At-risk alcohol users have disrupted valence discrimination during reward anticipation.
Alcohol use disorder is characterised by disrupted reward learning, underpinned by dysfunctional cortico-striatal reward pathways, although relatively little is known about the biology of reward processing in populations who engage in risky alcohol use. Cues that trigger reward anticipation can be categorized according to their learnt valence (i.e., positive vs. negative outcomes) and motivational salience (i.e., incentive vs. neutral cues). Separating EEG signals associated with these dimensions is challenging because of their inherent collinearity, but the recent application of machine learning methods to single EEG trials affords a solution. Here, the Alcohol Use Disorders Identification Test (AUDIT) was used to quantify risky alcohol use, with participants split into high alcohol (HA) (n = 22, mean AUDIT score: 13.82) and low alcohol (LA) (n = 22, mean AUDIT score: 5.77) groups. We applied machine learning multivariate single-trial classification to the electroencephalography (EEG) data collected during reward anticipation. The LA group demonstrated significant valence discrimination in the early stages of reward anticipation within the cue-P3 time window (400-550 ms), whereas the HA group was insensitive to valence within this time window. Notably, the LA, but not the HA group demonstrated a relationship between single-trial variability in the early valence component and reaction times for gain and loss trials. This study evidences disrupted hypoactive valence sensitivity in the HA group, revealing potential neurophysiological markers for risky drinking behaviours which place individuals at-risk of adverse health events.


Patterns of Opioid Prescribing for an Orthopaedic Trauma Population.
To determine opioid-prescribing practices to the orthopaedic trauma (OT) population at one Level I trauma center. A retrospective study of discharge prescriptions for adult patients with OT. Prescription details, injury burden, and patient demographics were abstracted for patients from initial injury through a 2-month follow-up. Level I trauma center. Adult patients with OT admitted over a 30-day period (n = 110). All discharge and follow-up opioid prescriptions were recorded. Morphine milligram equivalents (MMEs) per day, number of opioid prescriptions, type/dose of medication prescribed. One hundred thirty-five discharge prescriptions were written for 110 patients with orthopaedic injuries during the review period. All patients received opioids at the time of discharge. The MMEs prescribed at the time of discharge was 114 mg (54-300 mg) for a mean of 7.21 days (2-36.7 days). Although patients with preinjury risk factors were prescribed discharge opioids for a similar duration (7.00 days vs. 7.30 days, P = 0.81) than those without risk factors, they were prescribed significantly more MMEs than those without (130 vs. 108, P < 0.05) and were more likely to receive extended-release and long-acting opioids than those without (42.11% vs. 21.98%). Pain management after OT continues to be opioid-centric despite involving a population at risk. Further focus on prescriber and patient education, risk evaluation with mitigation, guideline development, and comprehensive pain management strategies are warranted in the OT population. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


The Deubiquitinating Enzymes UBP12 and UBP13 Positively Regulate MYC2 Levels in Jasmonate Responses.
The transcription factor MYC2 has emerged as a master regulator of jasmonate (JA)-mediated responses as well as crosstalk among different signaling pathways. The instability of MYC2 is in part due to the action of PUB10 E3 ligase, which can polyubiquitinate this protein. Here, we show that polyubiquitinated MYC2 can be deubiquitinated by UBP12 and UBP13 in vitro, suggesting that the two deubiquitinating enzymes can counteract the effect of PUB10 in vivo. Consistent with this view, UBP12 and UBP13 associate with MYC2 in the nucleus. Transgenic Arabidopsis thaliana plants deficient in UBP12 and UBP13 show accelerated decay of MYC2 and are hyposensitive to JA, whereas plants overexpressing UBP12 or UBP13 have prolonged MYC2 half-life and are hypersensitive to JA Our results suggest that there is a genetic link between UBP12, UBP13, and MYC2. Our results identify UBP12 and UBP13 as additional positive regulators of JA responses and suggest that these enzymes likely act by stabilizing MYC2.


Socioeconomic and Demographic Statuses as Determinants of Adherence to Antiretroviral Treatment in HIV Infected Patients: A Systematic Review of the Literature.
Socioeconomic and demographic statuses are associated with adherence to the treatment of patients with several chronic diseases. However, there is a controversy regarding their impact on adherence among HIV/AIDS patients. Thus, we performed a systematic review of the evidence regarding the association of socioeconomic and demographic statuses with adherence to antiretroviral therapy (ART) among HIV/AIDS patients. The PubMed database was used to search and identify studies concerning about socioeconomic and demographic statuses and HIV/AIDS patients. Data were collected on the association between adherence to ART and varies determinants factors of socioeconomic (income, education, and employment/occupation) and socio-demographic (sex and age). From 393 potentially-relevant articles initially identified, 35 original studies were reviewed in detail, which contained data that were helpful in evaluating the association between socioeconomic/ demographic statuses and adherence to ART among HIV patients. Two original research study has specifically focused on the possible association between socioeconomic status and adherence to ART. Income, level of education, and employment/occupational status were significantly and positively associated with the level of adherence in 7 studies (36.8%), 7 studies (28.0%), and 4 studies (23.5%) respectively out of 19, 25, and 17 studies reviewed. Sex (being male), and age (per year increasing) were significantly and positively associated with the level of adherence in 5 studies (14.3%), and 9 studies (25.7%) respectively out of 35 studies reviewed. However, the determinant of socioeconomic and demographic statuses was not found to be significantly associated with adherence in studies related to income 9(47.4%), education 17(68.0%), employment/ occupational 10(58.8%), sex 27(77.1%), and age 25(71.4%). The majority of the reviewed studies reported that there is no association between socio- demographic and economic variables and adherence to therapy. Whereas, some studies show that age of HIV patients (per year increasing) and sex (being male) were positively associated with adherence to ART. Among socio-economic factors, the available evidence does not provide conclusive support for the existence of a clear association with adherence to ART among HIV patients. There seems to be a positive trend between socioeconomic factors and adherence to ART in some of the reviewed studies.


Absorption and Emission Spectroscopic Investigation of Thermal Dynamics and Photo-Dynamics of the Rhodopsin Domain of the Rhodopsin-Guanylyl Cyclase from the Nematophagous Fungus Catenaria anguillulae.
The rhodopsin-guanylyl cyclase from the nematophagous fungus Catenaria anguillulae belongs to a recently discovered class of enzymerhodopsins and may find application as a tool in optogenetics. Here the rhodopsin domain CaRh of the rhodopsin-guanylyl cyclase from Catenaria anguillulae was studied by absorption and emission spectroscopic methods. The absorption cross-section spectrum and excitation wavelength dependent fluorescence quantum distributions of CaRh samples were determined (first absorption band in the green spectral region). The thermal stability of CaRh was studied by long-time attenuation measurements at room temperature (20.5 °C) and refrigerator temperature of 3.5 °C. The apparent melting temperature of CaRh was determined by stepwise sample heating up and cooling down (obtained apparent melting temperature: 62 ± 2 °C). The photocycle dynamics of CaRh was investigated by sample excitation to the first inhomogeneous absorption band of the CaRhda dark-adapted state around 590 nm (long-wavelength tail), 530 nm (central region) and 470 nm (short-wavelength tail) and following the absorption spectra development during exposure and after exposure (time resolution 0.0125 s). The original protonated retinal Schiff base PRSBall-trans in CaRhda photo-converted reversibly to protonated retinal Schiff base PRSBall-trans,la1 with restructured surroundings (CaRhla₁ light-adapted state, slightly blue-shifted and broadened first absorption band, recovery to CaRhda with time constant of 0.8 s) and deprotonated retinal Schiff base RSB13-cis (CaRhla₂ light-adapted state, first absorption band in violet to near ultraviolet spectral region, recovery to CaRhda with time constant of 0.35 s). Long-time light exposure of light-adapted CaRhla₁ around 590, 530 and 470 nm caused low-efficient irreversible degradation to photoproducts CaRhprod. Schemes of the primary photocycle dynamics of CaRhda and the secondary photocycle dynamics of CaRhla1 are developed.


Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.


Visualization of learning in multilayer perceptron networks using principal component analysis.
This paper is concerned with the use of scientific visualization methods for the analysis of feedforward neural networks (NNs). Inevitably, the kinds of data associated with the design and implementation of neural networks are of very high dimensionality, presenting a major challenge for visualization. A method is described using the well-known statistical technique of principal component analysis (PCA). This is found to be an effective and useful method of visualizing the learning trajectories of many learning algorithms such as backpropagation and can also be used to provide insight into the learning process and the nature of the error surface.


[Dengue haemorrhagic fever in children: ten years of clinical experience].
In Bucaramanga, Colombia, dengue haemorrhagic fever (DHF) has become endemo-epidemic since 1992. A cross-sectional study covering a period of 10 years (February, 1992 to February, 2002) was undertaken in children under 13 years of age hospitalized at the University Hospital. Observations were recorded on the clinical features, laboratory tests and the natural development of the disease. A total of 763 patients were examined, of whom 617 were classified as having DHF according to the WHO criteria (9.1% Grade I, 61.5% Grade II, 21.7% Grade III and 7.5% Grade IV). One hundred forty six patients could not be classified. The highest incidence took place in 1997, 1998 and 2001. Seventy four per cent of patients came from the metropolitan area of Bucaramanga; 48% were males; 0.3%, newborns; 11.8%, infants; 23%, pre-school children, and 64.9%, school children. The most important clinical features were fever and haemorrhagic manifestations (100%); vomiting (60%); abdominal pain (57%); headache (50%); osteomyalgia (40.8%); hepatomegaly (33%), and macular rash (29%). Among the haemorrhagic manifestations we found petechiae (56%); positive tourniquet test (35%); gastrointestinal bleeding (34%), and epistaxis (32%). Serous effusion was found in 17.7% of cases. Alarm signs of shock were found in 29%. Fifty two per cent had leucopenia and 37.3% atypic lymphocytes. Among other unusual manifestations were hepatitis, encephalopathy, alithiasic cholecystitis, acute renal failure, haemophagocytic syndrome and coinfections. Of the 617 cases, 12 died (1.5%).


Free-standing magnetic nanopillars for 3D nanomagnet logic.
Nanomagnet logic (NML) is a relatively new computation technology that uses arrays of shape-controlled nanomagnets to enable digital processing. Currently, conventional resist-based lithographic processes limit the design of NML circuitry to planar nanostructures with homogeneous thicknesses. Here, we demonstrate the focused electron beam induced deposition of Fe-based nanomaterial for magnetic in-plane nanowires and out-of-plane nanopillars. Three-dimensional (3D) NML was achieved based on the magnetic coupling between nanowires and nanopillars in a 3D array. Additionally, the same Fe-based nanomaterial was used to produce tilt-corrected high-aspect-ratio probes for the accurate magnetic force microscopy (MFM) analysis of the fabricated 3D NML gate arrays. The interpretation of the MFM measurements was supported by magnetic simulations using the Object Oriented MicroMagnetic Framework. Introducing vertical out-of-plane nanopillars not only increases the packing density of 3D NML but also introduces an extra magnetic degree of freedom, offering a new approach to input/output and processing functionalities in nanomagnetic computing.


Pre-laying climatic cues can time reproduction to optimally match offspring hatching and ice conditions in an Arctic marine bird.
Individuals breeding in seasonal environments are under strong selection to time reproduction to match offspring demand and the quality of the post-natal environment. Timing requires both the ability to accurately interpret the appropriate environmental cues, and the flexibility to respond to inter-annual variation in these cues. Determining which cues are linked to reproductive timing, what these cues are predicting and understanding the fitness consequences of variation in timing, is therefore of paramount interest to evolutionary and applied ecologists, especially in the face of global climate change. We investigated inter-annual relationships between climatic variation and the timing of reproduction in Canada's largest breeding population of Arctic common eiders (Somateria mollissima) in East Bay, Nunavut. Warmer spring temperatures predicted both earlier mean annual laying dates and the earlier ice-free conditions required by ducklings for post-natal growth. Warmer springs had higher variation in this temperature cue, and the population laying distribution became increasingly positively-skewed in warmer summers, potentially indicating that more low-quality females had the opportunity to commence laying in warmer years. Females that timed laying to match duckling hatching just prior to fully ice-free conditions obtained the highest duckling survival probability. Inter-annual data on repeated breeding attempts revealed that the individuals examined show a similar degree of laying flexibility in response to climatic variation; however, there was significant individual variation in the absolute timing of laying within an average year. This work sheds light on how reproductive timing is related to and influenced by variation in local climate and provides vital information on how climate-related variation in reproductive timing influence a fitness measure in an Arctic species. Results are especially relevant to future work in polar environments given that global climatic changes are predicted to be most intense at high latitudes.


Short-term exposure of dairy cows to pyrrolizidine alkaloids from tansy ragwort (Jacobaea vulgaris Gaertn.): effects on health and performance.
The increasing spread of ragworts is observed with concern. Ragworts like tansy ragwort (Jacobaea vulgaris Gaertn.) or marsh ragwort (J. aquatica) contain pyrrolizidine alkaloids (PA) which may induce hepatotoxic effects. Grazing animals usually avoid ragworts if their pasture management is appropriate. Preserved feed prepared from ragworts contaminated meadows may, however, lead to a significant exposure to PA. Previous studies on toxicity of PA for dairy cows revealed inconsistent results due to feeding ragwort plant material which was associated with heterogeneous PA exposure and thus failed to conclusively deduce critical PA doses. Therefore, the aim of the present study was to expose dairy cows (n = 4 per group) in a short-term scenario for 28 days with increasing PA doses (PA1: 0.47 mg PA/kg body weight (BW)/day (d); PA2: 0.95 mg PA/kg BW/d; PA3: 1.91 mg PA/kg BW/d) via oral administration by gavage of a defined PA-extract. While group PA3 was dosed with the PA-extract alone, groups PA2 and PA1 received PA-extracts blended in similar volumes with molasses to provide comparable amounts of sugar. Additionally, two control groups were treated either with water (CONWater) or with molasses (CONMolasses) to assess the effects of sugar without PA interference. While clinical traits including dry matter intake, milking performance, rectal body temperature, ruminal activity and body condition score (BCS) were not influenced by PA exposure, activities of enzymes indicative for liver damages, such as gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH), increased significantly over time at an exposure of 1.91 mg total PA/kg BW/d.


Meta-analysis of low molecular weight heparin versus placebo in patients undergoing total hip replacement and post-operative morbidity and mortality since their introduction.
1) To establish the clinical validity for in-patient low molecular weight heparin (LMWH) following total hip replacement (THR) through a meta-analysis of peer reviewed and published randomised placebo controlled trials (RCTs). 2) To establish whether modern peri-operative practices were associated with changes in rates of clinical venous thromboembolic (VTE) and all-cause mortality after THR by review of series of patients receiving in-patient LMWH published between 1985 and 2000. DATASOURCES: Medline and Embase (from 1980 to 2005), Datastar and Proquest databases were searched and references from bibliographies traced. Studies of adult patients receiving in-patient LMWH following elective primary or revision THR were sought and data abstracted. The first part of our analysis included only randomised placebo controlled trials. For the second part, randomised control trials were included and divided by their year of completion into three groups. We found no difference between LMWH and placebo in the risk of fatal pulmonary embolism (PE), other deaths, all cause mortality or major bleeding. LMWH reduced non-fatal PE (OR=0.14, 95%CI 0.03 to 0.74, p=0.029) at the expense of haematoma formation (7/147 vs 0/149, p=0.015). 35 studies were included in the second part of our analysis. Point estimates of rates of fatal and non-fatal pulmonary embolism and other deaths suggest a decline over time but fell short of statistical significance. Clinically relevant VTEs are a rare complication following THR. The lower risk of VTE narrows the risk benefit of potent pharmacological thromboprophylaxis. We do not support their use in patients undergoing THR without additional thromboembolic risk factors.


A community psychology of men and masculinity: historical and conceptual review.
This paper introduces the special section by presenting a historical and conceptual review of theory and research on the psychology of men and masculinity and then introducing the section's papers. Men have power because of their gender, but differ in access to power based on other individual characteristics such as social class, income, education, ethnicity, sexual orientation, or physical strength. Men typically have been studied as generic rather than gendered beings in psychology. In contrast, a gendered analysis of men highlights the ways in which men's experience, masculinity, and behavior contribute to health and social problems and to resources commonly addressed by community psychologists. Our gendered analysis suggests ways of working with men in group, organizational, and community settings to create positive individual and social change. Crucial to this analysis is the paradox that enacting masculinity both privileges and damages men. A second paradox stems from men having power as a group over women while individual men feel powerless or victimized by women as a group. The papers in this volume illustrate key themes of our historical and conceptual review through studies of adolescent and adult men as fathers, patients, partner abusers, support group participants and community members, and through examination of the impact of their gendered identities and behavior on health, well being, and justice.


Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy.
Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.


Models of dopaminergic and serotonergic signaling.
Mathematical models of dopaminergic and serotonergic synapses have enabled the authors to study quantitative aspects of the synthesis, release and reuptake of dopamine and serotonin, to investigate the effects of autoreceptors, and to explore the influence of the neurochemistry on the firing patterns of cells known to be involved in the behavioral responses to dopaminergic and serotonergic signaling. The models consist of coupled ordinary differential equations. Parameters are determined from biochemical and physiological measurements. Three results from recent IN SILICO experiments with the dopaminergic and serotonergic synapse models are described: (1) influence of substrate inhibition on the stability of dopamine and serotonin synthesis; (2) a predicted connection between serotonin reuptake transporter (SERT) density on terminals and tonic firing rates; (3) an explanation of data from autoreceptor knock-out experiments. Mathematical models are useful for studying the biology of dopaminergic and serotonergic signaling because these systems are complex and involve interactions between neurochemistry and neurobiology.


Diagnosis disclosure of prodromal Alzheimer disease-ethical analysis of two cases.
According to a recent proposal for revised diagnostic criteria for Alzheimer disease, the diagnosis could be made even in the absence of impairment of social function or daily life activities, provided positivity of one or more abnormal biomarkers. The use of the new proposed diagnostic criteria raises ethical issues and needs to be carefully evaluated. We describe two clinical cases of prodromal Alzheimer's disease and discuss the diagnosis disclosure, taking into consideration several issues: (i) the issue of the boundary between well founded research procedures and clinical practice, (ii) the issue of the fuzziness of the concepts of scientific evidence and scientific uncertainty, (iii) the issue of patient's autonomy and patient's best interest, and (iv) the issue of the patients' specific personal and social context. The degree of informativeness of the proposed diagnostic criteria for the single patient is already such as to deserve high regard in making the diagnosis and in the diagnosis disclosure process. During the disclosure process, the physician needs to take into account both what is known and what it is not sufficiently known. The patient's personal and environmental conditions should drive the physician to partial or full diagnostic disclosure, or delay communication. We proposed two different diagnosis disclosure processes, on the basis of the common neurological features and of the different global clinical situations, socio-personal contexts and attitudes towards the communication of the diagnosis.


[Growth, virulence and antigenecity of Leptospira interrogans serovar mozdok in modified EMJH medium].
The effect of higher Tween 80 concentrations in EMJH synthetic medium on the growth, virulence and antigenecity of Leptospira interrogans serovar mozdok was evaluated for increasing the performances and making a full use of the detoxifying capacity of bovine serum albumin. The growth was spectrophotographically evaluated by the analysis of the bacterial growth kinetics; the obtained biomass performance and the consumption of the carbon source. The virulence was estimated in Syrian Hamster model whereas antigenecity was determined through the microagglutination technique in rabbit's polyclonal antiserum. Under controlled culture conditions, the increase of Tween 80 concentration up to 3.25 mg/ml brought about an acceleration in bacterial metabolism that managed to double cell performances with a full consumption of the carbon source, without affecting virulence and antigenecity for a number of successive subcultures.


Remineralization of initial enamel carious lesions using fluoridated milk in vitro.
Milk is a universal dietary component and it is now recognized as an effective medium for the delivery of fluoride (F). This study sought (i) to evaluate fluoridated milk (2.5 ppm, 5 ppm, 10 ppm) for remineralizing carious lesions and (ii) to determine the optimum frequency for treating carious lesions with fluoridated milk. Artificial carious lesions, 90-180 μm deep, were created on extracted third molar teeth that were sectioned to produce specimens of 100-120 μm thickness. Specimens were randomly divided into 13 groups (n = 20) for treatment with deionized water, plain milk or fluoridated milk (2.5 ppm, 5 ppm, 10 ppm); once daily, twice daily or on alternate days as part of a 20-day pH cycling model. Lesion depth (LD) and mineral content were evaluated before and after pH cycling. Paired t-test, ANOVA and Student-Newman-Keuls tests were employed to make comparisons within and between the different groups. Fluoridated milk significantly reduced LD and increased the mineral content of the lesions compared to plain milk and deionized water (p < 0.05). The greatest reduction in LD was with 2.5 ppm F milk used twice daily (p < 0.05). Milk with 2.5 ppm F used twice daily demonstrated the greatest remineralization of artificial enamel carious lesions in vitro.


Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases.
Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.


Poorly Differentiated and Undifferentiated Thyroid Carcinomas.
Thyroid cancer is the most common endocrine malignancy and its incidence goes on increasing worldwide. The majority of thyroid tumours comprise well-differentiated (papillary and follicular) thyroid carcinomas that usually carry an excellent prognosis, while a minority progress to poorly differentiated carcinoma (PDTC) and, ultimately, to the highly aggressive and lethal undifferentiated carcinoma (UTC). Recently, some major advances have been made on the histologic and imunohistochemical identification, as well as on the molecular characterization of PDTC and UTC. In this review we summarize the most recent immunohistochemical and molecular findings in PDTC and UTC, giving a particular emphasis to the diagnostic and prognostic meaning of the genetic alterations.


Sub-100 nm patterning of TiO2 film for the regulation of endothelial and smooth muscle cell functions.
Previous studies have shown that fundamental cell functions such as adhesion, proliferation, and morphology are regulated by the interaction of cells with basement membrane nano- and micron- scale surface topography. By taking the basement membrane as a guiding principle, the surface can be designed with biophysical cues in the form of surface topographies to modulate the cellular functions of vascular endothelial and smooth muscle cells, which are crucial for vascular diseases. Titanium-based materials whose surfaces are covered by a thin layer of titanium dioxide (TiO2) are utilized in several regenerative medicine applications such as vascular prosthetics. The utilization of TiO2-covered materials makes it essential to understand the interaction of cells with the TiO2 layer to control the cell response. While it has been shown by means of patterned micro- and nano-topography that it is important to regulate cell functions on non-metallic materials, it would be of interest in the field of regenerative medicine to study the cell response on patterned TiO2 surface layers. Previous studies have mostly focused on studying the cell response on random micro- and nano-roughened metallic and metal oxide surfaces as it is challenging to fabricate patterned TiO2 surface layers. Here, the biocompatibility of a method that is capable of the rational patterning of a continuous TiO2 surface layer of sub-100 nm resolution scale using thermally curable resin-based nanoimprinting was studied. The responses of human umbilical vein endothelial cell (HUVEC), such as proliferation, morphology and focal adhesions, and smooth muscle cell (SMC) proliferation and morphology to the nano-patterned TiO2 layer were investigated. Overall, the TiO2 layer with surface nano-gratings showed enhanced proliferation of HUVECs, while it significantly lowered the proliferation of SMCs as compared to the unpatterned control. The HUVECs and SMCs were shown by topography to be sensitive to the 70 nm gratings as evident by the regulation of proliferation and cell shape. A significantly lower focal adhesion density was found of HUVECs on TiO2 nano-gratings, while a significantly higher average focal adhesion size of HUVECs was seen on TiO2 nano-wells and nano-gratings, compared to the unpatterned controls.


Simultaneous measurement of one- and two-photon excited fluorescence from a single sample: a detection method for oligonucleotides.
A new method has been developed that is based on the use of a single-excitation wavelength from a cw laser to excite simultaneously one-photon and two-photon fluorescence (TPF). Fluorescence bands of a sample containing two oligonucleotides, one labeled with a one-photon fluorescence dye and the other with a TPF dye, can be measured simultaneously. The two fluorescence bands are well separated, because the one-photon excited fluorescence band is redshifted, whereas the TPF band is blueshifted from the excitation wavelength. The spectral separation was found to be as large as 200 nm when ADS 840NCS was used to label one oligonucleotide for one-photon fluorescence and Rhodamine Red-X dye was used for TPF. Spectral overlapping problem that plagues current DNA sequencing techniques can be eliminated effectively with this method.


Clinical-laboratory characteristics of ANA-positive chronic idiopathic urticaria.
Despite the established association between chronic idiopathic/spontaneous urticaria (CIU) and presence of antinuclear antibodies (ANAs), the prevalence of autoimmune comorbidities in this population has not been analyzed. Here, we aim to identify clinical and laboratory manifestations associated with ANA-positive CIU. ANA-positive patients were identified via electronic data capture from the electronic patient record database of Leumit Health care Services (LHS) of Israel. Patient characteristics, medical histories, and details of diagnostic workup, medical treatment, and follow-up were retrieved by performing a chart review of electronic patient records (EPRs). The prevalence of target diseases among ANA(+) CIU(+), ANA(+) CIU(-), and ANA(-) CIU(+) patients was calculated. A total of 91 ANA(+) CIU(+), 3131 ANA(+) CIU(-), and 478 ANA(-) CIU(+) patients were identified. The ANA(+) CIU(+) group was characterized by higher prevalence of Sjögren's syndrome (SS)-A 52 antibodies (Ab) (7.7% versus 2.4%; p = 0.008), SS-A 60 Ab (11% versus 2.8%; p = < 0.001), and SS-B Ab (14.3% versus 3.2%; p < 0.001), compared with ANA(-) CIU(+) group. Additionally, ANA(+) CIU(+) patients were more likely to be diagnosed with thyroid autoimmune diseases, higher C-reactive protein (6.4 ± 10.3 versus 4.1 ± 8.8 mg/L; p = 0.027), and more profound basopenia (0.04 ± 0.09 versus 0.15 ± 0.11 cell/mm(3); p < 0.001) than ANA(-) CIU patients. More ANA(+) CIU(+) patients were resistant to four-fold standard licensed doses of antihistamines than ANA(-) CIU(+) patients [11 (12.1%) versus 29 (6.1%); p = 0.046]. ANA-positive CIU is characterized by higher prevalence of SS-A 52, SS-A 60, and SS-B antibodies and poorer clinical response to antihistamine medications.


Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection.
Recovery from Friend virus 3 (Rfv3) is a single autosomal gene encoding a resistance trait that influences retroviral neutralizing antibody responses and viremia. Despite extensive research for 30 years, the molecular identity of Rfv3 has remained elusive. Here, we demonstrate that Rfv3 is encoded by Apobec3. Apobec3 maps to the same chromosome region as Rfv3 and has broad inhibitory activity against retroviruses, including HIV. Not only did genetic inactivation of Apobec3 convert Rfv3-resistant mice to a susceptible phenotype, but Apobec3 was also found to be naturally disabled by aberrant messenger RNA splicing in Rfv3-susceptible strains. The link between Apobec3 and neutralizing antibody responses highlights an Apobec3-dependent mechanism of host protection that might extend to HIV and other human retroviral infections.


Finite element analysis of cemented prostheses for hip replacement in elderly patients with comminuted intertrochanteric fracture.
To determine postoperative stress distribution after cemented arthroplasty in elderly patients with comminuted intertrochanteric fracture, and assist in determining a rational prosthetic stem length. A three-dimensional (3D) model of intertrochanteric fracture was established using the Mimics and Unigraphics modeling software, which included the 3D model of comminuted intertrochanteric fracture, two long-stem(#4,#5) and one short stem(#3) prostheses, and the mantle layer of cement. The bone defect of the calcar femorale was replaced with a 5-mm thick cement. Then, the 3D finite element model of those materials was established, boundary conditions of force were imposed, and material parameters were set. Accordingly, a finite element analysis was performed to this model in stress. (1) The stress of the femur in the three-stem replacement prosthesis models increased from proximal end to distal end in the same pattern, while a stress concentration region was found at 5 mm from within the distal tip of the short-stem prosthesis (#3), which had a peak value of 67.85 MPa. However, no stress concentration was found on the long-stem prosthesis model. (2) For the short-stem prosthesis, the stress distribution of the cement-prosthesis interface was significantly concentrated in the distal region around the prosthesis end, in which the peak value of the lateral interface exceeded the fatigue strength of the bone cement. However, the biomechanics for the long prosthesis was better appreciated. Long prosthesis stems may theoretically be a better option for comminuted intertrochanteric fractures in elderly patients. However, the application of exceedingly long prosthesis stems would not be a better option. Comminuted intertrochanteric fracture, Elderly patients Finite element analysis, Prosthetic replacement.


Production and release of antimicrobial and immune defense proteins by mammary epithelial cells following Streptococcus uberis infection of sheep.
Investigating the innate immune response mediators released in milk has manifold implications, spanning from elucidation of the role played by mammary epithelial cells (MECs) in fighting microbial infections to the discovery of novel diagnostic markers for monitoring udder health in dairy animals. Here, we investigated the mammary gland response following a two-step experimental infection of lactating sheep with the mastitis-associated bacterium Streptococcus uberis. The establishment of infection was confirmed both clinically and by molecular methods, including PCR and fluorescent in situ hybridization of mammary tissues. Proteomic investigation of the milk fat globule (MFG), a complex vesicle released by lactating MECs, enabled detection of enrichment of several proteins involved in inflammation, chemotaxis of immune cells, and antimicrobial defense, including cathelicidins and calprotectin (S100A8/S100A9), in infected animals, suggesting the consistent involvement of MECs in the innate immune response to pathogens. The ability of MECs to produce and release antimicrobial and immune defense proteins was then demonstrated by immunohistochemistry and confocal immunomicroscopy of cathelicidin and the calprotectin subunit S100A9 on mammary tissues. The time course of their release in milk was also assessed by Western immunoblotting along the course of the experimental infection, revealing the rapid increase of these proteins in the MFG fraction in response to the presence of bacteria. Our results support an active role of MECs in the innate immune response of the mammary gland and provide new potential for the development of novel and more sensitive tools for monitoring mastitis in dairy animals.


Long-term modifiability of anomalous and delayed rectification in guinea pig inferior olivary neurons.
Delayed and anomalous rectification was studied in inferior olivary (I.O.) neurons in guinea pig brain stem slices maintained in vitro. Hyperpolarization of the I.O. cell beyond rest membrane potential was accompanied by anomalous rectification (AR). This consisted of 2 parts: an instantaneous and a time-dependent component. The "instantaneous" component was blocked by bath addition of Ba2+ or Cs+ and demonstrated inactivation following prolonged hyperpolarization. The time-dependent component, referred to as the gK(ol), was blocked by harmaline in concentrations of 0.1 mg/ml or by substitution of Co2+, Cd2+, or Mn2+ for Ca2+ in the bath. The gK(ol) was blocked by extracellular Cs+ but not by Ba2+. Delayed rectification (DR), consisting of 2 distinct components, was observed after membrane depolarization by more than 10 mV with respect to rest (usually at -65 mV). One of the components of the DR was found to be quite similar to the classical gK. It did not demonstrate significant inactivation with membrane potential change and was reduced by Ba2+ or tetraethylammonium (TEA). A second component of the DR demonstrated voltage-dependent inactivation and was thus referred to as gK(inact). This inactivation determined by current-clamp measurements had a sigmoidal time course, with approximately a 1 sec onset latency and a half-time to peak of 7 sec. The inactivation of gK(inact) outlasted current injection for tens of seconds to several minutes, depending on the duration and amplitude of the preceding depolarization. During this period, I.O. neurons could be easily activated and demonstrated full dendritic spikes following current injection or excitatory synaptic input that had previously been subthreshold for spike initiation. The inactivation component of the DR was removed by prolonged membrane hyperpolarization beyond rest. gK(inact) was blocked by 4-aminopyridine (4-AP; 100 microM) but not by Ba2+. This inactivation was dependent on the presence of extracellular Ca2+ or Ba2+. Addition of Co2+ or Cd2+ to the bath did not block gK(inact) but did prevent its inactivation. The modulatory effects of these different membrane conductances on the integrative properties of I.O. neurons are described. The long duration of the inactivation of DR and AR is considered as the basis for a dynamic long-term modulation of the electroresponsive and integrated properties of I.O. neurons.


Revisional endoscopic sleeve gastroplasty of laparoscopic sleeve gastrectomy: an international, multicenter study.
Laparoscopic sleeve gastrectomy (LSG) facilitates significant and durable weight loss; however, weight recidivism and need for revisional surgery occur in a subset of patients. Reduction of a dilated LSG using the revisional endoscopic sleeve gastroplasty (R-ESG) approach is an appealing and minimally invasive alternative to surgical revision that is congruent with obesity as a chronic relapsing disease model. In this study, we examine the safety and efficacy of the technique in a large multicenter international cohort. Prospectively collected data from 9 centers for 82 consecutive adults who underwent R-ESG for weight regain after LSG using the OverStitch device (Apollo Endosurgery, Austin, Tex, USA) from March 2014 to November 2019 were reviewed. Total body weight loss (TBWL) and adverse events were reported up to 12 months. Univariable logistic regression was used to identify predictors of response at 12 months. Eighty-two adults (92.7% female) experienced 27.9 ± 20.7 kg weight regain from post-LSG nadir weight, prompting R-ESG (mean age, 42.8 ± 10.4 years) at a mean weight of 128.2 ± 57.5 kg. Mean R-ESG procedure duration was 48.3 ± 20.5 minutes, and the median number of sutures used was 4 (interquartile range, 3-4). After R-ESG, TBWL (follow-up %) was 6.6% ± 3.2% at 1 month (81.7%), 10.6% ± 4.4% at 3 months (74.4%), 13.2% ± 10.1% at 6 months (63.4%), and 15.7% ± 7.6% at 12 months (51.2%). In a per-protocol analysis, ≥10% TBWL was achieved by 37 of 51 patients (72.5%) at 6 months and 34 of 42 patients (81.0%) at 12 months; ≥15% TBWL was achieved by 20 of 46 patients (43.5%) at 6 months and 22 of 42 patients (52.4%) at 12 months. Only 1 moderate adverse event occurred in the form of a narrowed gastroesophageal junction, which resolved after a single endoscopic dilation. R-ESG is a safe and effective means of facilitating weight loss for weight recidivism after LSG, with sustained results at 1 year. R-ESG should be considered before pursuing more-invasive surgical revisional options.


Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation.
Interleukin-1β (IL-1β) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1β-deficient mice, tumors begin to grow but subsequently regress. This change is due to recruitment and differentiation of inflammatory monocytes in the tumor microenvironment. In WT mice, macrophages heavily infiltrate tumors, but in IL-1β-deficient mice, low levels of the chemokine CCL2 hamper recruitment of monocytes and, together with low levels of colony-stimulating factor-1 (CSF-1), inhibit their differentiation into macrophages. The low levels of macrophages in IL-1β-deficient mice result in a relatively high percentage of CD11b+ dendritic cells (DCs) in the tumors. In WT mice, IL-10 secretion from macrophages is dominant and induces immunosuppression and tumor progression; in contrast, in IL-1β-deficient mice, IL-12 secretion by CD11b+ DCs prevails and supports antitumor immunity. The antitumor immunity in IL-1β-deficient mice includes activated CD8+ lymphocytes expressing IFN-γ, TNF-α, and granzyme B; these cells infiltrate tumors and induce regression. WT mice with 4T1 tumors were treated with either anti-IL-1β or anti-PD-1 Abs, each of which resulted in partial growth inhibition. However, treating mice first with anti-IL-1β Abs followed by anti-PD-1 Abs completely abrogated tumor progression. These data define microenvironmental IL-1β as a master cytokine in tumor progression. In addition to reducing tumor progression, blocking IL-1β facilitates checkpoint inhibition.


The effect of rainfall and competition intensity on forest response to drought: lessons learned from a dry extreme.
We investigated forest responses to global warming by observing: (1) planted Pinus halepensis forests, (2) an aridity gradient-with annual precipitation (P) ranging from ~300 to ~700 mm, and (3) periods of wet and dry climate that included the driest period during at least the last 110 years. We examined: (1) how the length of climatic integration periods to which trees are most responsive varies in space and time, (2) the extent to which competition modulates growth decline during drought (2011) and subsequent recovery (2012) years. The temporal scale of rainfall that was most influential on growth shortened in progressing southward, and in the drier than in the wetter period. Long-term underground water storage, as reflected in the relationship of growth to multiple-year rainfall, remained significant up to the point where P ≈ 500 mm. Under drier conditions (P < 500 mm) in both space and time, influential rainfall scales shortened, probably reflecting a diminishing role of water storage. These drier locations are the first from which the species would be likely to retreat if global warming intensified. Competition appeared to set an upper limit to growth, while growth variation among individual trees increased as competition-intensity decreased. That upper limit increased in 2012 compared with 2011. The observed insensitivity of slow-growing trees to competition implies that mortality risk may be density independent, when even any potential for higher soil moisture availability in open stands is lost to evapotranspiration before it can benefit tree growth.


A Post-Haustorial Defense Mechanism is Mediated by the Powdery Mildew Resistance Gene, PmG3M, Derived from Wild Emmer Wheat.
The destructive wheat powdery mildew disease is caused by the fungal pathogen Blumeria graminis f. sp. tritici (Bgt). PmG3M, derived from wild emmer wheat Triticum dicoccoides accession G305-3M, is a major gene providing a wide-spectrum resistance against Bgt. PmG3M was previously mapped to wheat chromosome 6B using an F6 recombinant inbred line (RIL) mapping population generated by crossing G305-3M with the susceptible T. durum wheat cultivar Langdon (LDN). In the current study, we aimed to explore the defense mechanisms conferred by PmG3M against Bgt. Histopathology of fungal development was characterized in artificially inoculated leaves of G305-3M, LDN, and homozygous RILs using fluorescence and light microscopy. G305-3M exhibited H2O2 accumulation typical of a hypersensitive response, which resulted in programmed cell death (PCD) in Bgt-penetrated epidermal cells, while LDN showed well-developed colonies without PCD. In addition, we observed a post-haustorial resistance mechanism that arrested the development of fungal feeding structures and pathogen growth in both G305-3M and resistant RIL, while LDN and a susceptible RIL displayed fully developed digitated haustoria and massive accumulation of fungal biomass. In contrast, both G305-3M and LDN exhibited callose deposition in attempt to prevent fungal invasion, supporting this as a mechanism of a basal defense response not associated with PmG3M resistance mechanism per se. The presented results shed light on the resistance mechanisms conferred by PmG3M against wheat powdery mildew.


"Neural" computation of decisions in optimization problems.
Highly-interconnected networks of nonlinear analog neurons are shown to be extremely effective in computing. The networks can rapidly provide a collectively-computed solution (a digital output) to a problem on the basis of analog input information. The problems to be solved must be formulated in terms of desired optima, often subject to constraints. The general principles involved in constructing networks to solve specific problems are discussed. Results of computer simulations of a network designed to solve a difficult but well-defined optimization problem--the Traveling-Salesman Problem--are presented and used to illustrate the computational power of the networks. Good solutions to this problem are collectively computed within an elapsed time of only a few neural time constants. The effectiveness of the computation involves both the nonlinear analog response of the neurons and the large connectivity among them. Dedicated networks of biological or microelectronic neurons could provide the computational capabilities described for a wide class of problems having combinatorial complexity. The power and speed naturally displayed by such collective networks may contribute to the effectiveness of biological information processing.


Nutritional efficiency of succinic acid and glutamic acid dimethyl esters in colon carcinoma cells.
The dimethyl esters of succinic acid (SAD) and glutamic acid (GME) were found to be efficiently metabolized in colon carcinoma cells of the Caco-2 line. The rate of [1,4-14C]SAD and [2,3-14C]SAD conversion to radioactive acidic metabolites, CO2, amino acids, pyruvic acid, and lactic acid suggested that the catabolism of the ester-derived succinic acid occurred mainly through the sequence of reactions catalyzed by succinate dehydrogenase, fumarase, and the malic enzyme. This coincided with a marked sparing action of SAD on the utilization of D-[2-(3)H]glucose and D-[5-(3)H]glucose and generation of 14C-labeled acid metabolites, CO2, and lactic acid from D-[U-14C]glucose by the enterocytes. Likewise, the conversion of [U-14C]GME to 14C-labeled amino acids, its oxidation compared with that of [1-(14)C]GME, and the production of NH4+ in the absence or presence of GME indicated efficient catabolism of the latter ester. Like SAD, GME decreased the utilization of D-[5-(3)H]glucose and generation of 14C-labeled acidic metabolites, pyruvate, and CO2 from D-[6-(14)C]glucose, while increasing the generation of 14C-labeled amino acids from the labeled hexose. The oxidation of D-[6-(14)C]glucose was even more severely inhibited by GME. In normal rat intestinal cells, SAM, SAD, and GME also exerted a marked sparing action on D-[U-14C]glucose oxidation. The present findings suggest, therefore, that these esters could possibly be used to sustain ATP generation in intestinal cells.


Immediate sequential bilateral surgery versus delayed sequential bilateral surgery for cataracts.
Age-related cataract affects both eyes in most cases. Most people undergo cataract surgery in both eyes on separate days, referred to as delayed sequential bilateral cataract surgery (DSBCS). An alternative procedure involves operating on both eyes on the same day, but as two separate procedures, known as immediate sequential bilateral cataract surgery (ISBCS). Potential advantages of ISBCS include fewer hospital visits for the patient, faster visual recovery, and lower healthcare costs. Nevertheless, concerns exist about possible bilateral, postoperative, sight-threatening adverse effects with ISBCS. Therefore, there is a clear need for evaluating evidence regarding the safety, effectiveness, and cost-effectiveness of ISBCS versus DSBCS. To assess the safety of ISBCS compared to DSBCS in people with bilateral age-related cataracts and to summarise current evidence for the incremental resource use, utilities, costs, and cost-effectiveness associated with the use of ISBCS compared to DSBCS in people with bilateral age-related cataracts (primary objectives). The secondary objective was to assess visual and patient-reported outcomes of ISBCS compared to DSBCS in people with bilateral age-related cataracts. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 5); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; the WHO ICTRP; and DARE and NHS EED on the CRD Database on 11 May 2021. There were no language restrictions. We limited the searches to a date range of 2007 onwards. We included randomised controlled trials (RCTs) to assess complications, refractive outcomes, best-corrected distance visual acuity (BCDVA) and patient-reported outcome measures (PROMs) with ISBCS compared to DSBCS. We included non-randomised (NRSs), prospective, and retrospective cohort studies comparing ISBCS and DSBCS for safety assessment, because of the rare incidence of important adverse events. To assess cost-effectiveness of ISBCS compared to DSBCS, we included both full and partial economic evaluations, and both trial-based and model-based economic evaluations. We used standard Cochrane methodological procedures and assessed risk of bias for NRSs using the ROBINS-I tool. For cost-evaluations, we used the CHEC-list, the CHEERS-checklist, and the NICE-checklist to investigate risk of bias. We assessed the certainty of evidence with the GRADE tool. We reported results for economic evaluations narratively. We included 14 studies in the review; two RCTs, seven NRSs, and six economic evaluations (one study was both an NRS and economic evaluation). The studies reported on 276,260 participants (7384 for ISBCS and 268,876 for DSBCS) and were conducted in Canada, the Czech Republic, Finland, Iran, (South) Korea, Spain (Canary Islands), Sweden, the UK, and the USA. Overall, we considered the included RCTs to be at 'high to some concerns' risk of bias for complications, 'some concerns' risk of bias for refractive outcomes and visual acuity, and 'high' risk of bias for PROMs. The overall risk of bias for NRSs was graded 'serious' regarding complications and 'serious to critical' regarding refractive outcomes. With regard to endophthalmitis, we found that relative effects were estimated imprecisely and with low certainty, so that relative estimates were not reliable. Nonetheless, we found a very low risk of endophthalmitis in both ISBCS (1/14,076 participants) and DSBCS (55/556,246 participants) groups. Based on descriptive evidence and partially weak statistical evidence we found no evidence of an increased risk of endophthalmitis with ISBCS. Regarding refractive outcomes, we found moderate-certainty (RCTs) and low-certainty (NRSs) evidence there was no difference in the percentage of eyes that did not achieve refraction within 1.0 dioptre of target one to three months after surgery (RCTs: risk ratio (RR) 0.84, 95% confidence interval (CI) 0.57 to 1.26; NRSs: RR 1.02, 95% CI 0.60 to 1.75). Similarly, postoperative complications did not differ between groups (RCTs: RR 1.33, 95% CI 0.52 to 3.40; NRSs: 1.04, 95% CI 0.47 to 2.29), although the certainty of this evidence was very low for both RCTs and NRSs. Furthermore, we found low-certainty (RCTs) to very low-certainty (NRSs) evidence that total costs per participant were lower for ISBCS compared to DSBCS, although results of individual studies could not be pooled. Only one study reported on cost-effectiveness. This study found that ISBCS is cost-effective compared to DSBCS, but did not measure quality-adjusted life years using preferred methods and calculated costs erroneously. Finally, regarding secondary outcomes, we found limited evidence on BCDVA (data of two RCTs could not be pooled, although both studies individually found no difference between groups (very low-certainty evidence)). Regarding PROMs, we found moderate-certainty evidence (RCTs only) that there was no difference between groups one to three months after surgery (standardised mean difference -0.08, 95% CI -0.19 to 0.03). Current evidence supports there are probably no clinically important differences in outcomes between ISBCS and DSBCS, but with lower costs for ISBCS. However, the amount of evidence is limited, and the certainty of the evidence was graded moderate to very low. In addition, there is a need for well-designed cost-effectiveness studies.


Abortion in a thoroughbred mare associated with an infection with avirulent Rhodococcus equi.
An eight-year-old thoroughbred mare with no previous history of illness aborted a fetus at 196 days of gestation, and its internal tissues were examined immunohistologically and bacteriologically. The placenta was not examined, but specimens of the intrauterine fluids and the dam's faeces were collected four days after the abortion and examined bacteriologically. No significant histological lesions were found in the fetus but the amnion and the umbilical cord were oedematous and had petechial haemorrhages. Rhodococcus equi was isolated in pure culture from the lung, heart and stomach contents of the fetus and from an intrauterine specimen and faeces of the dam. The anti-R equi antibody titre of the mare was high after the abortion. The diagnosis was confirmed in the lung of the fetus by immunohistochemical staining with R equi-specific antibodies. Isolates from the fetus and mare were identified as avirulent R equi by pcr and the mouse pathogenicity test. The avirulent isolates were characterised by pulsed-field gel electrophoresis, which yielded only one VspI profile in all the isolates from the fetus and its dam.


Temporal Artery Calciphylaxis Presenting as Temporal Arteritis in a Case of Rhinoorbitocerebral Mucormycosis.
Mucormycosis is a rare often fatal opportunistic fungal infection. It is typically described in patients with diabetes in ketoacidotic status and is rare in renal transplant recipients. Calciphylaxis is a rare and highly morbid disease of vascular calcification affecting patients with end-stage renal disease (ESRD). The first case of a renal transplant recipient who was inflicted with both rhinoorbitocerebral mucormycosis and calciphylaxis is reported. A 45-year-old man presented with 2-day history of left upper blepharoptosis, periorbital pain, left-sided headache, binocular diplopia, and left V2 numbness. He had undergone renal transplant for ESRD 7 months earlier with resultant immunosuppressive therapy. MRI and nasal biopsy confirmed rhinoorbitocerebral mucormycosis. Immunosuppressive therapy was stopped and antifungal therapy begun. He had orbital exenteration for progressive rhinoorbitocerebral mucormycosis. Two months later, the patient reported new-onset intermittent bitemporal headache and bilateral swollen, tender temporal arteries. Temporal artery biopsy revealed features consistent with calciphylaxis. Clinical presentation, treatment course, and follow up are discussed.


Length of Resuscitation for Severely Depressed Newborns.
Current guidelines for neonatal resuscitation suggest it may be reasonable to stop resuscitation after 10 minutes in infants born with no detectable heartbeat. This study describes the length of resuscitation provided in a cohort of profoundly compromised newborn infants. Chart review of a regional hospital system database of newborn infants from 2010 to 2017 with a documented 10-minute Apgar score of 0 or 1. From a total birth population of 49,876 infants, 172 newborns were identified. Of these, 133 infants did not receive resuscitation and died while receiving comfort care. In the 39 resuscitated infants, 15 (38%) achieved return of spontaneous circulation (ROSC) at an average of 20 minutes; 32 of these 39 newborns (82%) died within 24 hours. Average time to ROSC for survivors was 17.8 minutes. Death or severe neurologic disability at 15 to 24 months of age was present in 92% (36/39) of resuscitated infants. Prolonged resuscitation of newborns is rare. In this cohort, 92% died or had severe neurodevelopmental disability. Infants with ROSC received 20 minutes of resuscitation. Infants with ROSC typically did not survive beyond 24 hours unless they survived to discharge. To increase the number of infants with ROSC, continuing resuscitation beyond 10 minutes may be reasonable.


Current issues in national insurance for mental health services.
The current economic crisis has again placed in jeopardy the inclusion of mental health benefits under national health insurance. The author notes that progress has been made in establishing effective peer review systems and in demonstrating that costs of mental health services are reasonable. Yet the lack of agreement on diagnosis and appropriate treatment, the inadequacy of utilization, cost, and treatment outcome data, and the absence of professional self-regulation remain causes for concern in the effort toward eventual comprehensive coverage for mental disorders.


Lactobacillus crispatus L1: high cell density cultivation and exopolysaccharide structure characterization to highlight potentially beneficial effects against vaginal pathogens.
Vaginal lactic acid bacteria defend the host against pathogens through a combination of competitive exclusion, competition for nutrients, production of antimicrobial substances and through the activation of the immune system. A new human isolate named Lactobacillus crispatus L1 was characterized in this work, and a preliminary evaluation of its probiotic potential is described together with a process to obtain a high productivity of viable biomass. In a simulated digestion process 1.8⋅10(10) cells∙ml(-1) survived the gastric environment with 80% viability, without being affected by small intestine juices. Experiments on six different C sources were performed to analyze growth and organic acids production and, glucose, provided the best performances. A microfiltration strategy was exploited to improve the cellular yield in 2 L-fermentation processes, reaching 27 g · l(-1) of dry biomass. Moreover, L. crispatus L1 demonstrated a greater stability to high concentrations of lactic acid, compared to other lactobacilli. The specific L. crispatus L1 exopolysaccharide was purified from the fermentation broth and characterized by NMR showing structural features and similarity to exopolysaccharides produced by pathogenic strains. Live L. crispatus L1 cells strongly reduced adhesion of a yeast pathogenic strain, Candida albicans in particular, in adherence assays. Interestingly a higher expression of the human defensin HBD-2 was also observed in vaginal cells treated with the purified exopolysaccharide, indicating a possible correlation with C. albicans growth inhibition. The paper describes the evaluation of L. crispatus L1 as potential vaginal probiotic and the fermentation processes to obtain high concentrations of viable cells.


The public health implications of maternal care trade-offs.
The socioeconomic and ethnic characteristics of parents are some of the most important correlates of adverse health outcomes in childhood. However, the relationships between ethnic, economic, and behavioral factors and the health outcomes responsible for this pervasive finding have not been specified in child health epidemiology. The general objective of this paper is to propose a theoretical approach to the study of maternal behaviors and child health in diverse ethnic and socioeconomic environments. The specific aims are: (a) to describe a causal pathway between the utility that women obtain through work outside the home and through child care and disease hazard rates in childhood using an optimization model; (b) to specify the influence of ethnic and socioeconomic factors on model constraints; (c) to use the model as a tool to learn about how different combinations of maternal wage labor and child care time might influence child health outcomes in diverse social contexts; (d) to identify parameters that will require measurement in future research; (e) to discuss research strategies that will enable us to obtain these measurements; and (f) to discuss the implications of the model for biostatistical modeling and public health intervention. Optimization models are powerful heuristic tools for understanding how ethnic, environmental, family, and personal characteristics can place important constraints on both the quality and quantity of care that women can provide to their children. They provide a quantitative appreciation for the difficult trade-offs that most women face between working in order to purchase basic goods that children cannot do without (e.g., food, clothing, shelter, health insurance), and increasing offspring well-being through child care (e.g., training in social skills, affection, protection from environmental hazards, help with homework).


Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.
The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn in the epithelium is shown here to be associated with secretion of IgG into the lumen that allows for defense against an epithelium-associated pathogen (Citrobacter rodentium). This pathway of host resistance to a bacterial pathogen as mediated by FcRn involves retrieval of bacterial antigens from the lumen and initiation of adaptive immune responses in regional lymphoid structures. Epithelial-associated FcRn, through its ability to secrete and absorb IgG, may thus integrate luminal antigen encounters with systemic immune compartments and as such provide essential host defense and immunoregulatory functions at the mucosal surfaces.


A review of recent developments in buffalo reproduction - a review.
The buffalo is an important livestock resource in several countries of South Asia and the Mediterranean regions. However, reproductive efficiency is compromised due to known problems of biological and management origins, such as lack of animal selection and poor nutrition. Under optimal conditions puberty is attained at 15 to 18 months in river buffalo, 21 to 24 months in swamp buffalo and is influenced by genotype, nutrition, management and climate. However, under field conditions these values deteriorate up to a significant extant. To improve reproductive efficiency, several protocols of oestrus and ovulation synchronization have been adopted from their use in commercial cattle production. These protocols yield encouraging pregnancy rates of (30% to 50%), which are comparable to those achieved in buffaloes bred at natural oestrus. The use of sexed semen in buffalo heifers also showed promising pregnancy rates (50%) when compared with conventional non-sexed semen. Assisted reproductive technologies have been transferred and adapted to buffalo but the efficiency of these technologies are low. However, these latest technologies offer the opportunity to accelerate the genetic gain in the buffalo industry after improving the technology and reducing its cost. Most buffaloes are kept under the small holder farming system in developing countries. Hence, future research should focus on simple, adoptable and impact- oriented approaches which identify the factors determining low fertility and oestrus behaviour in this species. Furthermore, role of kisspeptin needs to be explored in buffalo.


Latent tuberculosis: is there a role for thioridazine?
Approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis. In the vast majority of cases this results in latent not active disease. Latent disease is defined as a positive reaction to tuberculin antigens but without any further clinical symptoms. Models have been developed to study latent tuberculosis with the two most prominent being the in vivo murine model and the in vitro Wayne model. In both cases M. tuberculosis undergoes a change in its respiratory profile as it shifts down to a nonreplicating state. However in both the mouse and the Wayne model, dormant M. tuberculosis is sensitive to the phenothiazine thioridazine. This antibiotic has several targets, and the main one is respiration. There is a growing burden of multidrug resistant and extensively drug resistant tuberculosis. Treatment of these cases is expensive with high mortality. We propose that thioridazine alone, or with other antibiotics, be used to treat drug resistant latent tuberculosis. The advantages are that thioridazine is inexpensive, effective against drug resistant tuberculosis, well characterized and unlikely to induce drug resistance. The disadvantages include possible side effects, although these should be rare at the doses and length of time of treatment. Recent patents involving analogs of thioridazine suggest this class of drugs may hold great promise for the future treatment of the most drug resistant strains.


Sensor Fusion to Infer Locations of Standing and Reaching Within the Home in Incomplete Spinal Cord Injury.
The objective of rehabilitation after spinal cord injury is to enable successful function in everyday life and independence at home. Clinical tests can assess whether patients are able to execute functional movements but are limited in assessing such information at home. A prototype system is developed that detects stand-to-reach activities, a movement with important functional implications, at multiple locations within a mock kitchen. Ten individuals with incomplete spinal cord injuries performed a sequence of standing and reaching tasks. The system monitored their movements by combining two sources of information: a triaxial accelerometer, placed on the subject's thigh, detected sitting or standing, and a network of radio frequency tags, wirelessly connected to a wrist-worn device, detected reaching at three locations. A threshold-based algorithm detected execution of the combined tasks and accuracy was measured by the number of correctly identified events. The system was shown to have an average accuracy of 98% for inferring when individuals performed stand-to-reach activities at each tag location within the same room. The combination of accelerometry and tags yielded accurate assessments of functional stand-to-reach activities within a home environment. Optimization of this technology could simplify patient compliance and allow clinicians to assess functional home activities.


Are Accelerometer-based Functional Outcome Assessments Feasible and Valid After Treatment for Lower Extremity Sarcomas?
Aspects of physical functioning, including balance and gait, are affected after surgery for lower limb musculoskeletal tumors. These are not routinely measured but likely are related to how well patients function after resection or amputation for a bone or soft tissue sarcoma. Small, inexpensive portable accelerometers are available that might be clinically useful to assess balance and gait in these patients, but they have not been well studied. In patients treated for lower extremity musculoskeletal tumors, we asked: (1) Are accelerometer-based body-worn monitor assessments of balance, gait, and timed up-and-go tests (TUG) feasible and acceptable? (2) Do these accelerometer-based body-worn monitor assessments produce clinically useful data (face validity), distinguish between patients and controls (discriminant validity), reflect findings obtained using existing clinical measures (convergent validity) and standard manual techniques in clinic (concurrent validity)? This was a prospective cross-sectional study. Out of 97 patients approached, 34 adult patients treated for tumors in the femur/thigh (19), pelvis/hip (3), tibia/leg (9), or ankle/foot (3) were included in this study. Twenty-seven had limb-sparing surgery and seven underwent amputation. Patients performed standard activities while wearing a body-worn monitor on the lower back, including standing, walking, and TUG tests. Summary measures of balance (area [ellipsis], magnitude [root mean square {RMS}], jerkiness [jerk], frequency of postural sway below which 95% of power of acceleration power spectrum is observed [f95 of postural sway]), gait [temporal outcomes, step length and velocity], and TUG time were derived. Body-worn monitor assessments were evaluated for feasibility by investigating data loss and patient-reported acceptability and comfort. In addition, outcomes in patients were compared with datasets of healthy participants collected in parallel studies using identical methods as in this study to assess discriminant validity. Body-worn monitor assessments were also investigated for their relationships with routine clinical scales (the Musculoskeletal Tumour Society Scoring system [MSTS], the Toronto Extremity Salvage Score [TESS], and the Quality of life-Cancer survivors [QoL-CS)] to assess convergent validity and their agreement with standard manual techniques (video and stopwatch) to assess concurrent validity. Although this was a small patient group, there were initial indications that body-worn monitor assessments were well-tolerated, feasible to perform, acceptable to patients who responded (95% [19 of 20] of patients found the body-worn monitor acceptable and comfortable and 85% [17 of 20] found it user-friendly), and produced clinically useful data comparable with the evidence. Balance and gait measures distinguished patients and controls (discriminant validity), for instance balance outcome (ellipsis) in patients (0.0475 m/s [95% confidence interval 0.0251 to 0.0810]) was affected compared with controls (0.0007 m/s [95% CI 0.0003 to 0.0502]; p = 0.001). Similarly gait outcome (step time) was affected in patients (0.483 seconds [95% CI 0.451 to 0.512]) compared with controls (0.541 seconds [95% CI 0.496 to 0.573]; p < 0.001). Moreover, body-worn monitor assessments showed relationships with existing clinical scales (convergent validity), for instance ellipsis with MSTS (r = -0.393; p = 0.024). Similarly, manual techniques showed excellent agreement with body-worn monitor assessments (concurrent validity), for instance stopwatch time 22.28 +/- 6.93 seconds with iTUG time 21.18 +/- 6.23 seconds (intraclass correlation coefficient agreement = 0.933; p < 0.001). P < 0.05 was considered statistically significant. Although we had a small, heterogeneous patient population, this pilot study suggests that body-worn monitors might be useful clinically to quantify physical functioning in patients treated for lower extremity tumors. Balance and gait relate to disability and quality of life. These measurements could provide clinicians with useful novel information on balance and gait, which in turn could guide rehabilitation strategies. Level III, diagnostic study.


Analysis of the Complete Mycoplasma hominis LBD-4 Genome Sequence Reveals Strain-Variable Prophage Insertion and Distinctive Repeat-Containing Surface Protein Arrangements.
The complete genome sequence of Mycoplasma hominis LBD-4 has been determined and the gene content ascribed. The 715,165-bp chromosome contains 620 genes, including 14 carried by a strain-variable prophage genome related to Mycoplasma fermentans MFV-1 and Mycoplasma arthritidis MAV-1. Comparative analysis with the genome of M. hominis PG21(T) reveals distinctive arrangements of repeat-containing surface proteins.


[Description of a sample of patients with chronic obstructive pulmonary disease treated at hospital-supervised respiratory clinics at primary care centers].
To study the general characteristics, health perception and limitations of patients with chronic obstructive pulmonary disease (COPD) treated at respiratory clinics at primary care centers staffed by pulmonologists from our hospital service. The study was carried out at 5 primary care centers that enrolled the patients consecutively. Questionnaires were used to collect information on sociodemographic aspects, perception of health, and limitations to activities of daily living. We also collected information on the treatments patients were receiving and comorbidities. Spirometry was also performed. Six hundred eleven patients with a mean age of 67.2 years were included in the study; 97.7% were male. The most common comorbidities were spinal column pathology (43%) and osteoarthritis (37%). The mean forced expiratory volume in 1 second (FEV1) was 1.37 L and FEV1% was 49.7% of predicted. Medications taken for COPD were mainly beta-adrenergics and anticholinergics; 66% of patients used inhaled steroids. The majority of patients (52.7%) referred to their health as fair and 59.9% declared having some degree of limitation to their activities of daily living which they attributed to their respiratory disease. Statistical differences were found between the degree of limitation and the degree of dyspnea (P<.0001), perception of health (P<.0001), and FEV1 (P=.001). Our study outlines the general characteristics of COPD patients and shows that dyspnea is closely related to the perception patients have of their degree of limitation.


Correlations between Structural and Electronic Properties in the Filled Skutterudite Smy(FexNi1-x)4Sb12.
A structural study of the filled skutterudite Smy(FexNi1-x)4Sb12 was performed by means of X-ray powder diffraction and μ-Raman spectroscopy with the aim to unveil the correlations between structural and electronic properties of this material and to favor the improvement of its thermoelectric performance. Samples were prepared by direct reaction of the elements at 1223 K, followed by quenching and subsequent sintering at 873 K; microstructure and composition of the obtained products were determined by SEM-EDS. The position of the boundary separating regions that obey hole- and electron-based conduction mechanisms was found by X-ray diffraction at x ≈ 0.63 and y ≈ 0.30, confirmed by measurements of room-temperature Seebeck coefficient, and discussed on the basis of crystallographic data. The presence of a discontinuity is observed in several structural and spectroscopic parameters at the p/n crossover; it is interpreted as associated with the change in the conduction mechanism. The role of the rare earth filling fraction in driving the structural response of the material is investigated too. The advantage of using X-ray diffraction and μ-Raman spectroscopy as aids in the study of electronic properties of this material is highlighted, as well as the complementarity of the two techniques.


Balloon pulmonary valvotomy performed in the first year of life.
Evaluation of the global results after percutaneous pulmonary valvotomy with a balloon catheter performed in the first year of life. We assessed retrospectively the data of 27 patients with pulmonary stenosis who underwent balloon valvotomy in the first 12 months of life, from January 1994 to July 2002. The following data were evaluated: gender, age at diagnosis, clinical presentation, echocardiographic features, other cardiac anomalies, age at balloon valvotomy, diameter of pulmonary annulus, initial and final pressure gradient across the valve, complications and follow-up. We used the median and the Wilcoxon test. For other variables we present the mean and standard deviation. Fourteen patients (52%) were female. We had two prenatal diagnoses. Age at diagnosis ranged between one and 60 days (median: 28.0). With regard to clinical presentation, one (4%) had isolated cyanosis, seven (28%) a systolic murmur and 17 (68%) both cyanosis and a systolic murmur. Associated malformations included: ventricular septal defect--two, dilatation of left pulmonary artery--one, supravalvar stenosis--one, and subvalvular membrane--one. The pulmonary annulus ranged between 4.5 and 11 mm (mean: 8.3 +/- 1.8). The procedure was performed in 23 patients aged 2 to 357 days (median: 60), 43.5% of cases in the first 28 days of life. Balloon diameter ranged from six to 14 mm (mean: 10.7 +/- 2.3). The median value of right ventricular peak systolic pressure before dilatation was 115 mmHg (variation: 60-212) and decreased to 48 mmHg (variation: 20-120) (p < 0.001). Significant infundibular stenosis was documented in five cases and propranolol was initiated after the procedure. In four cases the procedure was abandoned before dilatation. The follow-up period ranged from 0 to 101 months (mean: 40.1 +/- 32.1). The maximum instantaneous gradient between the right ventricle and the pulmonary artery ranged between 0 and 95 mmHg (mean: 23.7 +/- 19.5), and was more than 40 mmHg in 13% of the cases. Percutaneous pulmonary valvotomy with a balloon catheter performed in the first year of life is effective in relieving obstruction of the right ventricular outflow tract. The success rate was 78% (21 of 27 patients).


[Thyroid abcess. Apropos of 5 cases].
Thyroid abcess and acute suppurative thyroiditis are uncommon, representing 0.1 to 0.7% of surgically treated thyroid pathologies. More common in children than in adults, this rarity is associated with poorly indicative clinical symptoms, thus making diagnosis difficult. Five cases reports are presented, 4 of them in adults, illustrating the diagnostic difficulties and the various etiopathological mechanism, thereby explaining the wide diversity of pathogenic agents responsible. Treatment includes surgery (drainage or (partial) thyroidectomy, depending upon the presence or not of an underlying thyroid pathology) and intravenous antibiotics. It is absolutely necessary to eliminate the source of the infection, often a piriform sinus fistula whose total resection effectively prevents a relapse (1 case in this series).


Endemic goitre in Sarawak, Malaysia: I. Somatic growth and aetiology.
A comparative epidemiological and anthropometric survey was conducted among Ibans, the largest indigenous ethnic group in Sarawak, in three regions where the endemicity of goitre exhibited marked differences , to assess the effect of endemic goitre on somatic growth. In the Ai river region the prevalence of goitre was 99.5%; 35% having grade 3 goitres, 55% grade 2 goitres and 9.5% grade 1 goitres. At Rubu the prevalence of endemic goitre was 74%; 3% having grade 3 goitre, 16% grade 2 goitre and 55% grade 1 goitre. In the Bajong region relatively few people were detected with goitre and most of these had migrated from other regions. Neurological cretinism was estimated at 3.6% in the severely goitrous Ai river population but was not detected in the other regions. Anthropometric data obtained from the three adult populations did not reveal any statistically significant differences in the following parameters: weight, height, weight/height ratio, height/sitting height ratios, head circumference, scapular skinfold thickness and left mid arm muscle circumference. The haemoglobin, serum total protein and serum albumin concentrations were similar in the three populations. It is concluded that endemic goitre occurs with a frequency of close to 100% in certain Iban populations which represents one of the highest incidences of endemic goitre in the world. Neurological cretinism is common in this population. Our observations suggest that body proportions and somatic growth do not vary among similar ethnic populations exhibiting greatly different endemicity of goitre. Although no iodine balance studies were performed, assessment of diets suggested that iodine deficiency is a significant contributory factor in the development of endemic goitre in Sarawak. Urgent attention to iodine supplementation is indicated to prevent the development of endemic goitre and neurological cretinism.


Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway.
Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [(3)H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase α (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Finally, we documented several-fold increases in the uptake of [(3)H]choline in endometrial cancer cell lines compared with normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of noninvasive imaging biomarkers for endometrial cancer.


Inhibition of angiotensin II and calpain attenuates pleural fibrosis.
Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT1R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT1R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis.


Effects of Packing Density and Chain Length on the Surface Hydrophobicity of Thin Films Composed of Perfluoroalkyl Acrylate Chains: A Molecular Dynamics Study.
A good understanding of the surface hydrophobicity of fluorinated materials is useful for their application as coating materials. The present study investigates the surface hydrophobicity of perfluoroalkyl acrylate (PFA) thin films using molecular dynamics simulations. Surface hydrophobicity is characterized by examining the contact angle of a water droplet on PFA surfaces and the cavity formation free energy in the vicinity of the surface. It is found that the calculated microscopic contact angles are in good agreement with the experimental results and partially capture the difference in the hydrophobicity of the surface arising from the variation of packing density and side chain length of PFA. The variations of cavity formation free energy in the vicinity of the surface elucidate that the surface hydrophobicity is mainly governed by the packing density rather than the chain length of PFA. The hydrophobicity generally increases with decreasing the packing density to some extent and then turns to decrease as further reducing the packing density. At higher packing density, the surface hydrophobicity slightly decreases with increasing the chain length, while at the lower packing density, the surface hydrophobicity is increased when chain length of PFA is longer than six carbons. Furthermore, we found that the influence of packing density on the surface hydrophobicity is directly related to the variation of the surface roughness and chain flexibility, that is, the surface hydrophobicity increases with increase in the surface roughness, while the chain flexibility plays a secondary role in the enhancement by affecting the stability of water staying near the interface. The study provides a significant insight into the local hydrophobicity and microscopic structure of the PFA surfaces, which would be useful for the application of surface modification.


Ultrafast excited state dynamics of iridium(III) complexes and their changes upon immobilisation onto titanium dioxide layers.
Time-resolved spectroscopy was applied to investigate the excited state dynamics of two heteroleptic Ir(III) complexes with the general formula [Ir(C^N)2(N^N)](+), where C^N and N^N represent different cyclometalating and diimine ligands, respectively. The excited state relaxation is influenced by the ligand substitution as well as the light polarisation. Vibrational relaxation occurs in the sub-ps timescale and interligand charge transfer results in polarisation dependent signal dynamics with a time constant of about 30 ps. Electron injection from the iridium dye to TiO2 is analysed with respect to potential applications in solar energy conversion.


Quantifying condition-dependent intracellular protein levels enables high-precision fitness estimates.
Countless studies monitor the growth rate of microbial populations as a measure of fitness. However, an enormous gap separates growth-rate differences measurable in the laboratory from those that natural selection can distinguish efficiently. Taking advantage of the recent discovery that transcript and protein levels in budding yeast closely track growth rate, we explore the possibility that growth rate can be more sensitively inferred by monitoring the proteomic response to growth, rather than growth itself. We find a set of proteins whose levels, in aggregate, enable prediction of growth rate to a higher precision than direct measurements. However, we find little overlap between these proteins and those that closely track growth rate in other studies. These results suggest that, in yeast, the pathways that set the pace of cell division can differ depending on the growth-altering stimulus. Still, with proper validation, protein measurements can provide high-precision growth estimates that allow extension of phenotypic growth-based assays closer to the limits of evolutionary selection.


Periconceptional undernutrition programs changes in insulin-signaling molecules and microRNAs in skeletal muscle in singleton and twin fetal sheep.
Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We determined the effect of maternal undernutrition in the periconceptional period (PCUN, i.e., 60 days prior to 6 days after conception) and the preimplantation period (PIUN, i.e., 0-6 days after conception) on mRNA expression and protein abundance of key insulin-signaling molecules as well as the global microRNA expression in quadriceps muscle of singleton and twin fetal sheep in late gestation. In singleton fetuses, exposure to PCUN resulted in lower protein abundance of PIK3CB (P < 0.01), PRKCZ (P < 0.05), and pPRKCZ (Thr410) (P < 0.05) in skeletal muscle compared to controls. In PIUN singletons, there was a higher protein abundance of IRS1 (P < 0.05), PDPK1 (P < 0.05), and SLC2A4 (P < 0.05) compared to controls. In twins, PCUN resulted in higher protein abundance of IRS1 (P < 0.05), AKT2 (P < 0.05), PDPK1 (P < 0.05), and PRKCZ (P < 0.001), while PIUN also resulted in higher protein abundance of IRS1 (P < 0.05), PRKCZ (P < 0.001), and SLC2A4 (P < 0.05) in fetal muscle compared to controls. There were specific patterns of the types and direction of changes in the expression of 22 microRNAs in skeletal muscle after exposure to PCUN or PIUN and clear differences in these patterns between singleton and twin pregnancies. These findings provide evidence that maternal undernutrition around the time of conception induces changes in the expression of microRNAs, which may play a role in altering the abundance of the key insulin-signaling molecules in skeletal muscle and in the association between PCUN undernutrition and insulin resistance in adult life.


Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption.
A 30 cm segment of the duodenum, jejunum, or ileum of normal human volunteers was perfused, on separate occasions, with test solutions containing either glycylglycine, free glycine, glycylleucine, or equimolar amounts of free glycine and free leucine. Luminal fluid contained no hydrolytic activity against glycylglycine and minimal activity against glycylleucine. In each intestinal segment, amino acid absorption rates were significantly greater from the test solutions containing the same amount of amino acids in dipeptide than in free form(as high as 185% increase). Perfusion of each intestinal segment with a test solution containing the equimolar mixture of free glycine and free leucine always resulted in a greater leucine than glycine absorption rate. This preferential absorption of leucine, however, was either diminished (jejunum) or almost abolished (duodenum and ileum) when the glycylleucine solution instead of the equimolar mixture was presented to the intestinal mucosa. Among the three segments, the duodenum exhibited the least potential for the disappearance of dipeptides. The jejunal and ileal dipeptide disappearance rates were either similar for glycylleucine (94% vs. 92%) or slightly different for glycylglycine (92% vs. 79%). Despite lack of a remarkable difference in the disappearance rates, absorption rates of constituent amino acids were markedly greater in the jejunum than in the ileum. This reduced amino acid absorption was brought about by a greater accumulation of free amino acids in the lumen of the ileal segment (3 to 10-fold difference). Inhibition of free glycine absorption by leucine during the perfusion of the intestine with a test solution containing glycylglycine and leucine did not result in any greater concentration of free glycine in the lumen than when the glycylglycine test solution did not contain free leucine. Similarly, inhibition of free glycine and free leucine absorption by isoleucine was not accompanied by any remarkable alteration of absorption rates of the constituent amino acids of glycylleucine. The results of these studies suggest that: (a) dipeptide disappearance in the gut lumen is principally accomplished by intact absorption and not by hydrolysis; (b) intracellular hydrolysis of dipeptides is markedly greater in the ileum than in the jejunum, while dipeptide absorption rates are either similar or only slightly different in these two segments; (c) there is no appreciable hydrolysis of glycylglycine by the membrane-bound enzymes and only a small fraction of glycylleucine is hydrolyzed by these enzymes.