on phenotype are caused by aberrant dosage of sequences in the affected regions. However, we know little about why the abnormal gene copy number causes disease or why specific features result from deficits in specific chromosomes. Mice are the organism of choice to help us try to tease apart the complex relationships between genotype and phenotype in aneuploidy and segmental aneusomy syndromes. As new technologies such as chromosome engineering and the creation of transchromosomic mice become routine, these will help us identify individual dosage-sensitive genes that are causative in specific syndromes and will enable us to produce mouse models to accurately recapitulate human chromosomal disorders.


Cell Penetrating Peptides: A Promising Tool for the Cellular Uptake of Macromolecular Drugs.
The lipid bilayer of the plasma membrane is a selective impermeable barrier for the internalization of most macromolecules. Cell penetrating peptides (CPPs) could cross the plasma membrane barrier to deliver various molecules into cells and are considered as a promising tool to deliver macromolecular drugs. However, the exact cellular uptake mechanisms of CPPs are still ambiguous. It was reported that the exact cellular uptake pathway was determined by numerous factors such as the amino acid sequences (hydrophobicity and net charge), extracellular CPP concentration, cargoes' properties, cell type and the temperature. No matter what kind of mechanisms, the electrostatic interaction between the positive charged amino acids and the membrane with negatively charged glycosaminoglycans (GAGs), especially heparan sulphate proteoglycans (HSPGs), was supposed to be the first crucial step for CPPs uptake. The first recognition triggers cytoskeletal remodeling via activating Rho/Rac GTPases and kinase C, followed by the cell surface microdomains changing, ligand binding and cellular uptake. This review briefly discusses the classification, structure-activity relationships, cellular uptake mechanisms and biomedical applications of CPPs.


Intestinal pseudo-obstruction as a complication of paragangliomas: case report and literature review.
Intestinal pseudo-obstruction is a rare and relatively unknown complication of phaeochromocytoma÷ paraganglioma (PCC÷PGL). Its pathophysiology can be explained by the hypersecretion of catecholamines, which may reduce the peristaltic activity of the gastrointestinal tract. Clinically, this can result in chronic constipation, intestinal pseudo-obstruction or even intestinal perforation. We conducted a comprehensive literature search and retrieved 34 cases of pseudo-obstruction caused by either benign or malignant PCC÷PGL. We also included a case from our centre that has not been described earlier. We conclude that intestinal pseudo-obstruction is a rare but potentially life-threatening complication of PCC÷PGL. Intravenous administration of phentolamine is the most frequently described treatment when surgical resection of the PCC÷PGL is not feasible.


[Factors associated with educational guidance regarding oral health during prenatal care].
The scope of this article is to verify the factors associated with providing educational guidance related to oral health during prenatal care in the Metropolitan Region of Greater Vitória - ES, Brazil. It involved a cross-sectional study of 1,035 postpartum women in public or affiliated private hospitals in the SUS in 2010. A descriptive analysis of the main educational information and binomial logistic regression was conducted to test the association between individual and contextual variables and "receiving educational guidance through meetings and/or pregnant mother groups in the health unit and/or through home visits". The information given most during prenatal care was "the advantage of exclusive breastfeeding until six months of life" (52.0%) and least was "the importance of fluoride use in health" (18.9%). Being attended by the Family Health Strategy (FHS) (OR=1.94), having adequate living conditions for women and children (OR=1.73) and an additional prenatal visit (OR=1.08), increased the chance of providing educational guidance in prenatal care. Frequent pre-natal visits, coverage of health services in line with the FHS, and adequate conditions of housing were factors that were positively associated with educational guidance during prenatal care.


Synthesis of p-Azaquinodimethane-based Quinoidal Fluorophores.
Quinoidal π-conjugated systems are sought-after materials for semiconducting applications because of their rich optical and electronic characteristics. However, the analogous fluorescent compounds are extremely rare, with just two reports in the literature. Here, we present the design and development of a third series of quinoidal fluorophores [(2,5-diarylidene)-3,6-bis(hexyloxy)-2,5-dihydropyrazine (Q1-Q5)] that incorporates p-azaquinodimethane. The fluorophores are synthesized in a two-step synthetic approach employing Knoevenagel condensation of N,N-diacetyl-piperazine-2,5-dione with different aromatic aldehydes followed by O-alkylation in high yields. Q1-Q5 are strongly emissive, and by altering the aryl-substituents, the emission colors can be modulated from blue to orange. The compounds possess emission maxima (λem) at 475-555 nm in the solution state and 510-610 nm in the solid state, with fluorescence quantum yields of up to 60%. To the best of our knowledge, the reported systems are the first quinoidal dual-state emissive (solution- and solid-state) compounds. In trifluoroacetic acid, Q5 exhibits halochromic behavior, with a dramatic color change from yellow to blue. Furthermore, the preliminary fluorescent sensing studies demonstrated that Q5 could act as a selective turn-off fluorescence probe for electron-deficient picric acid (PA), with an emission quenching of >90% in the solution state. The thin-layer chromatography (TLC) strip sensor of Q5 was also designed to detect PA in water.


Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells.
To determine the ocular anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA) in primary human conjunctival fibroblasts and epithelial cells. Two primary human conjunctival cell types, human conjunctival epithelial cells (HConEpiC) and human conjunctival fibroblasts (HConF), were challenged with interleukin-4 (IL-4) or IL-13 plus tumor necrosis factor-alpha (TNF-α). Luminex technology was used to profile the resulting inflammatory response. The effects of mapracorat on the release of eotaxin and regulated on activation, normal T cell expressed and secreted (RANTES), two allergy-related chemokines, as well as proinflammatory cytokines and intercellular adhesion molecule 1 (ICAM-1) were then determined. Small interfering RNA was used to determine whether the effects of mapracorat were mediated via the glucocorticoid receptor (GR). Dexamethasone was used as the control. IL-13 or IL-4 plus TNF-α in the HConF or HConEpiC significantly increased eotaxin-1 (HConF only), eotaxin-3, RANTES, multiple proinflammatory cytokines, and ICAM-1. Synergistic effects of IL-13 or IL-4 plus TNF-α were observed in the HConEpiC for RANTES and monocyte chemoattractant protein-1, and in the HConF for eotaxin-1, eotaxin-3, and RANTES. Mapracorat significantly reduced IL-4 or IL-13 plus TNF-α-induced cytokine release and ICAM-1 protein in a dose-dependent manner in both cell types, with comparable efficacy to dexamethasone. These effects were mediated through the glucocorticoid receptor (GR), as demonstrated by the reversal of inhibitory effects after silencing of glucocorticoid receptor expression. Data from these in vitro models indicate that mapracorat is efficacious and potent in reducing IL-4 or IL-13 plus TNF-α-induced release of allergy-related and proinflammatory cytokines from the HConF and the HConEpiC, supporting clinical evaluation of the compound in reducing allergic and inflammatory reactions in allergic conjunctivitis.


Does Early Childhood Vaccination Protect Against COVID-19?
The coronavirus disease 2019 (COVID-19) is an on-going pandemic caused by the SARS-coronavirus-2 (SARS-CoV-2) which targets the respiratory system of humans. The published data show that children, unlike adults, are less susceptible to contracting the disease. This article aims at understanding why children constitute a minor group among hospitalized COVID-19 patients. Here, we hypothesize that the measles, mumps, and rubella (MMR) vaccine could provide a broad neutralizing antibody against numbers of diseases, including COVID-19. Our hypothesis is based on the 30 amino acid sequence homology between the SARS-CoV-2 Spike (S) glycoprotein (PDB: 6VSB) of both the measles virus fusion (F1) glycoprotein (PDB: 5YXW_B) and the rubella virus envelope (E1) glycoprotein (PDB: 4ADG_A). Computational analysis of the homologous region detected the sequence as antigenic epitopes in both measles and rubella. Therefore, we believe that humoral immunity, created through the MMR vaccination, provides children with advantageous protection against COVID-19 as well, however, an experimental analysis is required.


Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia.
Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.


Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study.
Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.


Synthesis and chemistry of zwitterionic tantala-3-boratacyclopentenes: olefin-like reactivity of a borataalkene ligand.
The compounds, where Cp' = C(5)H(5), a series, and C(5)H(4)Me, b series, are generated via treatment of with HB(C(6)F(5))(2). When allowed to undergo irreversible methane loss in the presence of an excess of the sterically modest alkynes 2-butyne or phenylacetylene, the putative intermediates 1a and 1b are trapped as the tantala-3-boratacyclopentene compounds 2 and 3, respectively. In these complexes, the alkyne and borataalkene ligands have reductively coupled at the d(2) tantalum center. For the unsymmetrical alkyne, a kinetic product resulting from coupling in the opposite regiochemical sense is observed; the thermodynamic products 3-t incorporate the phenyl group in the alpha position of the tantalaboratacyclic ring. Two of these compounds (2b and 3b-t) were characterized crystallographically. For bulkier alkynes (diphenylacetylene, 1-phenyl-1-propyne, and 3-hexyne), intermediates with similar spectroscopic properties to the tantala-3-boratacyclopentenes were observed, but the ultimate products were the vinylalkylidene compounds 5-(R,R'). Compound 5-(Ph,Me) was characterized crystallographically, and it was found that the vinylalkylidene binds to the metal in an eta(1)-bonding mode, with the tantalum center receiving further ligation through a hydridoborate moiety. Mechanistic studies suggest that these products arise via retrocyclization of the tantala-3-boratacyclopentenes formed kinetically. These studies represent the first studies concerning the reactivity of a borataalkene ligand at a transition metal center and show that it can behave in an "olefin-like" manner, despite having a more flexible array of bonding modes available to it than an olefin.


Carotid stenting without angioplasty.
Carotid angioplasty and stenting is gaining popularity as an alternative to carotid endarterectomy for the treatment of carotid bifurcation stenosis. The major concern with the procedure is the risk of embolic stroke which may be initiated by balloon angioplasty of friable atherosclerotic plaque. Elimination of angioplasty may result in a lower incidence of embolic complications. We describe a case in which a self-expanding stent alone, without balloon angioplasty, was used to successfully dilate an atherosclerotic stenosis of the carotid bifurcation. A moderate increase in vessel diameter, from 75% to 50%, was immediately observed after stent placement alone. No embolic complications were observed and follow-up plain film and ultrasound examinations showed progressive stent enlargement with excellent anatomic and hemodynamic results. In this case of severe carotid stenosis, the use of a self-expanding stent alone, without balloon angioplasty, resulted in excellent anatomic and hemodynamic improvement.


A Versatile Method of Patterning Proteins and Cells.
Substrate and cell patterning techniques are widely used in cell biology to study cell-to-cell and cell-to-substrate interactions. Conventional patterning techniques work well only with simple shapes, small areas and selected bio-materials. This article describes a method to distribute cell suspensions as well as substrate solutions into complex, long, closed (dead-end) polydimethylsiloxane (PDMS) microchannels using negative pressure. This method enables researchers to pattern multiple substrates including fibronectin, collagen, antibodies (Sal-1), poly-D-lysine (PDL), and laminin. Patterning of substrates allows one to indirectly pattern a variety of cells. We have tested C2C12 myoblasts, the PC12 neuronal cell line, embryonic rat cortical neurons, and amphibian retinal neurons. In addition, we demonstrate that this technique can directly pattern fibroblasts in microfluidic channels via brief application of a low vacuum on cell suspensions. The low vacuum does not significantly decrease cell viability as shown by cell viability assays. Modifications are discussed for application of the method to different cell and substrate types. This technique allows researchers to pattern cells and proteins in specific patterns without the need for exotic materials or equipment and can be done in any laboratory with a vacuum.


An adaptable multiple power source for mass spectrometry and other scientific instruments.
An Adaptable Multiple Power Source (AMPS) system has been designed and constructed. The AMPS system can provide up to 16 direct current (DC) (±400 V; 5 mA), 4 radio frequency (RF) (two 500 VPP sinusoidal signals each, 0.5-5 MHz) channels, 2 high voltage sources (±6 kV), and one ∼40 W, 250 °C temperature-regulated heater. The system is controlled by a microcontroller, capable of communicating with its front panel or a computer. It can assign not only pre-saved fixed DC and RF signals but also profiled DC voltages. The AMPS system is capable of driving many mass spectrometry components and ancillary devices and can be adapted to other instrumentation/engineering projects.


[Hohmann's procedure for epicodylitis humeri ulnaris (author's transl)].
Report about 4 operations using Hohmann's procedure in therapy-resistent epicondylitis humeri ulnaris. The ulnar nerve was not seen during operation. The intervention is as simple as on the radial side. It can be recommended.


Wobble inosine tRNA modification is essential to cell cycle progression in G(1)/S and G(2)/M transitions in fission yeast.
Inosine (I) at position 34 (wobble position) of tRNA is formed by the hydrolytic deamination of a genomically encoded adenosine (A). The enzyme catalyzing this reaction, termed tRNA A:34 deaminase, is the heterodimeric Tad2p/ADAT2.Tad3p/ADAT3 complex in eukaryotes. In budding yeast, deletion of each subunit is lethal, indicating that the wobble inosine tRNA modification is essential for viability; however, most of its physiological roles remain unknown. To identify novel cell cycle mutants in fission yeast, we isolated the tad3-1 mutant that is allelic to the tad3(+) gene encoding a homolog of budding yeast Tad3p. Interestingly, the tad3-1 mutant cells principally exhibited cell cycle-specific phenotype, namely temperature-sensitive and irreversible cell cycle arrest both in G(1) and G(2). Further analyses revealed that in the tad3-1 mutant cells, the S257N mutation that occurred in the catalytically inactive Tad3 subunit affected its association with catalytically active Tad2 subunit, leading to an impairment in the A to I conversion at position 34 of tRNA. In tad3-1 mutant cells, the overexpression of the tad3(+) gene completely suppressed the decreased tRNA inosine content. Notably, the overexpression of the tad2(+) gene partially suppressed the temperature-sensitive phenotype and the decreased tRNA inosine content, indicating that the tad3-1 mutant phenotype is because of the insufficient I(34) formation of tRNA. These results suggest that the wobble inosine tRNA modification is essential for cell cycle progression in the G(1)/S and G(2)/M transitions in fission yeast.


Influence of W-doping on electrochemical performance of spinel LiMn2O4.
The structural and electrochemical properties of W-doped LiMn2O4 and LiAl0.025Mn1.975O4 have been investigated to determine the role of W. The cathodic materials were synthesized by sol-gel method, using citric acid as the chelating agent. The results revealed that the substitution of W affects the lattice dimension, the morphology, and the electrochemical performance. Substitution of Al induces an obvious decrease in the electrochemical capacity (but higher capacity retention) and in the case of W the decrease was drastic. As observed from XRD, only a fraction of W is included in the spinel structure. However, for the LiAl0.025W0.025Mn1.95O4, a compromised value is reached between the Al-doped and W-doped LiMn2O4 in terms of capacity and cyclic performance. The pristine spinel LiMn2O4 synthesized by this method shows a relatively superior electrochemical performance at high C-rate with excellent capacity retention.


Unravelling and Quantifying the "NMR-Invisible" Metabolites Interacting with Human Serum Albumin by Binding Competition and T2 Relaxation-Based Decomposition Analysis.
Quantitative profiling of low-molecular-weight metabolites (LMWMs) by 1H NMR is routinely used in high-throughput serum metabolomics. First, the protein background is attenuated using a T2 filter; then, the LMWM signals are resolved by line-shape fitting. However, protein-binding modifies the motional properties of LMWM, and their signal partially attenuates with the T2 filter, along with the protein background. Consequently, the quantified LMWM signals do not reflect the total concentration in serum but the nonbinding part. Here we present a novel strategy based on binding competition to promote the release of the "NMR-invisible" metabolites from serum proteins and achieve quantifications closer to total concentrations. The study focuses on five clinically relevant amino acids with different binding properties (valine, isoleucine, leucine, tyrosine, and phenylalanine). We analyzed their binding affinity to human serum albumin (HSA) in serum mimic samples and promoted the release of their bound fraction by TSP titration. Furthermore, we used a novel combination of pseudo-2D CPMG and multivariate curve resolution analysis, allowing the separation of LMWM and protein signals and providing LMWM quantifications corrected for transverse relaxation effects. We found that TSP concentrations larger than 3 mM released most of the bound fraction and validated these findings in real serum/plasma samples.


Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.
Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies. Our data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.


[Effect of blood derivatives with immunomodulators on the immunoprotein profile in calves under clinical conditions].
The data on the selected humoral and cellular parameters of the immuno-protein profile were evaluated in calves in a critical period of the availability of immunoglobulins (Ig), in dependence on the administration of the blood derivative with levamisole (group AL) and on the administration of levamisole solution (group L). The preparations were administered intramuscularly at a rate of 10 mg levamisole per 1 kg of live weight. No statistical significance was recorded in the comparison of the humoral parameters after repeated administration (interval of five days) of the Algalev (AL) and levamisole (L) preparations. During the same investigation, the administration of AL produced a significant increase in the T lymphocytes of the blood both in comparison with the T lymphocyte concentration before treatment (P less than 0.05 on the 5th, 7th, 11th, 14th and 20th day of experiment) and in comparison with the calves of group L (P less than 0.05 on the 7th, 11th, 14th, and 20th day); in the case of B lymphocytes an increase was recorded only in comparison with the initial value (P less than 0.01 on the 2nd, 5th and 7th day). Administration of levamisole alone led to a positive change in T lymphocyte concentration (P less than 0.05 on the 5th, 7th, 11th, 15th and 20th day) but not in the concentration of the B cells (P greater than 0.05). In another experiment, administration of the AL preparation (repeatedly after six days) led to a significant increase in the percentage of T lymphocytes (P less than 0.01 the 8th day and P less than 0.05 the 2nd, 6th, 15th, 21st and 35th day) and B lymphocytes (P less than 0.01 the 15th and 21st day), in comparison with their levels before administration as well as in comparison with the control (T lymph.: P less than 0.01 the 6th day and P les than 0.05 the 8th, 15th, 21st and 35th day; B lymph.: P less than 0.05 the 15th day). The maximum percent proportion of T lymphocytes after administration of the AL preparation was recorded on the seventh and eighth day after the first administration.


Athletes, yogis and individuals with sedentary lifestyles; do their lung functions differ?
Buffalo health study concluded that pulmonary function is a long-term predictor for overall survival rates. It is essential to be involved in physical activity or sports which help in achieving better lung function. Cross sectional observation study was conducted to determine if yoga and athletic activity (running) are associated with better lung functions as compared to subjects with sedentary lifestyles and how does athletes and yogis differ in lung function. Spirometric parameters were assessed in randomly selected 60 healthy male, non-smoking; non-obese subjects-athletes, yogis and sedentary workers. The groups differed significantly in FEV1 and PEFR. The highest mean FEV1 and PEFR were observed in yogis. Both yogis and athletes had significantly better FEV1 as compared to sedentary workers. Yogis also had significantly better PEFR as compared to sedentary workers and athletes. Yogis and athletes had similar lung functions except for better PEFR amongst yogis. Involvement in daily physical activity or sport preferably yoga can help in achieving better pulmonary function.


Enteroendocrine peptides regulate feeding behavior via controlling intestinal contraction of the silkworm Bombyx mori.
Our previous study demonstrated that predominant feeding inhibitory effects were found in the crude extracts of foregut and midgut of the silkworm Bombyx mori larvae. To address the entero-intestinal control crucial for the regulation of insect feeding behavior, the present study identified and functionally characterized feeding inhibitory peptides from the midgut of B. mori larvae. Purification and structural analyses revealed that the predominant inhibitory factors in the crude extracts were allatotropin (AT) and GSRYamide after its C-terminal sequence. In situ hybridization revealed that AT and GSRYamide were expressed in enteroendocrine cells in the posterior and anterior midgut, respectively. Receptor screening using Ca2+-imaging technique showed that the B. mori neuropeptide G protein-coupled receptor (BNGR)-A19 and -A22 acted as GSRYamide receptors and BNGR-A5 acted as an additional AT receptor. Expression analyses of these receptors and the results of the peristaltic motion assay indicated that these peptides participated in the regulation of intestinal contraction. Exposure of pharynx and ileum to AT and GSRYamide inhibited spontaneous contraction in ad libitum-fed larvae, while exposure of pharynx to GSRYamide did not inhibit contraction in non-fed larvae, indicating that the feeding state changed their sensitivity to inhibitory peptides. These different responses corresponded to different expression levels of their receptors in the pharynx. In addition, injection of AT and GSRYamide decreased esophageal contraction frequencies in the melamine-treated transparent larvae. These findings strongly suggest that these peptides exert feeding inhibitory effects by modulating intestinal contraction in response to their feeding state transition, eventually causing feeding termination.


κ-Carrageenan Enhances the Biomineralization and Osteogenic Differentiation of Electrospun Polyhydroxybutyrate and Polyhydroxybutyrate Valerate Fibers.
Novel electrospun materials for bone tissue engineering were obtained by blending biodegradable polyhydroxybutyrate (PHB) or polyhydroxybutyrate valerate (PHBV) with the anionic sulfated polysaccharide κ-carrageenan (κ-CG) in varying ratios. In both systems, the two components phase separated as shown by FTIR, DSC and TGA. According to the contact angle data, κ-CG was localized preferentially at the fiber surface in PHBV/κ-CG blends in contrast to PHB/κ-CG, where the biopolymer was mostly found within the fiber. In contrast to the neat polyester fibers, the blends led to the formation of much smaller apatite crystals (800 nm vs 7 μm). According to the MTT assay, NIH3T3 cells grew in higher density on the blend mats in comparison to neat polyester mats. The osteogenic differentiation potential of the fibers was determined by SaOS-2 cell culture for 2 weeks. Alizarin red-S staining suggested an improved mineralization on the blend fibers. Thus, PHBV/κ-CG fibers resulted in more pronounced bioactive and osteogenic properties, including fast apatite-forming ability and deposition of nanosized apatite crystals.


Anti-inflammatory and analgesic effects of Spartium junceum L. flower extracts: a preliminary study.
Our objective was to study the anti-inflammatory and analgesic activity of extract of Spartium junceum L. flowers. Samples of flowers were collected from wild plants, dried, powdered, and extracted with hexane and methanol. The extracts were evaporated to dryness and then suspended in suitable solvent. They were then tested for anti-inflammatory activity in the carrageenin rat paw edema test and for analgesic activity in the Randall and Selitto mechanical pressure test and in the tail-flick test. Twenty-four hours after treatment, the gastric mucosa of each rat was observed macroscopically. Based on these results the hexane extract was fractioned by column chromatography, and the fractions obtained were tested in the same way. The results showed good anti-inflammatory activity only for a single fraction of the hexane extract, while all the extracts and all the other hexane fractions showed both peripheral and central analgesic activity. In rats treated with the tested compounds hyperemia and ulcers were absent. The data from this preliminary study reveal interesting pharmacological properties of S. junceum L. flowers extract related to the marked analgesic activity and the absence of gastric ulcerogenic activity.


Conscious sedation training received by specialist registrars in restorative dentistry in the UK: a survey.
To investigate conscious sedation training received by Specialist Registrars in Restorative Dentistry (SpRs) during their training programme. Postal questionnaire survey in the UK. Setting SpRs and recently certificated Consultants in Restorative Dentistry (CRDs). A questionnaire was sent to 81 current SpRs in Restorative Dentistry and CRDs who had been awarded a Certificate of Completion of Specialist Training within the previous three years. One follow-up letter was sent to non-responders. The completed questionnaire was returned by 67 (83%) SpRs and CRDs. Analysis revealed that 44 (69%) respondents had received conscious sedation training during their specialist training programme and that 50 (78%) respondents carried out restorative dental treatment under sedation during their programme. Thirteen (20%) respondents had not received conscious sedation training in their programmes but eight (13%) SpRs indicated that sedation training was planned. Training experiences differed throughout the UK: 29 (66%) respondents gained experience in inhalational and single agent intravenous sedation techniques under the supervision of an experienced colleague. Fourteen (32%) respondents who performed sedation had not been on a resuscitation course in the previous year. These included nine (21%) current SpRs. Sixteen (53%) current SpRs intended to offer restorative dental treatment under sedation after specialist training. Fifty-nine (92%) respondents thought that all SpRs in Restorative Dentistry should receive sedation training and 42 (71%) thought that a structured core course would be the most appropriate format. Although the majority of SpRs and recently certificated CRDs considered that all SpRs should receive training in conscious sedation via a core course during the restorative dentistry training programme, a small number had not received or planned to undertake such training. Conscious sedation training experiences differed throughout the UK and SpRs treated a wide range of deserving patient categories under sedation. It is encouraging that many SpRs hope to continue employing sedation techniques after their restorative dentistry training has finished. The results of this survey should inform all those involved with restorative dentistry training programmes.


Biomechanical evaluation of the human mandible after temporomandibular joint replacement under different biting conditions.
Temporomandibular joint (TMJ) replacement with an implant is only used when all other conservative treatments fail. Despite the promising short-term results, the long-term implications of TMJ replacement in masticatory function are not fully understood. Previous human and animal studies have shown that perturbations to the normal masticatory function can lead to morphological and functional changes in the craniomaxillofacial system. A clearer understanding of the biomechanical implications of TMJ replacement in masticatory function may help identify design shortcomings that hinder their long-term success. In this study, patient-specific finite element models of the intact and implanted mandible were developed and simulated under four different biting tasks. In addition, the impact of re-attaching of the lateral pterygoid was also evaluated. The biomechanics of both models was compared regarding both mandibular displacements and principal strain patterns. The results show an excessive mediolateral and anteroposterior displacement of the TMJ implant compared to the intact joint in three biting tasks, namely incisor (INC), left moral (LML), and right molar (RML) biting. The main differences in principal strain distributions were found across the entire mandible, most notably from the symphysis to the ramus of the implanted side. Furthermore, the re-attachment of the lateral pterygoid seems to increase joint anteroposterior displacement in both INC, LML and RML biting while reducing it during LGF. Accordingly, any new TMJ implant design must consider stabilising both mediolateral and anteroposterior movement of the condyle during biting activities and promoting a more natural load transmission along the entire mandible.


Prediction of the indication criteria for endoscopic resection of early gastric cancer.
To find risk factors of lymph node metastasis (LNM) in early gastric cancer (EGC) and to find proper endoscopic therapy indication in EGC. We retrospectively reviewed the 2270 patients who underwent curative operation for EGC from January 2001 to December 2008. EGC was defined as malignant lesions that do not invade beyond the submucosal layer of the stomach wall irrespective of presence of lymph node metastasis. Among 2270 enrolled patients, LNM was observed in 217 (9%) patients. LNM in intramucosal (M) cancer and submucosal (SM) cancer was detected in 38 (2.8%, 38/1340) patients and 179 (19%, 179/930) patients, respectively. In univariate analysis, the risk factors for LNM in EGC were size of tumor, Lauren classification, ulcer, lymphatic invasion, vascular invasion, and depth of invasion. However, in multivariate analysis, size of tumor, lymphatic invasion, vascular invasion, and depth of invasion were risk factors for LNM in EGC. Size of tumor, lymphatic invasion, vascular invasion, and depth of invasion were risk factors for LNM in cases of intramucosal cancer and submucosal cancer. In particular, there was no lymph node metastasis in cases of well differentiated early gastric cancer below 1 cm in size without ulcer regardless of lymphovascular invasion. Tumor size, perilymphatic-vascular invasion, and depth of invasion were risk factors for LNM in EGC. There was no LNM in EGC below 1 cm regardless risk factors.


Transducin inhibition of light-dependent rhodopsin phosphorylation: evidence for beta gamma subunit interaction with rhodopsin.
Rhodopsin kinase was purified from bovine retina rod outer segments as a 62-64-kDa protein that phosphorylated purified rhodopsin reconstituted into egg phosphatidylcholine/phosphatidylethanolamine liposomes. A competition binding assay in which transducin competes with rhodopsin kinase for binding sites on rhodopsin was used to assess the interaction of purified transducin subunits with rhodopsin. Preincubation of purified holotransducin with rhodopsin, in the absence of guanosine triphosphate, blocked the ability of the kinase to phosphorylate rhodopsin. Transducin-dependent inhibition of phosphorylation was relieved when guanosine 5'-(3-O-thio)triphosphate was present during the preincubation. Resolved alpha and beta gamma transducin subunits, in the absence of guanosine triphosphate, were each capable of specifically blocking phosphorylation of rhodopsin. A maximally effective concentration of T alpha or T beta gamma (1 microM) subunits inhibited phosphorylation of rhodopsin (0.23 microM) 45-65%. A similar concentration of reconstituted transductin (T alpha and T beta gamma) or native holotransducin (T alpha beta gamma) inhibited phosphorylation greater than 98%. The results indicate that rhodopsin must have a binding site for T beta gamma as well as a binding site for T alpha, and each subunit influences the recognition of bleached rhodopsin by rhodopsin kinase.


Standards and controls for genetic testing.
The majority of genetic tests done today are completely home brew assays. A few of the more common tests are based on ASR level reagents. To date the only genetic assays that are available as FDA-approved in vitro diagnostic (IVD) kits are for analysis of the Factor V (Leiden) and Factor II (promoter G to A) mutations associated with thrombophilia risk for assessment of cytochrome P450 2D6 and 2C19 polymorphisms and for analysis of mutations in the CFTR gene. In this regard, the lab community has taken the lead in development of standards and controls for genetic tests. As genetic testing enters the mainstream, we expect to see more approvals of IVD kits, and the IVD manufacturing community will take a larger role in providing the control materials for these assays. Commercially run proficiency testing programs are only available for the most common genetic tests. All other tests must use approaches such as sample swapping between labs to fulfill this requirement.


Anatomical and histological observation on the pancreas in adult zebrafish.
To investigate the anatomic structure of the pancreas and the distribution of the islets in adult zebrafish. In situ immunofluorescent staining, electron microscopy, and serial paraffin-embedded sectioning with hematoxylin/eosin staining were applied. The pancreas along the intestine included 4 relatively independent and concentrated lobes, in which 4 kinds of islets-principal islets, Brockmann bodies, diffusely existing islets, and single beta-cell-were observed. Some islets contained both alpha and beta cells, whereas some contained only beta cells. The islet number in each adult zebrafish averaged 84.53 +/- 43.77; and the lower quartile, median, and upper quartile were 55.25, 70.50, and 112.00, respectively (n = 40). The different islets were differently distributed in the 4 pancreatic lobes with statistical significance (P < 0.05). Meanwhile, 3 kinds of secretory granules were found in the cytoplasm of different islet cells. According to the distinct distribution, concentration of the pancreas, and different contents of the islets within the pancreas, 4 lobes of the pancreas along the intestine-the gallbladder-spleen lobe, the middle lobe, the left lobe, and the ventral lobe-were identified in adult zebrafish.


The Significant Predictors for Breast, Cervical, Colorectal, or Oral Cancer Screening Intention and Behavior in Taiwan.
Cancer screening can improve outcomes in patients with cancer. Accordingly, under the direction of the National Health Insurance program, the Taiwan government conducts screenings for breast cancer, cervical cancer, oral cancer, and colorectal cancer. The aim of this study was to identify the primary predictors of cancer screening intention and behavior at 1 and 6 months after patients are provided information and an invitation by telephone to attend cancer screenings. In this prospective longitudinal study, 339 participants meeting the screening criteria were recruited. At baseline, telephone interviews were used to collect information on demographic characteristics, exercise and smoking habits, family cancer history, screening beliefs, and screening intention. Screening behavior was followed up at 1 and 6 months after the telephone interviews. At baseline, 87.02% of the participants intended to undergo screening, and 31.86% and 63.42% had undergone screening after 1 and 6 months, respectively. The predictors of screening intention were awareness of the screening policy, willingness to learn about screening, and believing in the health benefits of screening. The predictor of screening behavior after 1 month was screening intention at baseline, and the predictors of behavior after 6 months were screening intention, marital status, and belief that cancer is a hereditary disease. Adults with screening intention tended to undergo cancer screenings. The use of strategies based on screening intention, beliefs, and information can be used to improve participation in cancer screening in Taiwan.


Celibate Gay Christians: Sexual Identity and Religious Beliefs and Practices.
The purpose of the study is to explore the experiences of gay Christians who choose celibacy. Chief milestone events, beliefs and attitudes toward God and faith, as well as participants' experiences of church climate toward gay Christians were assessed through a structured interview. Eight interviews were analyzed, using grounded theory methodology and consensual qualitative analysis to identify several salient themes.


Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.
A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.


Transition to adult care for youth with medical complexity: Assessing needs and setting priorities for a health care improvement initiative.
Technological advances have led to more youth with medical complexity (YMC) who are living into adulthood and being transferred from pediatric to adult care. The transition to adult care is a complex and challenging process, partly due to differences in how pediatric and adult systems deliver health care. YMC and their families need support from their health care providers to ease this transition. To identify how to better support transitioning YMC, a needs assessment was conducted to examine the current state of transitional support for youth and families cared for by a pediatric Complex Care Program. The aims of this needs assessment were to understand the transition practices of pediatric Complex Care Programs, explore transition-related needs of YMC and their families, and identify priorities for future quality improvement. This project involved three components: a literature review, a benchmarking survey of pediatric Complex Care Programs in Ontario, and key informant interviews. The benchmarking survey identified transition planning and transfer of care as areas of strength in the Complex Care Program, while transition readiness and transfer completion provided opportunities for improvement. Stakeholder collaboration, an early start, and knowledgeable providers facilitated a successful transition. Barriers included lack of time, poor access to adult services and resources, higher medical complexity, and inadequate support for adult health care providers. Recommendations for improving transitional care for YMC are provided, along with resources, tools, and considerations for implementation.


Toxoplasmosis in a patient with common variable immunodeficiency.
We describe here a case of common variable immunodeficiency with depression of both humoral and cellular immunity, manifested primarily by chronic toxoplasmosis. The presence of a lymphoma as the underlying etiology of the immunodeficiency was excluded. The clinical, histological, and immunological interrelations between immunodeficiency, toxoplasmosis and lymphoma are discussed.


The motor cortex is involved in reflexive compensatory adjustment of speech articulation.
Although speech articulation relies heavily on the sensorimotor processing, little is known about its brain control mechanisms. Here, we investigate, using transcranial magnetic stimulation, whether the motor cortex contributes to the generation of quick sensorimotor responses involved in speech motor coordination. By applying a jaw-lowering perturbation, we induced a reflexive compensatory upper-lip response, which assists in maintaining the intact labial aperture in the production of bilabial fricative consonants. This reflex response was significantly facilitated by subthreshold transcranial magnetic stimulation over the motor cortex, whereas a simple perioral reflex that is mediated only within the brainstem was not. This suggests that the motor cortex is involved in generating this functional reflexive articulatory compensation.


The effect of parentage on the prevalence, severity and location of lesions of osteochondrosis in swine.
The aims of this study were to determine the effects of parentage and gender on the prevalence, severity and location of lesions of osteochondrosis manifesta (OCM) and osteochondrosis dissecans (OCD) in offspring from different Norwegian Landrace boars and to examine the relationships between lesion characteristics and selected growth parameters. Fifteen sires were selected based on their high breeding value for osteochondrosis. Seven locations in the distal humerus and the distal femur from 1680 offspring of these animals were evaluated for severity of OCM and presence of OCD by gross examination of serially sectioned humeri and femora. Osteochondrosis manifesta was most prevalent in the trochlea of humerus, the sagittal ridge of humerus, the medial condyle of femur and the medial sulcus obliquus of femur. The severity of the lesions and the prevalence of OCD were highest in the trochlea and the sagittal ridge of humerus. Castrates had significantly higher OCM scores than sows. There were significant effects of both sire and dam on the OCM scores of the offspring in most locations; however, growth rate and weight at slaughter did not influence the OCM score.


The trends and projections in the incidence and mortality of liver cancer in urban Shanghai: a population-based study from 1973 to 2020.
In 2012, liver cancer ranked as the fifth and eighth most common cancer in men and women, respectively, in urban Shanghai. This study aims to present the trend and projection of age-specific incidence and mortality of liver cancer in Shanghai. We extracted data of liver cancer incident cases and deaths between 1973 and 2012. An age-period-cohort model was used to analyze the data. A total of 47,344 men and 18,692 women were diagnosed with liver cancer from 1973 to 2012. The overall age-standardized incidence was 26.89 and 8.89 per 100,000 for men and women, respectively. Correspondingly, a total of 44,355 and 18,084 men and women died from liver cancer during this period. The overall age-standardized death rate was 25.34 per 100,000 in men and 9.39 per 100,000 in women. Between 1973 and 2012, liver cancer incidence and mortality in all age groups, except people aged 0-19 years, experienced a significant decline. Similar temporal patterns were detected in liver cancer mortality in both sexes when compared with incidence. Liver cancer incidence and mortality are expected to further decline among all age groups in 2013-2020 in both sexes, though the numbers of incident cases will remain stable. Incidence and mortality of liver cancer in urban Shanghai have decreased by about 40% and 50%, respectively, over the past four decades. This decline is expected to continue in the near future. However, the population is aging, which is reflected in the increasing crude rates and decreasing age-adjusted rates.


Topochemical fluorination of Sr3(M(0.5)Ru(0.5))2O7 (M = Ti, Mn, Fe), n = 2, Ruddlesden-Popper phases.
Reaction of the appropriate Sr3(M(0.5)Ru(0.5))2O7 (M = Ti, Mn, Fe), n = 2, Ruddlesden-Popper oxide with CuF2 under flowing oxygen results in formation of the oxide-fluoride phases Sr3(Ti(0.5)Ru(0.5))2O7F2, Sr3(Mn(0.5)Ru(0.5))2O7F2, and Sr3(Fe(0.5)Ru(0.5))2O(5.5)F(3.5) via a topochemical anion insertion/substitution process. Analysis indicates the titanium and manganese phases have Ti(4+), Ru(6+) and Mn(4+), Ru(6+) oxidation state combinations, respectively, while Mössbauer spectra indicate an Fe(3+), Ru(5.5+) combination for the iron phase. Thus, it can be seen that the soft fluorination conditions employed lead to formation of highly oxidized Ru(6+) centers in all three oxide-fluoride phases, while oxidation states of the other transition metal M cations remain unchanged. Fluorination of Sr3(Ti(0.5)Ru(0.5))2O7 to Sr3(Ti(0.5)Ru(0.5))2O7F2 leads to suppression of magnetic order as the fluorinated material approaches metallic behavior. In contrast, fluorination of Sr3(Mn(0.5)Ru(0.5))2O7 and Sr3(Fe(0.5)Ru(0.5))2O7 lifts the magnetic frustration present in the oxide phases, resulting in observation of long-range antiferromagnetic order at low temperature in Sr3(Mn(0.5)Ru(0.5))2O7F2 and Sr3(Fe(0.5)Ru(0.5))2O(5.5)F(3.5). The influence of the topochemical fluorination on the magnetic behavior of the Sr3(M(0.5)Ru(0.5))2O(x)F(y) phases is discussed on the basis of changes to the ruthenium oxidation state and structural distortions.


A two-body frictional wear test.
Enamel abraders used in two-body wear tests suffer the disadvantage that standardization is difficult or impossible to obtain. The aim of this study was to test whether steatite (a ceramic material with a Vickers Hardness similar to that of enamel) could be used as a satisfactory human enamel analogue. The friction and wear characteristics of 'spherical' abraders made from these two materials against composite and amalgam specimens were therefore compared. A two-body wear test for restorative materials was devised which could be carried out in a Universal Testing Machine and which allowed for continuous monitoring of the frictional forces during wear. The results showed that steatite and enamel abraders produced similar coefficients of friction (correlation coefficient, r = 0.98). A linear relationship was found between depth (and volume) of wear and number of cycles (r = 0.98 to 0.99). Wear rate was not affected by the increase in abrader facet area. The wear rate against the steatite abrader was slightly greater than that against enamel, but the two abraders were reasonably correlated (r = 0.94). Friction and wear were correlated for the steatite abrader (P < 0.05, r = 0.88) but not the enamel abrader. The hybrid composites had a high wear rate and wore both the abraders more than did the microfilled composites or amalgam. These findings suggest that steatite is a suitable substitute for enamel in this type of test.


[Pulmonary renal syndrome].
Pulmonary-renal syndrome is a potentially life-threatening disorder, characterised by diffuse alveolar hemorrhage on the basis of pulmonary capillaritis in association with rapidly progressive glomerulonephritis. It can originate from various systemic autoimmune diseases. ANCA-associated vasculitides account for approximately 60% and Goodpasture's syndrome for approximately 20% of the cases. Fulminant pulmonary capillaritis can result in acute respiratory failure with the more subtle forms only being detectable by bronchoalveolar lavage. Kidney biopsy displays extracapillary proliferating glomerulonephritis and renal immunohistology facilitates detection of the underlying systemic disease. By accelerating the diagnosis of the specific underlying disease, auto-antibody testing fosters rapid initiation of treatment and thereby strongly improves the prognosis of pulmonary-renal syndrome. Intense immunosuppression with cyclophosphamide and glucocorticoids, augmented by plasmapheresis in the event of Goodpastures's syndrome, is the mainstay of therapy. Supportive measures such as temporary ventilation and hemodialysis have further reduced mortality.


HPLC-MS/MS-based analysis of everolimus in rabbit aqueous humor: pharmacokinetics of in situ gel eye drops of suspension.
Aim: Everolimus is an inhibitor of mTOR which is derived from rapamycin. Its high corneal permeability and bioavailability makes it an effective treatment for ocular disorders. To study the pharmacokinetics of in situ gel eye drops of everolimus suspension after ocular administration in rabbit aqueous humor, we developed a rapid and reliable HPLC-MS/MS method. Methodology/results: Ascomycin was selected as the internal standard. HPLC-MS/MS method was used to investigate the concentration-time relationship of everolimus in rabbit aqueous humor through protein precipitation technique. The validated results showed good linearity, accuracy and precision. Conclusion: The method developed in this study is rapid, sensitive and reliable for the determination of the concentration of everolimus in rabbit aqueous humor.


Transient-Ligand-Enabled ortho-Arylation of Five-Membered Heterocycles: Facile Access to Mechanochromic Materials.
Reported herein is the first example of a direct arylation of heteroarenes by a transient-ligand-directed strategy without the need to construct and deconstruct the directing group. A wide range of heteroarenes undergoes the coupling with diverse aryl iodides to assemble a large library of highly selective and functionalized 3-arylthiophene-2-carbaldehydes. This route provides an opportunity to rapidly access new mechanofluorochromic materials. Moreover, a novel strategy for mechanochromic luminogens with chromism trends of red- and blue-shifts has been disclosed for the first time by facile functional-group modifications to a common structural core.


Skeleton Segmentation on Bone Scintigraphy for BSI Computation.
Bone Scan Index (BSI) is an image biomarker for quantifying bone metastasis of cancers. To compute BSI, not only the hotspots (metastasis) but also the bones have to be segmented. Most related research focus on binary classification in bone scintigraphy: having metastasis or none. Rare studies focus on pixel-wise segmentation. This study compares three advanced convolutional neural network (CNN) based models to explore bone segmentation on a dataset in-house. The best model is Mask R-CNN, which reaches the precision, sensitivity, and F1-score: 0.93, 0.87, 0.90 for prostate cancer patients and 0.92, 0.86, and 0.88 for breast cancer patients, respectively. The results are the average of 10-fold cross-validation, which reveals the reliability of clinical use on bone segmentation.


[Effects of Xuebijing on hypothalamus-pituitary-adrenal axis in early stage of septic rats].
To explore the levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cortisone (CORT) and ultrastructural abnormalities in hypothalamus, pituitary, adrenal specimens and potential effects of Xuebijing injection in septic rats. Sepsis was induced in adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). A total of 40 rats were randomly divided into control group (n = 10), sham-operated group (n = 10), saline treatment group (NS, 4 ml/kg, n = 10), Xuebijing injection treatment group (XBJ, 4 ml/kg, n = 10). The histological abnormalities associated with sepsis were examined in hypothalamus, pituitary and adrenals. Radioimmunoassay (RIA) was used to detect the levels of CRH in hypothalamic tissue and the plasma levels of ACTH and CORT. Compared with normal control or sham group, the levels of CRH in hypothalamus tissue of CLP group and plasma levels of ACTH and CORT increased in early stage of sepsis. In NS group, the plasma CORT concentration ((30.66 ± 1.55) ng/ml) was significantly higher than that in normal control group ((7.63 ± 0.56) ng/ml, P < 0.01) and sham group ((11.85 ± 0.87) ng/ml, P < 0.01). In XBJ group, the plasma CORT concentration ((22.13 ± 1.49) ng/ml) was significantly lower than that in NS group (P < 0.01). There was no significant difference between normal control and sham groups (P > 0.05). In NS group, the plasma concentration of ATCH ((26.26 ± 1.63) pg/ml) was significantly higher than that in normal control group ((8.84 ± 1.39) pg/ml, P < 0.01) and sham group ((11.43 ± 0.47) pg/ml, P < 0.01). In XBJ group, the plasma concentration of ATCH ((22.13 ± 1.49) ng/ml) was significantly lower than that in NS group (P < 0.01). No significant difference existed between normal control and sham groups (P > 0.05). In NS group, the level of CRH in hypothalamus tissue ((101.92 ± 6.61) ng/ml) was significantly higher than that in normal control group ((61.65 ± 6.05) ng/ml, P < 0.05) and sham group ((66.65 ± 4.04) ng/ml, P < 0.05). In XBJ group, the concentration of CRH in hypothalamus tissue ((84.90 ± 2.54) ng/ml) was significantly lower than that in NS group (P < 0.05). There was no significant difference between normal control and sham groups (P > 0.05). The ultrastructures of hypothalamus, pituitary and adrenal changed. In CLP group, the ultrastructure of hypothalamus was as follows: rough endoplasmic reticulum expanded. There were degranulation and Golgi complex swelling. A large number of endocrine granules could be seen in ATCH cells in pituitary and a depletion of adrenal lipid droplets. Xuebijing injection can lessen the excessive activated status of hypothalamic-pituitary-adrenal axis.


BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma.
Translocations affecting the chromosomal region 15q11-13 and various other partners are recurrent in diffuse large-cell lymphomas (DLCL). To identify the putative gene, here named BCL8, involved in these translocations we have cloned the breakpoint region from a DLCL patient with t(14;15)(q32;q11-13) and the corresponding germ-line region from chromosome 15. The genomic locus on chromosome 15 is clonally rearranged in about 4% of DLCL in agreement with the frequency of 15q11-13 translocations. A probe derived from the BCL8 locus on chromosome 15 detected a transcript in human testis and prostate, whereas no expression was found in spleen, thymus, and blood leukocytes. Analysis of the BCL8 cDNA clones isolated from human testis cDNA library showed that the BCL8 gene generates a major transcript of 2.6 kb and a less prominent 4.5-kb species due to differential polyadenylylation. By reverse transcription-PCR analysis of RNA extracted from frozen DLCL samples and lymphoma cell lines, BCL8 expression was detected in all patients carrying 15q11-13 abnormalities and in a fraction of randomly selected DLCL patients. These results suggest that the BCL8 gene is not normally expressed in lymphoid tissues, but its expression can be activated by chromosomal translocation or by other mechanisms in DLCL. Ectopic expression of BCL8 in a significant proportion of DLCL suggests an important role for this gene in the molecular pathogenesis of B cell lymphoma.


Case of hepatic flexure ectopic pregnancy medically managed with methotrexate.
Abdominal pregnancies represent 1.4% of extrauterine pregnancies. A literature search of six cases involving bowel ectopic pregnancies provided anecdotal treatment options. This case involves a woman admitted at 6 weeks gestation with right iliac fossa and shoulder tip pain. An ultrasound scan revealed an empty uterus with free fluid in both adnexa and a 31×21 mm heterogenous mass adjacent to the right ovary. At laparoscopy, an ectopic pregnancy was identified at the hepatic flexure. The patient received two doses of methotrexate and monitored until the beta human chorionic gonadotropin reduced. The decision to manage with methotrexate was balanced against reported cases of bowel perforation and the possibility that a section of bowel may need removal if the pregnancy showed signs of invasion. Maternal mortality rate with abdominal pregnancy is 20% due to the risk of massive haemorrhage from placental separation or invasion of bowel vasculature. Medical treatment here was successful and avoided extensive surgery.


Effects of implant orientation and implant material on tibia bone strain, implant-bone micromotion, contact pressure, and wear depth due to total ankle replacement.
The aim of this study is to investigate the effects of implant orientation and implant material on tibia bone strain, implant-bone micromotion, maximum contact pressure, and wear depth at the articulating surface due to total ankle replacement. Three-dimensional finite element models of intact and implanted ankle were developed from computed tomography scan data. Four implanted models were developed having varus and valgus orientations of 5° and 10°, respectively. In order to determine the effect of implant material combination on tibia bone strain, micromotion, contact pressure, and wear depth, three other finite element models were developed having a different material combination of the implant. Dorsiflexion, neutral, and plantarflexion positions were considered as applied loading condition, along with muscle force and ligaments. Implant orientation alters the strain distribution in tibia bone. Strain shielding was found to be less in the case of the optimally positioned implant. Apart from the strain, implant orientation also affects implant-bone micromotion, contact pressure, and wear depth. Implant materials have less influence on tibia bone strain and micromotion. However, wear depth was reduced when ceramic and carbon fibre-reinforced polyetheretherketone material combination was used. Proper orientation of the implant is important to reduce the strain shielding. The present result suggested that ceramic can be used as an alternative to metal and carbon fibre-reinforced polyetheretherketone as an alternative to ultra-high molecular weight polyethylene to reduce wear, which would be beneficial for long-term success and fixation of the implant.


A Fast Hybrid Feature Selection Based on Correlation-Guided Clustering and Particle Swarm Optimization for High-Dimensional Data.
The "curse of dimensionality" and the high computational cost have still limited the application of the evolutionary algorithm in high-dimensional feature selection (FS) problems. This article proposes a new three-phase hybrid FS algorithm based on correlation-guided clustering and particle swarm optimization (PSO) (HFS-C-P) to tackle the above two problems at the same time. To this end, three kinds of FS methods are effectively integrated into the proposed algorithm based on their respective advantages. In the first and second phases, a filter FS method and a feature clustering-based method with low computational cost are designed to reduce the search space used by the third phase. After that, the third phase applies oneself to finding an optimal feature subset by using an evolutionary algorithm with the global searchability. Moreover, a symmetric uncertainty-based feature deletion method, a fast correlation-guided feature clustering strategy, and an improved integer PSO are developed to improve the performance of the three phases, respectively. Finally, the proposed algorithm is validated on 18 publicly available real-world datasets in comparison with nine FS algorithms. Experimental results show that the proposed algorithm can obtain a good feature subset with the lowest computational cost.


Prognostic factors for survival in scleroderma associated pulmonary arterial hypertension.
Identification of prognostic factors for survival in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is necessary for appropriate monitoring, interventions, and timely referral for lung transplantation. Our objectives were (1) to identify factors associated with survival in SSc-PAH and (2) to evaluate the methodologic quality of prognostic studies against current standards. A systematic review was performed to identify studies evaluating factors associated with survival in SSc-PAH. The methodologic quality of each study was evaluated using a methodologic quality index. HLA-DRw6 (RR 54.52, p = 0.01), HLA-DRw52 (RR not reported, p = 0.02), initial systolic pulmonary artery pressure (sPAP) > 60 mmHg (HR 3.60, 95% CI 1.42, 9.15), elevated mean right atrial pressure (mRAP) (HR 20.7, p = 0.0001), and shorter time between SSc onset and observed PAH (5.24 vs 9.93 yrs, p < 0.01) were associated with decreased survival. Age > 50 years (HR 2.34, 95% CI 0.54, 10.2), male sex (HR 2.02, 95% CI 0.65, 6.20), limited subtype (HR 2.37, 95% CI 0.68, 8.20), pulmonary fibrosis [Kaplan-Meier (KM) curves, p = 0.3], change in pulmonary vascular resistance (KM curves, p = 0.8), anti-centromere (HR 1.67, 95% CI 0.66, 4.26) and anti-ScL-70 (HR 0.28, 95% CI 0.03, 1.99) antibodies were not definitively associated with survival. Attributes of participants, prognostic factors, and outcome measures were well reported. Study attrition, confounding, and analysis were not well reported. HLA-DRw52 and -DRw6, initial sPAP > 60 mmHg, mRAP, and shorter time between SSc onset and observed PAH were associated with decreased survival; however, methodologic quality of study reporting was variable. Prognostic factor research is needed using current methodologic standards.


N-terminal or signal peptide sequence engineering prevents truncation of human monoclonal antibody light chains.
Monoclonal antibodies (mAbs) contain short N-terminal signal peptides on each individual polypeptide that comprises the mature antibody, targeting them for export from the cell in which they are produced. The signal peptide is cleaved from each heavy chain (Hc) and light chain (Lc) polypeptide after translocation to the ER and prior to secretion. This process is generally highly efficient, producing a high proportion of correctly cleaved Hc and Lc polypeptides. However, mis-cleavage of the signal peptide can occur, resulting in truncation or elongation at the N-terminus of the Hc or Lc. This is undesirable for antibody manufacturing as it can impact efficacy and can result in product heterogeneity. Here, we describe a truncated variant of the Lc that was detected during a routine developability assessment of the recombinant human IgG1 MEDI8490 in Chinese hamster ovary cells. We found that the truncation of the Lc was caused due to the use of the murine Hc signal peptide together with a lambda Lc containing an SYE amino acid motif at the N-terminus. This truncation was not caused by mis-processing of the mRNA encoding the Lc and was not dependent on expression platform (transient or stable), the scale of the fed-batch culture or clonal lineage. We further show that using alternative signal peptides or engineering the Lc SYE N-terminal motif prevented the truncation and that this strategy will improve Lc homogeneity of other SYE lambda Lc-containing mAbs. Biotechnol. Bioeng. 2017;114: 1970-1977. © 2017 Wiley Periodicals, Inc.


Pleural effusion adenosine deaminase: a candidate biomarker to discriminate between Gram-negative and Gram-positive bacterial infections of the pleural space.
Delay in the treatment of pleural infection may contribute to its high mortality. In this retrospective study, we aimed to evaluate the diagnostic accuracy of pleural adenosine deaminase in discrimination between Gram-negative and Gram-positive bacterial infections of the pleural space prior to selecting antibiotics. A total of 76 patients were enrolled and grouped into subgroups according to Gram staining: 1) patients with Gram-negative bacterial infections, aged 53.2±18.6 years old, of whom 44.7% had empyemas and 2) patients with Gram-positive bacterial infections, aged 53.5±21.5 years old, of whom 63.1% had empyemas. The pleural effusion was sampled by thoracocentesis and then sent for adenosine deaminase testing, biochemical testing and microbiological culture. The Mann-Whitney U test was used to examine the differences in adenosine deaminase levels between the groups. Correlations between adenosine deaminase and specified variables were also quantified using Spearman's correlation coefficient. Moreover, receiver operator characteristic analysis was performed to evaluate the diagnostic accuracy of pleural effusion adenosine deaminase. Mean pleural adenosine deaminase levels differed significantly between Gram-negative and Gram-positive bacterial infections of the pleural space (191.8±32.1 U/L vs 81.0±16.9 U/L, p<0.01). The area under the receiver operator characteristic curve was 0.689 (95% confidence interval: 0.570, 0.792, p<0.01) at the cutoff value of 86 U/L. Additionally, pleural adenosine deaminase had a sensitivity of 63.2% (46.0-78.2%); a specificity of 73.7% (56.9-86.6%); positive and negative likelihood ratios of 2.18 and 0.50, respectively; and positive and negative predictive values of 70.6% and 66.7%, respectively. Pleural effusion adenosine deaminase is a helpful alternative biomarker for early and quick discrimination of Gram-negative from Gram-positive bacterial infections of the pleural space, which is useful for the selection of antibiotics.


Current concepts on the pathogenesis of the antiphospholipid syndrome.
The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (beta2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies.


An active immune defense with a minimal CRISPR (clustered regularly interspaced short palindromic repeats) RNA and without the Cas6 protein.
The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3' handle are still active in triggering an interference reaction. The complete 3' handle could be removed without loss of activity. However, manipulations of the 5' handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Δcas6b) is still active in interference.


[Beta-blocking drugs and anxiety. A proven therapeutic value].
The therapeutic value of propranolol and other beta-adrenergic receptor blockers in anxiety disorders is reviewed. The potential side-effects of benzodiazepines, eg psychomotor impairment and dependance, suggest that the main indicators of these compounds are the acute anxiety states and the short term treatment of anxiety disorders requiring sedation. Thus, other psychotropic drugs may be of potential value in the treatment of these disorders. The results of the placebo-controlled studies reviewed here strongly suggest that propranolol is useful in the treatment of anxiety disorders, especially those: 1) characterized by the presence of somatic symptoms related to increased adrenergic tone; 2) of moderate intensity and/or seen in general practice; 3) of recent onset and not fulfilling DSM III criteria for specific chronic anxiety disorders. Propranolol and other beta-blockers may also be useful in the prevention of performance anxiety such as the fear of speaking in public or specific social phobias when limited in number in the same patients. Average therapeutic doses range from 20 to 40 mg, once to three times a day; the clinical efficacy of beta-blockers administered for periods longer than 4 weeks remains to be demonstrated. The potential impairment of cognitive functions by propranolol is still a matter of controversy as well as its ability to induce depressive states in predisposed patients. Furthermore, the efficacy of beta-blockers that do not cross the blood-brain barrier in the treatment of anxiety raises unresolved questions concerning the mode of action (central vs peripheric) of these medications. In short, beta-blocking agents, and especially propranolol, should be considered as potential therapeutic agents in the pharmacological treatment of anxiety disorders besides benzodiazepines, antidepressant compounds and the newer azapirones, eg buspirone.


Cytoplasmic aggregation of TRAF2 and TRAF5 proteins in the Hodgkin-Reed-Sternberg cells.
We previously reported that ligand-independent signaling by highly expressed CD30 in Hodgkin-Reed-Sternberg (H-RS) cells is responsible for constitutive activation of NF-kappa B. In the present study, we characterize the intracellular localization of tumor necrosis factor (TNF) receptor associated factor (TRAF) proteins in H-RS cells. Confocal immunofluorescence microscopy of cell lines derived from H-RS cells and HEK293 transformants highly expressing CD30 revealed aggregation of TRAF2 and TRAF5 in the cytoplasm as well as clustering near the cell membrane. In contrast, TRAF proteins were diffusely distributed in the cytoplasm in cell lines unrelated to Hodgkin's disease (HD) and control HEK293 cells. Furthermore, the same intracellular distribution of TRAF proteins was demonstrated in H-RS cells of lymph nodes of HD, but not in lymphoma cells in lymph nodes of non-Hodgkin's lymphoma. Dominant-negative TRAF2 and TRAF5 suppressed cytoplasmic aggregation along with constitutive NF-kappa B activation in H-RS cell lines. Confocal immunofluorescence microscopy also revealed co-localization of IKK alpha, NIK, and I kappa B alpha with aggregated TRAF proteins in H-RS cell lines. These results suggest involvement of TRAF protein aggregation in the signaling process of highly expressed CD30 and suggest they function as scaffolding proteins. Thus, cytoplasmic aggregation of TRAF proteins appears to reflect constitutive CD30 signaling which is characteristic of H-RS cells.


Hypertensive encephalopathy in cats with reduced renal function.
The clinical, hemodynamic, and pathologic features of hypertensive encephalopathy in two cats with reduced renal mass are described. The cats developed a progressive syndrome of lethargy, ataxia, blindness, stupor, and seizures following an abrupt increase in blood pressure associated with a surgical reduction in renal mass. The cats had severe gross brain edema, evidenced by cerebellar changes of caudal coning and cranial displacement over the corpora quadrigemina and cerebral changes of widening and flattening of the gyri. Histologically, interstitial edema was most pronounced in the cerebral white matter. Hypertensive vascular lesions were present as hyaline arteriolosclerosis in one cat and hyperplastic arteriolosclerosis in the other. Rare foci of parenchymal microhemorrhages and necrosis were also observed. Systemic hypertension (especially severe or rapidly developing) accompanied by neurologic signs and the pathologic findings of diffuse brain edema with cerebral arteriolosclerosis are consistent with an etiologic diagnosis of hypertensive encephalopathy.


Quality of life as medicine. II. A pilot study of a five-day "quality of life and health" cure for patients with alcoholism.
Alcoholism can be understood as a self-treatment for existential pain. A 5-day treatment was designed to relieve this psychological pain and existential anxiety, and thereby diminish the need for self-treatment with alcohol. The basic principle behind the treatment was holistic, restoring the quality of life (QOL) and relationship with self, which according to the life mission theory happens when life-denying views are corrected and inner emotional conflicts are solved. The method in this treatment was a course with teachings in philosophy of life, psychotherapy, and body therapy. The synergy attained was considerable and the outcome demonstrates that in the course of 1 week, people have time to revise essential life-denying views and to integrate important, unfinished life events involving negative feelings. This was demonstrated by an improved QOL and a decrease in their dependency and need for alcohol abuse. In the week before, after the 5-day course, and again after 1 and 3 months, the 16 participants completed the SEQOL questionnaire on QOL and health. This was a pilot study based on a pre-experimental design, without a control group and without clinical control. Common for the group were a low QOL, numerous health problems, and alcohol dependency in spite of treatment with Antabus (disulfiram). The study showed an increase in QOL from 57.6% before the course to 69.4% 3 months after the course, or an improvement in QOL of 11.8%. There was a 24.0% improvement in self-perceived mental health, and satisfaction with health in general was improved by 11.1%. The total sum of health symptoms in the group was reduced from 59% of maximum to 33%. It is concluded that for this small and motivated group with alcohol problems, it was possible to improve QOL and health in only 5 days with a holistic treatment that combined philosophy of life, psychotherapy, and body therapy, but the results are not final. Further research is needed.


HIV and the Right to Health in Colombia.
The first Colombian to claim a judicially enforceable right to health was a gay man living with HIV, who in 1992 claimed a violation of his constitutional rights on account of being denied antiretroviral therapy. Since then, HIV activists have been at the forefront of advancing both the judicialization and social reconstruction of health as a human right. However, their role-and its implications today-has been sometimes overlooked in the study of Colombia's right to health. Based on semi-structured interviews with key stakeholders, we evaluate the HIV movement's effect on the progression of the right to health and resulting health care reform, and analyze the reform's success in addressing the needs of people living with HIV. While the landmark Constitutional Court decision T-760 and resulting health care reform are not the result of any one group, the HIV movement played a significant role in these developments, and its values are largely reflected in the country's new sociopolitical conceptualization of the right to health. However, the movement has faced division over the issue of generic medication availability and among subpopulations who have not been strongly represented or consistent beneficiaries of its successes.


The Age of Anxiety: Stones, Feathers and Re-institutionalization.
Although the value of the Italian psychiatric reform is widely acknowledged and hotly contested, a meticulous comment on its roots and progress is required. This paper attempts to examine the current state of mental health services in Italy and emphasizes Franco Basaglia's writings. The aim of the paper is to: (1) respond to the challenge of providing adequate and human rights-based mental health services, (2) contrast the new Italian tendency of medicalization, which is supported by a law proposal to re-institutionalize the mental health care system. The analysis is based on both current and historical library work and literature review. Since the present policy seems to be proceeding backwards, the direct study of Basaglia's writings assumes significance in not forgetting the past as well as in re-interpreting the present risk of re-institutionalization. The paper then emphasizes the veracity of Basaglia's thought and suggests a re-reading of his work.