Beyond borderline personality disorder: the mindful brain.
Numerous studies have showed an improvement in symptoms characteristic of borderline personality disorder (BPD) when mindfulness-based interventions were integrated into the daily lives of individuals with BPD. Although these studies have examined the etiology and diagnostic prognosis of BPD, and have discussed the use of mindfulness-based treatments, few researchers have attempted to interpret the neuroscientific findings, which have showed an increase in gray matter in key areas of the brain in clients with BPD who engaged in mindfulness practice. Some clients who had originally met a minimum of five of the DSM-IV-TR diagnostic criteria for BPD no longer did so upon engaging in mindfulness-based treatment. This article highlights the efficacy of mindfulness-based interventions with an emphasis on meditation, which leads to overall better psychological functioning in clients with BPD in three key areas: impulsivity, emotional irregularity, and relationship instability.


An assessment of phase field fracture: crack initiation and growth.
The phase field paradigm, in combination with a suitable variational structure, has opened a path for using Griffith's energy balance to predict the fracture of solids. These so-called phase field fracture methods have gained significant popularity over the past decade, and are now part of commercial finite element packages and engineering fitness- for-service assessments. Crack paths can be predicted, in arbitrary geometries and dimensions, based on a global energy minimization-without the need for ad hoc criteria. In this work, we review the fundamentals of phase field fracture methods and examine their capabilities in delivering predictions in agreement with the classical fracture mechanics theory pioneered by Griffith. The two most widely used phase field fracture models are implemented in the context of the finite element method, and several paradigmatic boundary value problems are addressed to gain insight into their predictive abilities across all cracking stages; both the initiation of growth and stable crack propagation are investigated. In addition, we examine the effectiveness of phase field models with an internal material length scale in capturing size effects and the transition flaw size concept. Our results show that phase field fracture methods satisfactorily approximate classical fracture mechanics predictions and can also reconcile stress and toughness criteria for fracture. The accuracy of the approximation is however dependent on modelling and constitutive choices; we provide a rationale for these differences and identify suitable approaches for delivering phase field fracture predictions that are in good agreement with well-established fracture mechanics paradigms. This article is part of a discussion meeting issue 'A cracking approach to inventing new tough materials: fracture stranger than friction'.


Intrastriatal infusions of brain-derived neurotrophic factor: retrograde transport and colocalization with dopamine containing substantia nigra neurons in rat.
The pattern of retrogradely transported BDNF, a member of the nerve growth family of neurotrophins, following intrastriatal infusion was immunohistochemically visualized within the rodent central nervous system. Human recombinant BDNF was infused at a rate of 3 micrograms/h for 7 days with an Alzet 2002 minipump prior to sacrifice. Tissue immunohistochemically processed using a turkey anti-BDNF antibody revealed retrogradely transported BNDF within neurons located mainly within the ipsilateral frontoparietal cortex (predominantly layer V), parafascicular and posterior thalamic nuclei, and substantia nigra, pars compacta. Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF. Experiments in which a mixture of BDNF and the retrograde tracer fluorogold were simultaneously infused for 7 days into the striatum revealed BDNF and fluorogold single-labeled neurons as well as BDNF and fluorogold dual-labeled cells within the substantia nigra, pars compacta. These observations indicate that only a subpopulation of neurons within the substantia nigra retrogradely transport BDNF following intrastriatal infusion and thus only a subpopulation of cells may be responsive to the trophic influences of BDNF. The retrograde transport of trophins, such as BDNF, represents a unique neuroanatomical tool to selectivity map the location of specific neurotrophin-responsive systems. Unraveling the trophic anatomy of BDNF will aid in understanding its role in development, degeneration, and experimental animal models of regeneration providing essential data for its use in clinical neurodegenerative disorders including Parkinson's disease.


Same Same but Different: A Clinical Characterization of Men with Hypersexual Disorder in the Sex@Brain Study.
Problems arising from hypersexual behavior are often seen in clinical settings. We aimed to extend the knowledge about the clinical characteristics of individuals with hypersexual disorder (HD). A group of people who fulfilled the proposed diagnostic criteria for HD (men with HD, n = 50) was compared to a group of healthy controls (n = 40). We investigated differences in sociodemographic, neurodevelopmental, and family factors based on self-report questionnaires and clinical interviews. Men with HD reported elevated rates of sexual activity, paraphilias, consumption of child abusive images, and sexual coercive behavior compared to healthy controls. Moreover, rates of affective disorders, attachment difficulties, impulsivity, and dysfunctional emotion regulation strategies were higher in men with HD. Men with HD seem to have experienced various forms of adverse childhood experiences, but there were no further differences in sociodemographic, neurodevelopmental factors, and family factors. Regression analyses indicated that attachment-related avoidance and early onset of masturbation differentiated between men with HD and healthy controls. In conclusion, men with HD appear to have the same neurodevelopment, intelligence levels, sociodemographic background, and family factors compared to healthy controls, but they report different and adverse experiences in childhood, problematic sexual behavior, and psychological difficulties.


Stroke following coronary artery bypass grafting: a ten-year study.
To identify possible risk factors for the occurrence of stroke during coronary artery bypass grafting (CABG), the cases of 3,279 consecutive patients having isolated CABG from 1974 to 1983 were reviewed. During this period, the risk of death fell from 3.9% to 2.6%. The stroke rate, however, fell initially but then rose from 0.57% in 1979 to 2.4% in 1983. Adjustment of these data for age clearly demonstrated that the risk of stroke has increased largely because of an increase in the mean age of patients undergoing CABG procedures. A case-control study involving all 56 stroke victims and 112 control patients was used to identify those risk factors significantly associated with the development of stroke in univariate analysis: increased age (63 versus 57 years in stroke patients and controls, respectively; p less than 0.0001); preexisting cerebrovascular disease (20% versus 8%; p less than 0.03); severe atherosclerosis of the ascending aorta (14% versus 3%; p less than 0.005); protracted cardiopulmonary bypass time (122 minutes versus 105 minutes; p less than 0.005); and severe perioperative hypotension (23% versus 4%; p less than 0.0001). Other variables not found to correlate with postoperative stroke included previous myocardial infarction, hypertension, diabetes mellitus, lower extremity vascular disease, preoperative left ventricular function, and intraoperative perfusion techniques. Elderly patients who have preexisting cerebrovascular disease or severe atherosclerosis of the ascending aorta or who require extensive revascularization procedures have a significantly increased risk of postoperative stroke.


Cell cycle- and terminal differentiation-associated regulation of the mouse mRNA encoding a conserved mitotic protein kinase.
We determined the nucleotide sequence of a mouse and a human cDNA, which we designate STPK13, that encodes an apparent protein kinase related to that encoded by the Drosophila melanogaster polo gene and the Saccharomyces cerevisiae CDC5 gene. The polo and CDC5 gene products are required for normal mitosis. The STPK13 mRNA is regulated during terminal erythrodifferentiation and during the cell cycle. Within the precommitment period of murine erythroleukemia cell terminal differentiation, most of the poly(A) tail is lost from the STPK13 mRNA, but the body of the mRNA remains unchanged in abundance; this poly(A) loss does not occur in mutant erythroleukemia cells that fail to commit to terminal differentiation. During the cell cycle, the abundance of the body of the STPK13 mRNA fluctuates. The mRNA is present in growing but not in nongrowing cells. It reaches a maximum abundance during G2/M phase, is absent or present at only low levels during G1 phase, and begins to reaccumulate at approximately the middle of S phase. The cell cycle-associated accumulation and loss of the STPK13 mRNA could cause a similar fluctuation in abundance of its encoded protein kinase, thereby providing a maximum amount during M phase, when the kinase is thought to function, and little or none at other times of the cell cycle. Posttranscriptional regulation must be responsible for the cell cycle-associated fluctuations because transcription rates are relatively constant during different times of the cell cycle when there are large differences in mRNA abundance.


Modeling an adiabatic quantum computer via an exact map to a gas of particles.
We map adiabatic quantum evolution on the classical Hamiltonian dynamics of a 1D gas (Pechukas gas) and simulate the latter numerically. This approach turns out to be both insightful and numerically efficient, as seen from our example of a CNOT gate simulation. For a general class of Hamiltonians we show that the escape probability from the initial state scales no faster than |lambda|gamma, where |lambda| is the adiabaticity parameter. The scaling exponent for the escape probability is gamma=1/2 for all levels, except the edge (bottom and top) ones, where gamma approximately < 1/3. In principle, our method can solve arbitrarily large adiabatic quantum Hamiltonians.


GTP consumption of elongation factor Tu during translation of heteropolymeric mRNAs.
The stoichiometry of elongation factor Tu (EF-Tu) and GTP in the complex with aminoacyl-tRNA and the consumption of GTP during peptide bond formation on the ribosome were studied in the Escherichia coli system. The ribosomes were programmed either with two different heteropolymeric mRNAs coding for Met-Phe-Thr-Ile ... (mMFTI) or Met-Phe-Phe-Gly ... (mMFFG) or with poly(U). The composition of the complex of EF-Tu, GTP, and Phe-tRNA(Phe) was studied by gel chromatography. With equimolar amounts of factor and Phe-tRNA(Phe), a pentameric complex, (EF-Tu.GTP)2.Phe-tRNA(Phe), was observed, whereas the classical ternary complex, EF-Tu.GTP.Phe-tRNA(Phe), was found only when Phe-tRNA(Phe) was in excess. Upon binding of the purified pentameric complex to ribosomes carrying fMet-tRNA(fMet) in the peptidyl site and exposing a Phe codon in the aminoacyl site, only one out of two GTPs of the pentameric complex was hydrolyzed per Phe-tRNA bound and peptide bond formed, regardless of the mRNA used. In the presence of EF-G, the stoichiometry of one GTP hydrolyzed per peptide bond formed was found on mMFTI when one or two elongation cycles were completed. In contrast, on mMFFG, which contains two contiguous Phe codons, UUU-UUC, two GTP molecules of the pentameric complex were hydrolyzed per Phe incorporated into dipeptide, whereas the incorporation of the second Phe to form tripeptide consumed only one GTP. Thus, generally one GTP is hydrolyzed by EF-Tu per aminoacyl-tRNA bound and peptide bond formed, and more than one GTP is hydrolyzed only when a particular mRNA sequence, such as a homopolymeric stretch, is translated. The role of the additional GTP hydrolysis is not known; it may be related to frameshifting of peptidyl-tRNA during translocation.


Digital X-rays are here; why aren't you using them?
Digital imaging is here. It is cost-effective and helps dentists glean more useful information to make treatment decisions. Many more choices of digital systems are available for dentists to adopt than when the technology was introduced. The hardware is less costly than it was even one year ago, and image storage is now very inexpensive. Technical time is reduced, and no special training is required if the dentist or auxiliary has used a paralleling system. Insurance companies are gearing up to accept image files attached to claims. Why, then, are dentists not buying these systems as fast as manufacturer's can build them? This article explores that question and discusses the false assumptions behind perceived obstacles.


Genistein, a soybean isoflavone, inhibits inward rectifier K(+) channels in rat osteoclasts.
Genistein, a soybean-derived isoflavone with an inhibitory effect on protein tyrosine kinases (PTKs), has been shown to suppress osteoclastic bone resorption. To clarify the mechanisms underlying this action, we investigated the effects of genistein on inward rectifier K(+) current (I(Kir)) in rat osteoclasts by using the whole-cell patch-clamp technique. Extracellularly applied genistein inhibited I(Kir) in a concentration-dependent manner. Physiologically attainable concentrations of genistein inhibited I(Kir). IC(50) values obtained 5 and 10 min after the application of genistein were 54 and 27 microM, respectively. The removal of genistein partially restored the current. Daidzein, an isoflavone without PTK-inhibiting activity, also showed a weak inhibitory effect on I(Kir), but genistin had no effect. Other PTK inhibitors, tyrphostin A25, tyrphostin B42, and tyrphostin B46, inhibited I(Kir), whereas herbimycin A and lavendustin A were without effect. The inactive tyrphostin, A1, showed a similar inhibitory effect as tyrphostin A25. The tyrosine phosphatase inhibitor, orthovanadate, did not affect the inhibitory potency of genistein on I(Kir). The inhibitory action of genistein was unaffected by changing intracellular Ca(2+) concentration ([Ca(2+)]i) or by pretreatment of the cell with GDPbetaS, Rp-cAMPS, okadaic acid, or staurosporine. Therefore the inhibition of I(Kir) by genistein does not depend on PTK inhibition, involvement of changes in [Ca(2+)]i, or secondary interaction with protein kinase A or protein kinase C. Genistein-induced inhibition of I(Kir) would cause membrane depolarization, elevation of [Ca(2+)]i, and inhibition of osteoclastic bone resorption.


Comparison Study of Iron Bioaccessibility from Dietary Supplements and Microencapsulated Preparations.
Iron deficiency is the most common form of malnutrition. Factors responsible for this so-called "hidden hunger" include poor diet, increased micronutrient needs and health problems such as diseases and infections. Body iron status can be increased by the intake of dietary supplements and fortified food. The aim of the present study was to compare iron bioaccessibility from commercial nutritional supplements and iron microcapsules. A comparison study was performed under conditions mimicking gastric and gastrointestinal digestion. A preparation of encapsulated ferrous sulphate or lactate and vitamin C, in a formula, showed bioaccessibility factors of up to 100% when digested individually, and around 60% in the presence of a food matrix. The degree of oxidation of the ferrous ions differed, depending on the type of preparation, the presence of vitamin C and the food matrix. The highest percentage content of ferrous ion, in the soluble fractions after gastrointestinal digestion, was shown by the preparation containing microencapsulated ferrous lactate or ferrous sulphate and vitamin C. Encapsulation seems to limit the interaction of iron with the food matrix and protect it against oxidation, thus making it more accessible for intestinal uptake.


Assignment of the human a-tropomyosin gene TPM3 to 1q22-->q23 by fluorescence in situ hybridisation.
The human tropomyosin 3 (TPM3) gene was previously localized to chromosome 1. The non-muscle isoform of the TPM3 gene product becomes fused to a gene product from the tyrosine kinase receptor gene (NTRK1), previously localized to 1q23-->q24, to generate an active oncogene. Two sequence tagged sites spanning three exons and two introns in the carboxy coding region of the gene were used to localize TPM3 to 1q22-->q23 by fluorescence in situ hybridization. This localization now places the NTRK1 and TPM3 genes in close proximity, so that a gene fusion rearrangement would not be cytologically detected. The 1q22-->q23 localization of TPM3 is within the NEM1 locus associated with autosomal dominant nemaline myopathy, making TPM3 a candidate for this disorder.


Organizational effects on patient satisfaction in hospital medical-surgical units.
The purpose of this study was to examine the relationships between hospital context, nursing unit structure, and patient characteristics and patients' satisfaction with nursing care in hospitals. Although patient satisfaction has been widely researched, our understanding of the relationship between hospital context and nursing unit structure and their impact on patient satisfaction is limited. The data source for this study was the Outcomes Research in Nursing Administration Project, a multisite organizational study conducted to investigate relationships among nurse staffing, organizational context and structure, and patient outcomes. The sample for this study was 2,720 patients and 3,718 RNs in 286 medical-surgical units in 146 hospitals. Greater availability of nursing unit support services and higher levels of work engagement were associated with higher levels of patient satisfaction. Older age, better health status, and better symptom management were also associated with higher levels of patient satisfaction. Organizational factors in hospitals and nursing units, particularly support services on the nursing unit and mechanisms that foster nurses' work engagement and effective symptom management, are important influences on patient satisfaction.


A fiber optic nanoplasmonic biosensor for the sensitive detection of ampicillin and its analogs.
A novel optical immunosensor for the screening of ampicillin (Amp) residues has been developed. The biosensor is based on fiber optic particle plasmon resonance detection and uses an enhancement method called as fiber optic nanogold-linked immunosorbent assay (FONLISA) for the sensitive detection of antibiotics. A commercial antibody which had a higher affinity for ampicillin than for other β-lactam antibiotics was chosen. A surface competitive binding assay was used in which a fixed concentration of antibiotic-conjugated gold nanoparticles (AuNPs) competes with free unlabeled antibiotic molecules to measure the amount of binding with antibody molecules immobilized on an optical fiber. The synthesis of the 11-mercaptoundecanoic acid (MUA)-ampicillin conjugate facilitates the attachment of the Amp molecules to AuNPs via MUA which acts as a linker between them. This AuNP-Amp conjugate was then used for the detection of β-lactam antibiotics. The practical limit of detection obtained for Amp was 0.74 ppb (7.4 × 10-10 g/mL) which is lower than the recommended maximum residue limit (MRL) for β-lactams. The method also shows a wide linear range of 4 orders. Its applicability to the determination of ampicillin in spiked milk samples has been demonstrated with good recovery and reproducibility. Graphical abstract.


HA coatings in implant dentistry: hype, hysteria, or clinical reality?
Hydroxylapatite (HA) coatings have shown promise due to the enhanced integration of osseous tissues to coated implant surfaces, particularly in sites where bone quality or quantity is compromised. This promise has resulted in a dramatic increase in clinical utilization of HA-coated implants. In spite of encouraging clinical findings, the long-term stability of the hydroxylapatite/bone interface has been challenged. Microbiologically the HA-coated implant surface may be more susceptible to the formation of bacterial plaque. Additionally, critical variations exist between implant coatings that may affect long-term survival. Despite such concerns, after eight years of clinical utilization, the hydroxylapatite-coated implant surface has not been shown to be predisposed to increased long-term failure.


Characterisation and expression analysis of cathepsins and ubiquitin-proteasome genes in gilthead sea bream (Sparus aurata) skeletal muscle.
The proteolytic enzymes involved in normal protein turnover in fish muscle are also responsible for post-mortem softening of the flesh and are therefore potential determinants of product quality. The main enzyme systems involved are calpains, cathepsins, and the ubiquitin-proteasome (UbP). In this study on Sparus aurata (Sa), the coding sequences of cathepsins (SaCTSB and SaCTSDb) and UbP family members (SaN3 and SaUb) were cloned from fast skeletal muscle, and their expression patterns were examined during ontogeny and in a fasting/re-feeding experiment. The amino acid sequences identified shared 66-100% overall identity with their orthologues in other vertebrates, with well conserved characteristic functional domains and catalytic residues. SaCTSDb showed phylogenetic, sequence and tissue distribution differences with respect to its paralogue SaCTSDa, previously identified in the ovary. Expression of gilthead sea bream cathepsins (B, L, Da, Db) and UbP members (N3, Ub, MuRF1 and MAFbx) in fast skeletal muscle was determined at three different life-history stages and in response to fasting and re-feeding in juveniles. Most of the proteolytic genes analysed were significantly up-regulated during fasting, and down-regulated with re-feeding and, between the fingerling (15 g) and juvenile/adult stages (~50/500 g), consistent with a decrease in muscle proteolysis in both later contexts. In contrast, SaCTSDa and SaMuRF1 expression was relatively stable with ontogeny and SaUb had higher expression in fingerlings and adults than juveniles. The data obtained in the present study suggest that cathepsins and UbP genes in gilthead sea bream are co-ordinately regulated during ontogeny to control muscle growth, and indicate that feeding regimes can modulate their expression, providing a potential dietary method of influencing post-mortem fillet tenderisation, and hence, product quality.


Fusion of two divergent fungal individuals led to the recent emergence of a unique widespread pathogen species.
In a genome alignment of five individuals of the ascomycete fungus Zymoseptoria pseudotritici, a close relative of the wheat pathogen Z. tritici (synonym Mycosphaerella graminicola), we observed peculiar diversity patterns. Long regions up to 100 kb without variation alternate with similarly long regions of high variability. The variable segments in the genome alignment are organized into two main haplotype groups that have diverged ∼3% from each other. The genome patterns in Z. pseudotritici are consistent with a hybrid speciation event resulting from a cross between two divergent haploid individuals. The resulting hybrids formed the new species without backcrossing to the parents. We observe no variation in 54% of the genome in the five individuals and estimate a complete loss of variation for at least 30% of the genome in the entire species. A strong population bottleneck following the hybridization event caused this loss of variation. Variable segments in the Z. pseudotritici genome exhibit the two haplotypes contributed by the parental individuals. From our previously estimated recombination map of Z. tritici and the size distribution of variable chromosome blocks untouched by recombination we estimate that the hybridization occurred ∼380 sexual generations ago. We show that the amount of lost variation is explained by genetic drift during the bottleneck and by natural selection, as evidenced by the correlation of presence/absence of variation with gene density and recombination rate. The successful spread of this unique reproductively isolated pathogen highlights the strong potential of hybridization in the emergence of pathogen species with sexual reproduction.


High throughput accurate method for estimating in vitro dry matter digestibility of maize silage.
Since the introduction of studies on maize silage digestibility at the end of the nineteenth century, protocols to estimate dry matter digestibility have not stopped evolving. Since the early 1980s, the protocol developed by Aufrère became a benchmark in many laboratories to estimate in vitro dry matter digestibility. In order to increase its throughput, to facilitate its execution and to decipher the impact of the different parameters of the protocol we decided to test the combination of 7 parameters in 21 different protocols. We thus tested the impact of (1) the presence or absence of pepsin in HCl solution, (2) the temperature of incubation during enzymatic hydrolysis, (3) the presence or absence of a gelatinization step, (4) washing/rinsing versus neutralization step, (5) the presence or absence of α-amyloglucosidase in enzymatic solution, (6) the duration of cellulase incubation, and (7) the concentration of the cellulase solution. The major result of our work highlighted that it was essential to carry out a gelatinization step to correctly estimate the in vitro dry matter digestibility of maize silage. The proposed protocol in this paper is innovative, reliable, highthroughput and easy to implement in many laboratories to accurately quantity in vitro dry matter digestibility.


Using neural networks to support high-quality evidence mapping.
The Living Evidence Map Project at the Norwegian Institute of Public Health (NIPH) gives an updated overview of research results and publications. As part of NIPH's mandate to inform evidence-based infection prevention, control and treatment, a large group of experts are continously monitoring, assessing, coding and summarising new COVID-19 publications. Screening tools, coding practice and workflow are incrementally improved, but remain largely manual. This paper describes how deep learning methods have been employed to learn classification and coding from the steadily growing NIPH COVID-19 dashboard data, so as to aid manual classification, screening and preprocessing of the rapidly growing influx of new papers on the subject. Our main objective is to make manual screening scalable through semi-automation, while ensuring high-quality Evidence Map content. We report early results on classifying publication topic and type from titles and abstracts, showing that even simple neural network architectures and text representations can yield acceptable performance.


Quantitative hepatitis B surface antigen analysis in hepatitis B e antigen-positive nucleoside-naive patients treated with entecavir.
Entecavir is a potent nucleoside analogue for treating chronic hepatitis B (CHB). Quantitative hepatitis B surface antigen (qHBsAg) levels are predictive of response to interferon-α in CHB treatment; however, the clinical utility of qHBsAg in nucleoside/nucleotide analogue-based CHB therapy is not fully characterized. This study assessed changes in qHBsAg in patients treated with entecavir in the Phase III study ETV-022. This retrospective post hoc analysis included nucleoside/nucleotide-naive, hepatitis B e antigen (HBeAg)-positive patients receiving entecavir (0.5 mg daily) in ETV-022 who had samples available for qHBsAg analysis through week 48. qHBsAg, HBV DNA and alanine aminotransferase levels were assessed for the overall patient cohort, for cohorts with or without HBeAg loss or HBsAg loss by week 48, and by HBV genotype. Overall, 95 patients from ETV-022 had available samples for qHBsAg analysis through week 48. In all cohorts, 48 weeks of entecavir therapy resulted in effective HBV DNA suppression. In the overall cohort, qHBsAg declined by -0.92 log10 IU/ml through week 48. The decline in qHBsAg was more pronounced in patients with subsequent HBeAg loss or HBsAg loss, and in patients infected with HBV genotype D or A. On-treatment qHBsAg changes did not correlate with changes in HBV DNA; no on-treatment or baseline factor was found to be predictive of HBeAg loss or HBsAg loss. Through 48 weeks of entecavir therapy, qHBsAg declined predominantly in those patients who achieved seroclearance of HBeAg or HBsAg. However, unlike with interferon-α-based therapy, early qHBsAg decline was not predictive of serological response at year 1 of entecavir treatment.


Malic Enzyme 1 Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species.
Malic enzyme 1 (ME1) catalyzes malate to pyruvate and thus promotes glycolysis. Its function in breast cancer remains to be fully clarified. The aim of this work was to investigate the prognostic value of ME1 and its possible mechanism in breast cancer. We evaluated ME1 expression in 220 early breast cancer patients with tissue microarray-based immunohistochemistry and explored the relationships between ME1 expression and clinicopathological features. Survival analyses were further performed to determine its prognostic value. The public database was used to confirm tissue microarray results. Further, cell proliferation, migration, invasion ability and reactive oxygen species (ROS) were examined in breast cancer cells. In breast cancer tissues, high ME1 expression was significantly associated with larger tumor size, higher incidence of lymph node metastasis and higher incidence of lymph-vascular invasion. High ME1 expression significantly correlated with worse recurrence-free survival (RFS), and was an independent prognostic factor for RFS, which was confirmed by mRNA results in the public database. In vitro, upregulation of ME1 by transfecting MCF-7 cells with virus vector remarkably enhanced viability, motility and epithelial-mesenchymal transition (EMT) and decreased ROS levels, whereas knockdown in MDA-MB-468 cells produced totally opposite effects as expected. When pretreated with oxidizing agent, MCF-7 cells overexpressing ME1 lost its motility, whereas MDA-MB-468 cells with knockdown of ME1 restored its motility when pretreated with antioxidant. To our knowledge, these clinical and experiment works first suggested that ME1 may be a novel biomarker and potential therapeutic target for breast cancer metastasis, and its biological effect is mainly controlled by manipulating ROS.


Release of nitric oxide, but not prostaglandin E2, by bone cells depends on fluid flow frequency.
Loading frequency is an important parameter for the stimulation of bone formation in vivo. It is still unclear how the information of external loading characteristics is conveyed to osteoblasts and osteoclasts. Osteocytes are thought to detect mechanical loads by sensing fluid flow through the lacuno-canalicular network within bone and to translate this information into chemical signals. The signaling molecules nitric oxide (NO) and prostaglandin E2 (PGE2) are known to play important roles in the adaptive response of bone to mechanical loads. We have investigated the effects of fluid flow frequency on the production of PGE2 and NO in bone cells in vitro. Pulsatile fluid flow with different frequencies stimulated the release of NO by MC3T3-E1 osteoblasts in a dose-dependent manner. In contrast, PGE2 production was enhanced consistently by all fluid flow regimes, independent of flow frequency. This implies that the NO response may play a role in mediating the differential effects of the various loading patterns on bone.


"My story for my better self": love, loss, and working through in the diary of Elizabeth Barrett Browning.
An approach to the diary as more than a private record, but a psychologically meaningful act and object, is demonstrated by a close reading of the diary of the English poet Elizabeth Barrett Browning. Attending to both formal and thematic aspects, this study attempts to illustrate the variable uses of diary-keeping, as well as to identify its uses of specific importance to this particular diarist. The more expansive and profound insight thus gained into the poet's life and work points to the potential of a psychoanalytic approach to such uniquely intimate documents. Evidence is offered to support the position that Browning's diary served important integrating functions during a critical period of her life: modulating overwhelming affect, organizing experiences beyond her control, and serving as a concrete symbol of preservation in the face of accumulative painful losses. The diary-keeping was a self-therapeutic endeavor, mediating and metabolizing these losses into a work of mourning as the poet elaborated and memorialized them.


Perspectives of using pulmonary arterial stiffness indicators to evaluate the prognosis of patients with pulmonary arterial hypertension.
The aim of the study was to characterize the mechanical properties of the pulmonary arterial wall (PA) in patients with pulmonary arterial hypertension (PAH) using magnetic resonance imaging (MRI) of the heart, and to determine their diagnostic and prognostic value. 57 patients with PAH were examined. The diagnosis of PAH was verified according to the recommendations of the ERS/ESC from 2015. All patients underwent a detailed echocardiographic (ECHO) study, MRI of the heart and right heart catheterization (RHC). To calculate the stiffness of the pulmonary artery wall, the MRI and RHC data were used. We identified a correlation between the functional class of PAH and the parameters of hemodynamic, physical performance, ECHO parameters of the right chambers. There were no differences in the stiffness of the pulmonary artery wall, depending on the functional class of PAH. Among the six stiffness indicators, only pulsation index was associated with the structural and functional parameters of the right ventricle and pulmonary vascular resistance. The MRI pulsation index is the simpleststiffness index of the pulmonary artery wall and the most promising one for evaluating the prognosis of patients with PAH.


Regulatory T cells suppress the motility of cytotoxic T cells in Friend retrovirus-infected mice.
Antiviral immunity often requires CD8+ cytotoxic T lymphocytes (CTLs) that actively migrate and search for virus-infected targets. Regulatory T cells (Tregs) have been shown to suppress CTL responses, but it is not known whether this is also mediated by effects on CTL motility. Here, we used intravital 2-photon microscopy in the Friend retrovirus (FV) mouse model to define the impact of Tregs on CTL motility throughout the course of acute infection. Virus-specific CTLs were very motile and had frequent short contacts with target cells at their peak cytotoxic activity. However, when Tregs were activated and expanded in late-acute FV infection, CTLs became significantly less motile and contacts with target cells were prolonged. This phenotype was associated with development of functional CTL exhaustion. Tregs had direct contacts with CTLs in vivo and, importantly, their experimental depletion restored CTL motility. Our findings identify an effect of Tregs on CTL motility as part of their mechanism of functional impairment in chronic viral infections. Future studies must address the underlying molecular mechanisms.


Preferences for a good death: a cross-sectional survey in advanced cancer patients.
The aim of this study was to describe preferences for a good death among Chinese patients with advanced cancer and then to explore factors contributing to their preferences including patient demographics and disease variables. A convenience sample of 275 patients with advanced cancer was recruited from a tertiary cancer hospital in Beijing, China, between February and December 2017. A Chinese version of the Good Death Inventory (GDI) was used to measure patients' preferences for dying and death. Besides, data were collected using a multi-itemed questionnaire focusing on demographic and disease characteristics of patients. Of the 275 questionnaires returned, 248 responses were analysed (effective response rate 90.2%). According to the total scores for each of the 20 domains, the five most important domains of a good death were: good relationship with family (19.80±2.39), independence (19.66±2.56), maintaining hope and pleasure (19.56±2.55), good relationship with medical staff (18.92±3.73), not being a burden to others (18.89±3.30). Patients' characteristics including age, educational status, religious belief, medical payment types, family economic status, past experiences of the death of others, the period since cancer diagnosis, past experiences of hospitalisation and subjective physical condition influenced their preferences for a good death (all p<0.05). We had an in-depth knowledge and understanding of their preferences for good death among Chinese patients with advanced cancer. Meanwhile, we found some patients' factors contributed to different preferences for a good death. These findings have the potential to guide hospice care services aimed at achieving a good death for patients with advanced cancer.


Astigmatism evaluation prior to cataract surgery.
To evaluate and summarize literature from the past 18 months reporting advancements and issues in astigmatism assessment prior to cataract surgery. New and updated toric calculators and regression formulas offer the opportunity for more accurate lens selection for our patients. Concurrently, improvements in topographic evaluation of corneal keratometry have allowed for a decrease in unplanned residual corneal astigmatism. Measuring posterior corneal astigmatism is especially valuable in eyes with keratoconus when planning to implant toric intraocular lens (IOL) and now allows access to this patient population. Improved accuracy of astigmatism evaluation now occurs with point reflections on the corneal surface along with the latest generation toric lens formulas which integrated posterior corneal astigmatism, predicted lens position, and intended spherical power of the IOL. These improvements can allow for incorporation of toric lenses in keratoconus patients.


Prognostic impact of RAS mutations in patients with myelodysplastic syndrome.
RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10-15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild-type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome.


Na(+)/Ca(2+) exchange regulates Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion in mice.
Stimulation of muscarinic receptors in duodenal mucosa raises intracellular Ca(2+), which regulates ion transport, including HCO(3)(-) secretion. However, the underlying Ca(2+) handling mechanisms are poorly understood. The aim of the present study was to determine whether Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of duodenal mucosal ion transport and HCO(3)(-) secretion by controlling Ca(2+) homeostasis. Mouse duodenal mucosa was mounted in Ussing chambers. Net ion transport was assessed as short-circuit current (I(sc)), and HCO(3)(-) secretion was determined by pH-stat. Expression of NCX in duodenal mucosae was analyzed by Western blot, and cytosolic Ca(2+) in duodenocytes was measured by fura 2. Carbachol (100 muM) increased I(sc) in a biphasic manner: an initial transient peak within 2 min and a later sustained plateau starting at 10 min. Carbachol-induced HCO(3)(-) secretion peaked at 10 min. 2-Aminoethoxydiphenylborate (2-APB, 100 muM) or LiCl (30 mM) significantly reduced the initial peak in I(sc) by 51 or 47%, respectively, and abolished the plateau phase of I(sc) without affecting HCO(3)(-) secretion induced by carbachol. Ryanodine (100 muM), caffeine (10 mM), and nifedipine (10 muM) had no effect on either response to carbachol. In contrast, nickel (5 mM) and KB-R7943 (10-30 muM) significantly inhibited carbachol-induced increases in duodenal mucosal I(sc) and HCO(3)(-) secretion. Western blot analysis showed expression of NCX1 proteins in duodenal mucosae, and functional NCX in duodenocytes was demonstrated in Ca(2+) imaging experiments where Na(+) depletion elicited Ca(2+) entry via the reversed mode of NCX. These results indicate that NCX contributes to the regulation of Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion that results from stimulation of muscarinic receptors.


Principles of laser-induced separation and transport of living cells.
Separation and transport of defined populations of living cells grown on a thin membrane can be achieved by laser microdissection (LMD) of the sample of interest, followed by a laser-induced forward transport process [laser pressure "catapulting" (LPC)] of the dissected cell cluster. We investigate the dynamics of LMD and LPC with focused and defocused UV-A laser pulses by means of time-resolved photography. Catapulting is driven by plasma formation when tightly focused pulses are used, and by confined thermal ablation at the bottom of the sample for defocused catapulting. With both modalities, the initial specimen velocity amounts to about 50 to 60 ms. Time-resolved photography of live cell catapulting reveals that in defocused catapulting, strong shear forces arise when the sample is accelerated out of the culture medium covering the cells. By contrast, pulses focused at the periphery of the specimen cause a fast rotational movement that minimizes the flow of culture medium parallel to the sample surface, and thus the resulting shear stresses. Therefore, the recultivation rate of catapulted cells is much higher when focused pulses are used. Compared to collateral damage by mechanical forces, side effects by heat and UV exposure of the cells play only a minor role.


Shoulder Muscle Activity While Swimming in Different Wetsuits and Across Different Paces.
A triathlon wetsuit is an important piece of equipment during the swim portion of the triathlon for the benefits of thermoregulation and additional buoyancy. However, a lack of knowledge exists about whether or not shoulder muscle activity is influenced by wearing a wetsuit. The purpose of this study was to determine if there were changes in shoulder muscle activity during front crawl with four different wetsuit conditions: Full sleeve (FSW), Sleeveless (SLW), Buoyancy shorts (BS), No wetsuit (NWS) in three different subjective swimming paces (slow, medium, and fast). Eight subjects (5 males, 3 females: mean ± SD, age = 39.1 ± 12.5 years; height = 1.8 ± 0.1 m; mass = 74.6 ± 12.9 kg; percent body fat = 19.0 ± 7.8%) completed twelve total swim conditions (4 wetsuits x 3 swimming pace) in a 25-m indoor pool. Muscle activity in anterior deltoid (AD) and posterior deltoid (PD) were measured using a wireless waterproofed electromyography (EMG) system. Stroke rate (SR) was calculated using the time to complete five-stroke cycles. The AD, PD EMG, and SR were compared using ANOVA with repeated measures. None of the dependent variables showed the interaction between wetsuit conditions and swimming paces (p > 0.05). Both AD and PD muscle activity as well as SR were influenced by swimming pace (p < 0.05) but not wetsuit conditions (p > 0.05). In conclusion, shoulder muscle activity and SR were not influenced by types of wetsuits but influenced by swimming pace.


Dhr6, a Drosophila homolog of the yeast DNA-repair gene RAD6.
The RAD6 gene of the yeast Saccharomyces cerevisiae is required for DNA repair, for DNA damage-induced mutagenesis, and for sporulation, and it encodes a ubiquitin-conjugating enzyme. We have cloned the RAD6 homolog from Drosophila melanogaster and find that its encoded protein displays a very high degree of identity in amino acid sequence with the homologous RAD6 proteins from the two divergent yeasts, S. cerevisiae and Schizosaccharomyces pombe, and from human. Genetic complementation studies indicate that the Drosophila RAD6 homolog can functionally substitute for the S. cerevisiae RAD6 gene in its DNA-repair and UV-mutagenesis functions but cannot substitute in sporulation. The high degree of structural and functional conservation of RAD6 in eukaryotic evolution suggests that the various protein components involved in RAD6-dependent DNA repair and mutagenesis functions have also been conserved.


A NOVEL RAT MODEL OF CONTRAST-INDUCED ACUTE KIDNEY INJURY BASED ON RENAL CONGESTION AND THE RENO-PROTECTION OF MITOCHONDRIAL FISSION INHIBITION.
Contrast-induced acute kidney injury (CI-AKI) is a serious and common complication in patients receiving intravenous iodinated contrast medium (CM). Clinically, congestive heart failure is the most critical risk factor for CI-AKI and always leads to renal congestion for increased central venous pressure and fluid overload. Here, we aimed to investigate a novel CI-AKI rat model based on renal congestion. After the exploratory testing phase, we successfully constructed a CI-AKI rat model by inducing renal congestion by clamping the unilateral renal vein, removing the contralateral kidney, and a single tail vein injection of iohexol. This novel CI-AKI rat model showed elevated serum creatinine, urea nitrogen, and released tubular injury biomarkers (KIM-1 and NGAL), reduced glomerular filtration rate, and typical pathologic features of CM-induced tubular injury with extensive foamy degeneration, tubular edema, and necrosis. Electron microscopy and confocal laser scanning revealed excessive mitochondrial fission and increased translocation of Drp1 from the cytoplasm to the mitochondrial surface in tubular epithelial cells. As a Drp1 inhibitor, Mdivi-1 attenuated excessive mitochondrial fission and exerted reno-protection against CM injury. Simultaneously, Mdivi-1 alleviated oxidative stress, apoptosis, and inflammatory responses induced by CM toxicity. We concluded that renal congestion exacerbated CM toxicity and presented a novel CI-AKI rat model. Excessive mitochondrial fission plays a crucial role in CM reno-toxicity and is a promising target for preventing and treating CI-AKI.


The persistence of Chlamydia trachomatis elementary body cell walls in human polymorphonuclear leucocytes and induction of a chemiluminescent response.
Human polymorphonuclear leucocytes (HPMN) were incubated with [35S]methionine-labelled Chlamydia trachomatis (serovar L2/434/Bu) elementary bodies (EB) and EB cell walls. No net loss in the TCA-precipitable radioactivity was observed over 24 h in the HPMN that had taken up EB cell walls. SDS-polyacrylamide gel electrophoresis of the labelled C. trachomatis EB and EB cell wall proteins extracted from the HPMN at 2 and 24 h after infection demonstrated the persistence of most of the chlamydial cell wall polypeptides. Analysis of extracts of the HPMN that had taken up either EB or EB cell walls on Urografin density gradients at 2 and 24 h after infection, and electron microscopic observations on fractions representing the peaks, demonstrated the persistence of the EB cell walls in the HPMN. Electron microscopic observations of HPMN that had taken up EB or EB cell walls demonstrated EB cell walls in the HPMN phagosomes at 24 h after infection. The HPMN exposed to EB and EB cell walls of C. trachomatis gave chemiluminescent (CL) responses with peaks respectively 12 and 7 times greater than the peak value of the control. The significance of the persistence of the EB cell wall polypeptides and cell walls in the HPMN and activation of the HPMN to produce oxygen radicals (i.e. a CL response), and its possible relation to rheumatic diseases, is discussed.


Hyponatremia at the Emergency Department: a case-control study.
Hyponatremia (HNA) is a common electrolyte disturbance associated with morbidity and mortality. The aim of this study was to assess incidence and prognosis value of HNA in the Emergency Department (ED). A retrospective observational case-control study has been conducted in the ED during 10 months. Control patients (Na 135-145 mmol/L) were matched, in a 1:1 ratio, on age, gender and month of ED admission with hyponatremic patients (Na<130 mmol/L). Two hundred fifty-six patients (2.4% of patients with a blood analysis) had HNA among which 166 were matched with 166 normonatremic controls. HNA patients had more often a history of asthma/chronic obstructive pulmonary disease (P=0.002) and solid tumors (P=0.001), received more diuretics (P=0.026), and presented more often with vomiting (P=0.034). Admission to the hospital or to the ICU was more frequent in HNA patients (89% vs. 52%, P<0.001; 13% vs. 3%, P=0.003, respectively). Patients with HNA presented more frequently at least one complication (digestive, septic, respiratory, renal, and cardiovascular) during their hospital/ICU stay (40% vs. 4%, P<0.001). Mortality rate was higher in HNA than in controls (10% vs. 3%, P=0.021). The multivariable conditional logistic regression analysis showed an independent association of HNA with solid tumors (OR=4.12; 95% CI: 1.68 to 10.1) and hospital death (OR=2.90; 95% CI: 1.03 to 8.17). HNA was present in 2.4% of patients with a blood analysis and was associated independently with solid tumors and hospital death.


TDP-43 pathology in familial British dementia.
Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer's disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.


The missed HIV-positive children of Ethiopia.
As elsewhere, due to scarcity of data and limited awareness of HIV infection, especially in older children, the HIV epidemic among Ethiopian children appears neglected in national programs (children ART coverage is of only 12% in 2013). This paper estimates the country burden of HIV in older children and investigates the prevalence of HIV in orphans and vulnerable children (OVC) households. We analyzed national HIV data for Ethiopia, using Spectrum/ Estimation and Projection Package (EPP) and primary data on children living in households with at least one HIV-positive adult in the Amhara and Tigrai regions. Descriptive analysis of the age and sex distribution of HIV-positive OVC in Ethiopia was performed. Our Spectrum/EPP analysis estimated the population of HIV-positive children under 15 years old to be 160,000 in 2013. The majority of children (81•6%) were aged five to 14 years. The estimated number of orphans due to AIDS was 800,000. The empirical data from almost 10,000 OVC under 18 years showed 11•9% were HIV-positive, the majority of whom were between five and 10 years old with no significant difference between males and females. There is a large population of children living with HIV in Ethiopia, the magnitude of which not previously recognized. The majority were vertically infected and never identified nor linked into treatment. OVC represent a reachable group which could account for a substantial proportion of the HIV infected older children. We recommend that HIV programs urgently synergize with social protection sectors and address these children with HIV testing and related services.


Aqueous solutions of ionenes: interactions and counterion specific effects as seen by neutron scattering.
Aqueous solutions of ionenes with bromide and fluoride counterions have been investigated using small angle neutron scattering for the first time. Ionenes are a class of cationic polyelectrolytes based on quaternary ammonium atoms and, considering the very low solubility of their uncharged part (hydrocarbon chain), would be formally classified as hydrophobic. Ionenes present important structural differences over previously studied polyelectrolytes: (a) charge is located on the polyelectrolyte backbone, (b) the distance between charges is regular and tunable by synthesis, (c) hydrophobicity comes from methylene groups of the backbone and not from bulky side groups. Results for Br ionenes feature a disappearance of the well-known polyelectrolyte peak beyond a given monomer concentration. Below this concentration, the position of the peak depends on the chain charge density, f(chem), and scales as f(chem)(0.30±0.04). This is an indication of a hydrophilic character of the ionene backbone. In addition, osmotic coefficients of ionene solutions resemble again other hydrophilic polyelectrolytes, featuring no unusual increase in the water activity (or a significant counterion condensation). We conclude that despite the hydrophobicity of the hydrocarbon chain separating charged centers on ionenes, these chains behave as hydrophilic. In contrast to Br ionenes, the polyelectrolyte peak remains at all concentrations studied for the single F ionene investigated. This strong counterion effect is rationalized in terms of the different hydrating properties and ion pairing in the case of bromide and fluoride ions.


Quickstart for toddlers with autism spectrum disorder: A preliminary report of an adapted community-based early intervention program.
Early intervention (EI) for young children with autism spectrum disorder (ASD) must be resource-efficient while remaining effective; thus, clinicians are challenged to create and implement useful methods. Clinical evidence from community-based interventions that include reliable diagnoses, individual EI programs, along with comprehensive descriptions of participants, procedures, and participant outcomes can inform practice, translational research, and local policy. Parent-mediated EI for toddlers with ASD can promote positive developmental outcomes and lifelong well-being, but evidence of successful community uptake of research-based EIs is somewhat limited. The community-based, parent-mediated, evidence-informed QuickStart EI program aims to encourage toddlers' early social communication, social interactions, and relationship-building, in a community clinic setting.We aim to (1) describe our adaptations to the evidence-based Parent-Delivered Early Start Denver Model and (2) present promising findings for toddlers with or at risk for ASD and their families who received QuickStart. We also intend to motivate a similar study of EI in real-world situations to advance evidence-based practice and create relevant dialogue and questions for research. Complete data were identified and analyzed for up to 89 toddlers diagnosed with, or at risk of, ASD. Pre- and post-intervention parent- or self-report data were analyzed using descriptive statistics and paired-sample t-tests, as appropriate. Pre-intervention measures included demographic information (n = 89) and the Early Screening of Autism and Communication (ESAC; n = 89). Measures taken pre- and post-intervention included the Adaptive Behavior Assessment System-II (n = 60), MacArthur-Bates Communication Development Inventories (n = 58), and the parental sense of competence scale (n = 62). The Measure of Processes of Care (n = 60) was taken post-intervention. On enrollment, parents signed standard clinical agreements that included statements allowing their anonymous data to be analyzed for research. Using standardized parent/self-report measures, toddler gains were noted for social interaction, language, communication skills, and ASD symptoms, but not for parents' feelings of competence. Parents identified QuickStart procedures as family centered (Measure of Processes of Care). The QuickStart EI program, provided to toddlers and their families over 20 weeks in a community clinic, resulted in promising positive behavior and communication changes, as indicated on the parent-response measures, for a moderately large sample of toddlers. This study adds to the literature by describing a new EI program with clear procedures by which clinicians can create, provide, and evaluate a readily accessible, community-based EI for toddlers with or at risk of ASD. Methodological limitations inherent to our study design that precluded a control group and necessitated a reliance on available parent-report data are carefully critiqued and discussed.


[Non-allergenic bronchial hyperreactivity and occupational agents].
The relationship between occupational asthma (OA) and non-specific bronchial responsiveness (NSBR) is reviewed. Natural or laboratory exposure to ubiquitous allergens can induce or increase NSBR. Reduction of exposure has an opposite effect. Preliminary results suggest that NSBR is not a predisposing factor to OA. NSBR assessment can be useful in screening for OA, before employment to document baseline levels and serially afterwards, alone or combined to immediate skin reactivity to the occupational agent, to document the onset of OA. Showing NSBR is essential to the diagnosis of OA. Although specific broncho-provocation tests in a hospital laboratory still represent the gold standard to confirm OA, the demonstration of changes in peak expiratory flow rates, in particular if such changes are coupled to NSBR, is an important diagnostic tool. NSBR assessment is also an interesting guide to specific bronchoprovocation in the laboratory. Several studies have documented a reduction in NSBR in some cases of OA after removal from exposure to the causal agent. The degree of NSBR is one of the criteria that have been suggested in setting permanent disability in subjects with OA. Increased NSBR can exist in other occupational conditions and represents an essential feature of Reactive Airways Dysfunction Syndrome (RADS).


Preclinical Studies in Small Animals for Advanced Drug Delivery Using Hyperthermia and Intravital Microscopy.
This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia.


Disposition of sumatriptan in laboratory animals and humans.
Sumatriptan is a new 5HT1-like agonist that has proved a novel and effective treatment for migraine. The disposition of the 14C-radiolabeled drug in laboratory animals and humans after oral and parenteral administration is described. Oral absorption of sumatriptan is essentially complete in dogs and rabbits, but only approximately 50% in rat. In humans, at least 57% of an oral dose is absorbed. Bioavailabilities are species dependent (14, 23, 37, and 58% in humans, rabbits, rats, and dogs) reflecting differing degrees of first-pass metabolism. These data correlate well with hepatic extraction ratios, which are highest in rabbits and humans and lowest in dogs. Renal clearance is significant in all species and exceeds the glomerular filtration rate in rats, rabbits, and humans, but not in dogs. The compound is a weak base that shows widespread tissue distribution, including passage across the placental barrier and into milk, but low CNS penetration. Protein binding of sumatriptan is low in all species. Elimination half-lives of sumatriptan are approximately 1 hr in rats and rabbits, and approximately 2 hr in dogs and humans. In all species the majority of the absorbed dose is renally excreted, predominantly as the indole acetic acid metabolite and unchanged drug. Interesting species differences are evident in the metabolism of sumatriptan. Thus, in humans, the indole acetic acid metabolite is excreted partly as a glucuronide, whereas in animals conjugation of this metabolite is not apparent. In addition, demethylation of the sulfonamide side chain of the drug is evident in rodent and lagomorph species only.


Review of the genus Engyprosopon Günther, 1862 (Pleuronectiformes: Bothidae) from waters off Taiwan, with descriptions of two new species.
Species of the bothid genus Engyprosopon Günther, 1862 from the waters off Taiwan are reviewed. Nine species are recognized and described. Of the nine species, E. grandisquama (Temminck Schlegel, 1846), E. multisquama Amaoka, 1963 and E. maldivense (Regan, 1908) previously known from Taiwan are confirmed, whereas E. xystrias Hubbs, 1915, E. mogkii (Bleeker, 1854), E. longipelvis Amaoka, 1969 and E. mozambiquense Hensley, 2003 represent new records for Taiwan. Moreover, two further species are described new to science. Engyprosopon brevifrontale sp. nov. is characterized by a deep and short body, large eyes situated close to the head margin, 0 + 9-10 smooth gill rakers, strong rostral and upper orbital spines on the ocular side, small rostral spine on the blind side, and a dark blue peritoneum. Engyprosopon parvipectorale sp. nov. is characterized by the combination of serrate gill rakers, large head (3.1-3.4 in SL); extremely narrow or almost ridge-like interorbital in both sexes; ocular-side pectoral fin distinctly short (1.4-1.6 in HL) in both sexes; and no rostral or orbital spines in either sex. Detailed descriptions and a key to all of the species of Engyprosopon recorded from the waters off Taiwan are provided.


Angiomyolipoma located in the lumbar region of a newborn.
An unusual example of angiomyolipoma, which presented as a bulging mass on the right lumbar region of a newborn baby, is presented. The case described is the first report of a newborn with an unusually located angiomyolipoma. The most common predilection sites are the renal parenchyma and the retroperitoneum. However, most of the patients described are adults, and to the best of our knowledge no newborn patient has previously been reported in the literature.


Origin and evolution of the AmpC beta-lactamases of Citrobacter freundii.
To determine whether the widespread clinical use of beta-lactams has been selective for Citrobacter freundii-derived alleles of plasmid ampC genes, we generated a Bayesian consensus phylogeny of the published ampC sequences and compared the MICs of 16 beta-lactam antibiotics for Escherichia coli strains containing cloned copies of the C. freundii ampC alleles. We found that for the majority of compounds investigated, there has been essentially no increase in beta-lactam resistance conferred by those alleles. We also found that ampC alleles from the chromosomes of two beta-lactam-sensitive C. freundii strains isolated in the 1920s, before the clinical use of antibiotics, were as effective at providing beta-lactam resistance in E. coli as were the plasmid-borne alleles from beta-lactam-resistant clinical isolates. These results suggest that selection for increased resistance to beta-lactam antibiotics has not been a significant force directing the evolution of the C. freundii ampC alleles found in beta-lactam-resistant clinical isolates.


Use of i-Gel Supraglottic Airway in a Simulated Cardiac Arrest Resuscitation During Boat Rescue Transport by Los Angeles County Fire Lifeguard Division: A Proof-of-Concept Study.
The Los Angeles County Fire Department Lifeguard Division responds to water rescues and medical and dive emergencies across 72 miles of Southern California coastline and Catalina Island. Limited advanced life support resources make cardiac arrest resuscitations logistically challenging during transport to shore or the hyperbaric chamber. This proof-of-concept study looked to determine if an i-Gel (Intersurgical Complete Respiratory Systems, Wokingham, Berkshire, UK) supraglottic airway device would either become dislodged or compromise ventilations during prolonged resuscitation at high speeds over open water with an ongoing automatic chest compression device (ACCD). A simulated resuscitation was performed on the Los Angeles County Lifeguard rescue boat while underway at speeds up to 25 knots. A LUCAS ACCD (Jolife AB, Ideon Science Park, Lund, Sweden) and a size 3 i-Gel were used. The volume of ventilations and depth of compressions were continuously monitored using the AmbuMan Advanced manikin (Ambu, Ballerup, Denmark). The i-Gel supraglottic airway device delivered appropriate ventilations measuring between 300 and 400 mL/breath when delivered on the upstroke of compression. The i-Gel did not dislodge during transport. The i-Gel supraglottic airway device appears to provide adequate ventilations without dislodgment during ongoing compressions with an ACCD during high-speed water transport.


Elevated hydrostatic pressure stimulates ATP release which mediates activation of the NLRP3 inflammasome via P2X4 in rat urothelial cells.
Partial bladder outlet obstruction (pBOO) is a prevalent urological condition commonly accompanied by increased intravesical pressure, inflammation, and fibrosis. Studies have demonstrated that pBOO results in increased NLRP3 inflammasome and caspase-1 activation and that ATP is released from urothelial cells in response to elevated pressure. In the present study, we investigated the role of elevated pressure in triggering caspase-1 activation via purinergic receptors activation in urothelial cells. Rat urothelial cell line, MYP3 cells, was subjected to hydrostatic pressures of 15 cmH2O for 60 min, or 40 cmH2O for 1 min to simulate elevated storage and voiding pressure conditions, respectively. ATP concentration in the supernatant media and intracellular caspase-1 activity in cell lysates were measured. Pressure experiments were repeated in the presence of antagonists for purinergic receptors to determine the mechanism for pressure-induced caspase-1 activation. Exposure of MYP3 cells to both pressure conditions resulted in an increase in extracellular ATP levels and intracellular caspase-1 activity. Treatment with P2X7 antagonist led to a decrease in pressure-induced ATP release by MYP3 cells, while P2X4 antagonist had no effect but both antagonists inhibited pressure-induced caspase-1 activation. Moreover, when MYP3 cells were treated with extracellular ATP (500 µM), P2X4 antagonist inhibited ATP-induced caspase-1 activation, but not P2X7 antagonist. We concluded that pressure-induced extracellular ATP in urothelial cells is amplified by P2X7 receptor activation and ATP-induced-ATP release. The amplified ATP signal then activates P2X4 receptors, which mediate activation of the caspase-1 inflammatory response.


Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update.
Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such as anti-miRS), these therapeutics have shown promise in preclinical settings. Some miRNA-targeted therapeutics have been extended to clinical development, such as the mimic of miRNA-34 for treating cancer. Here, we discuss insights into the role of miRNAs and other non-coding RNAs in tumorigenesis and resistance and summarize some recent successful systemic delivery approaches and recent developments in miRNAs as targets for anticancer drug development. Furthermore, we provide a comprehensive overview of mimics and inhibitors that are in clinical trials and finally a list of clinical trials based on miRNAs.


Molecular analyses of KCNQ1-5 potassium channel mRNAs in rat and guinea pig inner ears: expression, cloning, and alternative splicing.
Expression of neuronal Kcnq gene family transcripts in the inner ear provides further evidence for cochlear M-type currents and for complex molecular heterogeneities of voltage-gated potassium channels composed of various KCNQ subunits and/or alternative splice variants. Furthermore, important roles in regulation of cellular excitability in the auditory system, and hearing disorders related to (hyper)excitability, e.g. tinnitus, are implied. Voltage-gated potassium channels play key roles in hearing, as evidenced by deafness resulting from disruption of genes encoding, for example, KCNQ1 or KCNQ4 subunits. Other members of the Kcnq gene family (Kcnq2, 3, and 5) are the molecular correlates of M currents, which regulate neuronal excitability. The expression of the latter has not previously been thoroughly investigated in the inner ear. The aim of this study was to identify genetic correlates of M currents, previously identified in cochlear hair cells by electrophysiological methods. Expression of Kcnq genes was investigated by reverse transcription-polymerase chain reaction (RT-PCR) using subtype-specific primers with total RNA isolated from whole guinea pig or rat cochlea as template. PCR products were confirmed by direct DNA sequencing. All members of the Kcnq family were expressed in guinea pig and rat cochlea. Cochlear expression of Kcnq2 exhibited two alternatively spliced forms, lacking exons 8, 15a, and 8, 12a, 15a, respectively. Novel molecular sequence data, e.g. guinea pig Kcnq cDNA sequences, were deposited in GenBank (AY684985-AY684990).


XMEN: welcome to the glycosphere.
XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients' mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG).


3-O-methyl-D-glucose transport in tumoral insulin-producing cells.
Tumoral insulin-producing cells of the RINm5F line were exposed at different temperatures, and for various lengths of time to increasing concentrations of 3-O-methyl-D-[U-14C]glucose. The uptake of the hexose represented a temperature-sensitive and saturable process, so that no rapid equilibration of hexose concentrations across the plasma membrane was reached, especially at low temperature and/or high concentrations of 3-O-methyl-D-glucose. The uptake of 3-O-methyl-D-[U-14C]glucose was not affected by a prior loading of the cells with the unlabeled hexose and its release from prelabeled cells was observed in the absence of any concentration gradient across the plasma membrane. The uptake of D-[U-14C]glucose and utilization of D-[5-3H]glucose was inhibited by 3-O-methyl-D-glucose, which failed, however, to affect D-[U-14C]glucose oxidation. At variance with the situation found in normal insulin-producing cells, the transport of D-glucose into the tumoral cells may thus play a regulatory role in its metabolism.


Oxidation of DJ-1 induced by 6-hydroxydopamine decreasing intracellular glutathione.
DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported to undergo preferential oxidation of the cysteine residue at position 106 (Cys-106) under oxidative stress; however, details of the molecular mechanisms are not well known. In the present study, mechanisms of DJ-1 oxidation induced by 6-hydroxydopamine (6-OHDA) were investigated by using SH-SY5Y cells. The treatment of these cells with 6-OHDA caused an obvious acidic spot sift of DJ-1 due to its oxidation. However, when catalase, which is an hydrogen peroxide (H(2)O(2))-removing enzyme, was added during the treatment, it failed to prevent the oxidation induced by 6-OHDA, suggesting that electrophilic p-quinone formed from 6-OHDA, but not H(2)O(2), was responsible for the DJ-1 oxidation. Benzoquinone, another electrophilic p-quinone, also induced DJ-1 oxidation. The intracellular glutathione (GSH) levels were significantly decreased by 6-OHDA, irrespective of the presence or absence of catalase. The inhibition of GSH synthesis by buthionine sulfoximine resulted in a decrease in GSH levels and enhancement of DJ-1 oxidation. The pretreatment of cells with N-acetyl-cysteine prevented the loss of intracellular GSH and subsequently DJ-1 oxidation induced by 6-OHDA. Collectively, these results suggest that electrophilic p-quinone formed from 6-OHDA induces DJ-1 oxidation by decreasing intracellular GSH.


Impact of scribes on performance indicators in the emergency department.
The objective was to quantify the effect of scribes on three measures of emergency physician (EP) productivity in an adult emergency department (ED). For this retrospective study, 243 clinical shifts (of either 10 or 12 hours) worked by 13 EPs during an 18-month period were selected for evaluation. Payroll data sheets were examined to determine whether these shifts were covered, uncovered, or partially covered (for less than 4 hours) by a scribe; partially covered shifts were grouped with uncovered shifts for analysis. Covered shifts were compared to uncovered shifts in a clustered design, by physician. Hierarchical linear models were used to study the association between percentage of patients with which a scribe was used during a shift and EP productivity as measured by patients per hour, relative value units (RVUs) per hour, and turnaround time (TAT) to discharge. RVUs per hour increased by 0.24 units (95% confidence interval [CI] = 0.10 to 0.38, p = 0.0011) for every 10% increment in scribe usage during a shift. The number of patients per hour increased by 0.08 (95% CI = 0.04 to 0.12, p = 0.0024) for every 10% increment of scribe usage during a shift. TAT was not significantly associated with scribe use. These associations did not lose significance after accounting for physician assistant (PA) use. In this retrospective study, EP use of a scribe was associated with improved overall productivity as measured by patients treated per hour (Pt/hr) and RVU generated per hour by EPs, but not as measured by TAT to discharge.


Enhanced production of alpha-amylase in fed-batch cultures of Bacillus subtilis TN106[pAT5].
Growth of Bacillus subtilis TN106[pAT5] and synthesis of plasmid-encoded protein (alpha-amylase) are investigated in batch, continuous, and fed-batch cultures using a defined medium containing glucose and/or starch as the carbohydrate source. The batch culture studies reveal that reduced availability of arginine hampers growth of recombinant cells (which lack an arginine synthesis gene) but promotes production of alpha-amylase and substitution of glucose by starch as the carbohydrate source leads to slower growth of recombinant cells and increased production of alpha-amylase per unit cell mass. Retention of recombinant cells over prolonged periods in continuous cultures is not possible without continuous application of antibiotic selection pressure owing to segregational plasmid instability. Fed-batch experiments with constant volumetric feed rate demonstrate that alpha-amylase production is enhanced at lower feed concentration of starch (sole carbohydrate source) and lower volumetric feed rate. Such slow addition of starch is however not conducive for growth of recombinant cells. The expression of the thermostable alpha-amylase gene carried on the recombinant plasmid pAT5 (derived from a plasmid isolated from a thermophilic bacterium) is promoted at higher temperatures, while growth of recombinant cells is depressed. In all batch and fed-batch experiments, production of alpha-amylase is observed to be inversely related to growth of recombinant cells. The efficacy of two-stage bioreactor operations, with growth of recombinant cells being promoted in the first stage and alpha-amylase production in the second stage, in attaining increased bulk alpha-amylase activity is demonstrated.


Impact of breath hold on regional nodal irradiation and heart volume in field in left breast cancer adjuvant irradiation.
Compared to the free-breathing technique, adjuvant left breast irradiation after breast-conserving surgery or mastectomy using the breath-hold method significantly reduces the heart mean dose, Left anterior descending artery, and ipsilateral lung doses. Movement with deep inspiration may also reduce heart volume in the field and regional node doses. Pre-radiotherapy planning CT was performed in the free-breathing, and breath-hold techniques using RPM, demographic information, clinicopathological data, heart volume in the field, heart mean dose, LAD mean dose, and regional nodal doses were calculated in both free breathing and DIBH. Fifty patients with left breast cancer receiving left breast adjuvant radiation were enrolled. There was no significant difference in axillary LN coverage between the two techniques, except for SCL maximum dose, Axilla I node maximum dose, and Axilla II minimum dose in favor of the breath hold technique. The mean age was 47.54 years, 78% had GII IDC, 66% had positive LVSI results, and 74% of patients had T2. The breath hold strategy resulted in considerably decreased mean heart dose (p = 0.000), LAD dose (p = 0.000), ipsilateral lung mean dose (p = 0.012), and heart volume if the field (p = 0.013). The mean cardiac dosage and the dose of the LAD were significantly correlated (p = 0.000, R = 0.673). Heart volume in the field and heart mean dosage was not significantly correlated (p = 0.285, r = - 0.108). When compared to free breathing scans, DIBH procedures result in considerably reduced dosage to the OAR and no appreciable changes in dose exposure to regional lymph node stations in patients with left-sided breast cancer.


You can't buy insurance when the house is on fire.
Why does health insurance cost so much? According to the vice president at the insurance company that pioneered high- deductible health insurance to go with medical savings accounts, a big factor is that insurance companies are being asked to solve social problems. Mr Hartnedy offers a solution to America's healthcare-delivery plight that includes empowerment of individuals and preservation of choice.


Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit.
Incomplete recovery of neuromuscular function may impair pulmonary and upper airway function and contribute to adverse respiratory events in the postanesthesia care unit (PACU). The aim of this investigation was to assess and quantify the severity of neuromuscular blockade in patients with signs or symptoms of critical respiratory events (CREs) in the PACU. We collected data over a 1-yr period. PACU nurses identified patients with evidence of a predefined CRE during the first 15 min of PACU admission. Train-of-four (TOF) ratios were immediately quantified in these patients using acceleromyography (cases). TOF data were also collected in a control group that consisted of patients undergoing a general anesthetic during the same period who were matched with the cases by age, sex, and surgical procedure. A total of 7459 patients received a general anesthetic during the 1-yr period, of whom 61 developed a CRE. Forty-two of these cases were matched with controls and constituted the study group for statistical analysis. The most common CREs among matched cases were severe hypoxemia (22 of 42 patients; 52.4%) and upper airway obstruction (15 of 42 patients; 35.7%). There were no significant differences between the cases and matched controls in any measured preoperative or intraoperative variables. Mean (+/-sd) TOF ratios were 0.62 (+/-0.20) in the cases, with 73.8% of the cases having TOF ratios <0.70. In contrast, TOF values in the controls were 0.98 (+/-0.07) (a difference of -0.36 with a 95% confidence interval of -0.43 to -0.30, P < 0.0001), and no control patients were observed to have TOF values <0.70 (the 95% confidence interval of the difference was 59%-85%, P < 0.0001). A high incidence of severe residual blockade was observed in patients with CREs, which was absent in control patients without CREs. These findings suggest that incomplete neuromuscular recovery is an important contributing factor in the development of adverse respiratory events in the PACU.


[Is coronary magnetic resonance angiography already a clinically useful diagnostic tool?].
Magnetic resonance imaging (MRI) allows the evaluation of coronary arteries non-invasively and without the use of ionizing radiation. Coronary magnetic resonance angiography (MRA) is technically demanding due to the small size, tortuous course, and bulk motion of the coronary arteries as well as signal from surrounding epicardial fat and myocardium. In comparison to invasive x-ray coronary angiography not all coronary artery segments can be assessed by coronary MRA. At present the diagnostic accuracy of coronary MRA for detection of significant stenosis in coronary arteries is suboptimal. The presence of coronary anomalies and the patency of aortocoronary bypass grafts can be assessed by MRA with high diagnostic accuracy. The combination of coronary MRA with other MRI techniques for detection of ischemia has the potential to be of clinical value in the diagnostic work-up of patients with coronary artery disease.


Freeze-drying as sample preparation for micellar electrokinetic capillary chromatography-electrochemical separations of neurochemicals in Drosophila brains.
Micellar electrokinetic capillary chromatography with electrochemical detection has been used to quantify biogenic amines in freeze-dried brains of Drosophila melanogaster. Freeze-drying samples offers a way to preserve the biological sample while making dissection of these tiny samples easier and faster. Fly samples were extracted in cold acetone and dried in a rotary evaporator. Extraction and drying times were optimized in order to avoid contamination by red pigment from the fly eyes and still have intact brain structures. Single freeze-dried fly brain samples were found to produce representative electropherograms as a single hand-dissected brain sample. With utilization of the faster dissection time that freeze-drying affords, the number of brains in a fixed homogenate volume can be increased to concentrate the sample. Thus, concentrated brain samples containing five or fifteen preserved brains were analyzed for their neurotransmitter content, and four analytes; N-acetyloctopamine, N-acetylserotonin, N-acetyltyramine, and N-acetyldopamine were found to correspond well with previously reported values.


Intrafascial supracervical hysterectomy without colpotomy and transuterine mucosal resection by pelviscopy and laparotomy.
Between September 1991 and December 1993, 253 patients were operated on using the Classical Intrafascial SEMM (Serrated Edged Macro Morcellator) Hysterectomy (CISH) technique. One hundred fifty-two patients were assigned to pelviscopic CISH and 101 to laparotomic CISH. Uterine leiomyomas with menstrual disorders and pressure symptoms topped the list of indications with 61%. In all cases, initially transuterine mucosal resection and coring of the cervicouterine cylinder were carried out followed by the intrafascial supracervical dissection of the uterus. The size of the uterus played a decisive role in selecting the cases for CISH technique either by pelviscopy or laparotomy. The cervicouterine mucosal cylinders were cored using the Calibrated Uterine Resection Tool (CURT). Cervical thickness and diameters were measured preoperatively by transvaginal sonography for facilitating the use of a specific-sized CURT. After removal of this cylinder, hemostasis in the area was secured by coagulating with an endocoagulation device. The advantage of this technique is that the pelvic floor integrity remains intact, and because uterine arteries and ureters were not touched, the so called "complication zone" is thus avoided.The histological findings are in agreement with the indications, the leiomyomas and leiomyomas with adenomyosis being the most frequent pathology. The histologic analysis showed that in all cases the squamocolumnar transformation zone was totally removed. There were 11 (4.4%) complications, promptly identified and treated without further problems.The value of the Classical intrafascial supracervical hysterectomy without colpotomy including the resection of transformation zone speaks for itself, because there is less physical stress and recovery is quick. However, it has yet to prove its value as compared with other techniques for hysterectomy for specific indications.


The impact of glutamine dipeptide-supplemented parenteral nutrition on outcomes of surgical patients: a meta-analysis of randomized clinical trials.
To evaluate the impact of glutamine dipeptide-supplemented parenteral nutrition (GLN-PN) on clinical outcomes in surgical patients. MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Clinical Trials Register were searched to retrieve the eligible studies. The studies were included if they were randomized controlled trials that evaluated the effect of GLN-PN and standard PN on clinical outcomes of surgical patients. Clinical outcomes of interest were postoperative morbidity of infectious complication, mortality, length of hospital stay, and cost. Statistical analysis was conducted by RevMan 4.2 software from the Cochrane Collaboration. Fourteen randomized controlled trials (RCTs) (N = 587) were included in this meta-analysis. The results showed that glutamine dipeptide significantly reduced the length of hospital stay by around 4 days in the form of alanyl-glutamine (weighted mean difference [WMD] = -3.84; 95% confidence interval [CI] -5.40, -2.28; z = 4.82; P < .001) and about 5 days in the form of glycyl-glutamine (WMD = -5.40; 95% CI -8.46, -2.33; z = 3.45; P < .001). The overall effect indicated a significant decrease in the infectious complication rates of surgical patients receiving GLN-PN (risk ratio = 0.69; 95% CI 0.50, 0.95; z = 2.26; P = .02). GLN-PN was beneficial to postoperative patients by shortening the length of hospital stay and reducing the morbidity of postoperative infectious complications.


Non-Programmed Versus Programmed Aging Paradigm.
There are two opposite paradigms to explain aging, here precisely defined as "age-related progressive mortality increase, i.e. fitness decline, in the wild". The first maintains that natural selection is unable to maintain fitness as age increases. The second asserts that, in particular ecological conditions, natural selection favors specific mechanisms for limiting the lifespan. The predictions derived from the two paradigms are quite different and often opposing. A series of empirical data and certain theoretical considerations (non-universality of aging; great inter-specific variation of aging rates; effects of caloric restriction on lifespan; damage of aging for the senescing individual but its advantage in terms of supra-individual selection; existence of fitness decline in the wild; proportion of deaths due to intrinsic mortality inversely related to extrinsic mortality, when various species are compared; impossibility of explaining the age-related fitness decline as a consequence of genes that are harmful at a certain age; age-related progressive decline of cell turnover capacities; on/off cell senescence; gradual cell senescence) are compared with the predictions of the two paradigms and their compatibility with each paradigm is considered. The result is that the above-mentioned empirical data and theoretical considerations strongly contradict and falsify in many ways all theories belonging to the first paradigm. On the contrary, they are consistent or compatible with the predictions of the second paradigm.


Runt-related transcription factor 2 in human colon carcinoma: a potent prognostic factor associated with estrogen receptor.
Runt-related transcription factor 2 (RUNX2) belongs to the RUNX family of heterodimeric transcription factors, and is mainly associated with osteogenesis. Previous in vitro studies demonstrated that RUNX2 increased the cell proliferation of mouse and rat colon carcinoma cells but the status of RUNX2 has remained unknown in human colon carcinoma. Therefore, we examined clinical significance and biological functions of RUNX2 in colon carcinoma. RUNX2 immunoreactivity was examined in 157 colon carcinoma tissues using immunohistochemistry. RUNX2 immunoreactivity was evaluated as percentage of positive carcinoma cells [i.e., labeling index (LI)]. We used SW480 and DLD-1 human colon carcinoma cells, expressing estrogen receptor-β (ER) in subsequent in vitro studies. RUNX2 immunoreactivity was detected in colon carcinoma cells, and the median value of RUNX2 LI was 67%. RUNX2 LI was significantly associated with Dukes' stage, liver metastasis and ERβ status. In addition, RUNX2 LI was significantly associated with adverse clinical outcome of the colon carcinoma patients, and turned out an independent prognostic factor following multivariate analysis. Results of in vitro studies demonstrated that both SW480 and DLD-1 cells transfected with small interfering RNA against RUNX2 significantly decreased their cell proliferation, migration and invasive properties. In addition, RUNX2 mRNA level was significantly decreased by ER antagonist in these two cells. These findings all suggest that RUNX2 is a potent prognostic factor in human colon carcinoma patients through the promotion of cell proliferation and invasion properties, and is at least partly upregulated by estrogen signals through ERβ of carcinoma cells.


Hemothorax induced by severe cough: An unusual presentation.
Massive hemothorax resulting from cough-induced rib fracture is a condition in which blood accumulates in the chest, compromising the lungs and mediastinal structures. The most common cause of massive hemothorax is acute pro-traumatic injury. We present a case of a 47-year-old gentleman with morbid obesity and psoriasis, who was admitted to the emergency department due to shortness of breath that has been increased progressively after coughing for a period of 2 weeks. Chest radiograph demonstrated a large density in the left hemithorax, collapsing the left lung. Chest computerized tomography showed a left seventh rib fracture and massive pleural effusion. A closed chest tube thoracostomy was performed draining 3 L of hemorrhagic effusion, likely due to bleeding from the intercostal artery tear due to severe and prolonged cough. Cough-induced hemothorax due to spontaneous rib fractures are rare and clinicians should be well aware of this entity to prevent hemorrhagic shock and organ damage.


Beriberi in Cambodia.
Beriberi had plagued humans for centuries. It was responsible for over 50% of infant deaths in the Philippines in the early 1900s. But since the discovery of its cause and treatment it has become a rarity, or has it?


Clonotypic architecture of a Gag-specific CD8+ T-cell response in chronic human HIV-2 infection.
The dynamics of T-cell receptor (TCR)selection in chronic HIV-1 infection, and its association with clinical outcome, is well documented for an array of MHC-peptide complexes and disease stages. However, the factors that may contribute to the selection and expansion of CD8+ T-cells in chronic HIV-2 infection, especially at the clonal level remain unclear. To address this question, we undertook a detailed molecular characterization of the clonotypic architecture of an HLA-B*3501 restricted Gag-specific CD8+ T-cell response in donors chronically infected with HIV-2 using a combination of flow cytometry, tetramer-specific CD8+ TCR clonotyping, and in vitro assays. We show that the response to the NY9 epitope is hierarchical and narrow in terms of T-cell receptor-alpha (TCRA) and -beta (TCRB) gene usage yet clonotypically diverse. Furthermore, clonotypic dominance in shared origin CTL clones was associated with a greater magnitude of cytokine production and antigen sensitivity at limiting antigen dilution as well as enhanced cross-reactivity for known HIV-2 variants. Hence, our data suggest that effector mobilization and expansion in human chronic HIV-2 infection may be linked to the qualitative features of specific CD8+ T-cell clonotypes, which could have implications for viral control and disease outcome.


Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression.
We have been studying the suppression of experimental autoimmune encephalomyelitis in the Lewis rat after oral administration of myelin basic protein (MBP). Suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress immune responses in vitro. This suppression is mediated by secretion of TGF-beta following triggering by the fed antigen. In the present study, we tested the ability of overlapping 20 amino acid peptides from MBP to trigger suppression mediated by spleen cells from Lewis rats orally tolerized to MBP. Using a transwell system, we found that spleen cells from MBP orally tolerized animals stimulated by residues 21-40, 51-70 and 101-120 of MBP suppress proliferative responses of an ovalbumin specific cell line. This suppression correlated with secretion of TGF-beta by cells stimulated with the peptide. In addition, T cells from animals fed the tolerogenic peptide 21-40 alone secreted TGF-beta whereas no TGF-beta release or in vitro suppression was observed in animals fed the MBP encephalitogenic determinant 71-90. The 71-90 peptide triggered proliferation of MBP primed cells from animals immunized with MBP/CFA whereas the suppressor epitopes identified above did not. Furthermore, oral administration of peptide 21-40 suppressed disease induced by peptide 71-90. DTH responses to 71-90 were not affected by oral administration of peptide 21-40 whereas DTH responses to whole MBP were suppressed. These results demonstrate that distinct suppressor determinants exist on MBP which are separate from encephalitogenic determinants, and that epitope-driven bystander suppression plays an important role in down-regulation of tissue specific autoimmune processes following oral tolerization. These findings have important implications for the design of tissue specific targeted immunotherapy by oral tolerization in humans.


DNA sequences at the ends of the genome of bacteriophage Mu essential for transposition.
We have determined the minimal DNA sequences at the ends of the genome of bacteriophage Mu that are required for its transposition. A mini-Mu was constructed on a multicopy plasmid that enabled the manipulation of the DNA sequences at its ends without affecting the genes essential for transposition. The genes A and B, which were cloned outside the ends of the mini-Mu on the same plasmid, were both needed for optimal transposition. In our experimental system the predominant end products of the transposition are cointegrates both in the presence and in the absence of B. Two regions ending approximately 25 and 160 bp from the left end and one ending approximately 50 bp from the right end appear to be essential for optimal transposition. Overlapping with these regions, a 22-base-pair sequence was recognized with the consensus Y-G-T-T-C-A-Y-T-N-N-A-A-R-Y-R-C-G-A-A-A-A, where Y and R represent any pyrimidine and purine, respectively. At the left end these sequences occur as direct repeats; at the right end this sequence is inverted with respect to those at the left end.