Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers.
The synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. Thirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood samples were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. There was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%-50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. This is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period.


Coulomb interactions for mediator-enhanced sensitized triplet-triplet annihilation upconversion in solution.
Sensitized triplet-triplet annihilation upconversion offers an attractive possibility to replace a high-energy photon by two photons with lower energy through the combination of a light-harvesting triplet sensitizer and an annihilator for the formation of a fluorescent singlet state. Typically, high annihilator concentrations are required to achieve an efficient initial energy transfer and as a direct consequence the most highly energetic emission is often not detectable due to intrinsic reabsorption by the annihilator itself. Herein, we demonstrate that the addition of a charge-adapted mediator drastically improves the energy transfer efficiency at low annihilator concentrations via an energy transfer cascade. Inspired by molecular dyads and recent developments in nanocrystal-sensitized upconversion, our system exploits a concept to minimize intrinsic filter effects, while boosting the upconversion quantum yield in solution. A sensitizer-annihilator combination consisting of a ruthenium-based complex and 9,10-diphenylanthracene (DPA) is explored as model system and a sulfonated pyrene serves as mediator. The impact of opposite charges between sensitizer and mediator - to induce coulombic attraction and subsequently result in accelerated energy transfer rate constants - is analyzed in detail by different spectroscopic methods. Ion pairing and the resulting static energy transfer in both directions is a minor process, resulting in an improved overall performance. Finally, the more intense upconverted emission in the presence of the mediator is used to drive two catalytic photoreactions in a two-chamber setup, illustrating the advantages of our approach, in particular for photoreactions requiring oxygen that would interfere with the upconversion system.


Emerging pathogens for pneumonia in Singapore.
The death rate from pneumonia in Singapore has increased steadily over the past decade. The emerging respiratory pathogens may have contributed to this increased mortality. New challenges have arisen from changes in the characteristics of the host and the susceptibilities of the various pathogens to antibiotics. There has been a 60-fold increase in the incidence of penicillin resistance in Streptococcus pneumoniae, the major pathogen for community-acquired pneumonia (CAP). Gram-negative bacilli are the major pathogens in severe CAP with Klebsiella pneumonia being the most frequently isolated organism. There has been a small increase in the number of cases of Legionnaire's disease and a marked increase in the incidence of melioidosis. While the overall incidence of tuberculosis has been unchanged, the number of non-residents with tuberculosis has doubled in the past 5 years. The rising prevalence of human immunodeficiency Virus infection is reflected in an increasing number of apparently healthy young men who present with CAP caused by Pneumocystis carinii. There is increasing resistance to antibiotics among gram-negative bacilli and Staphylococcus aureus, the dominant pathogens in hospital-acquired pneumonia. New strategies are urgently needed to prevent the emergence of pathogens in the hospital environment which may be resistant to all known antibiotics.


The dynamics of a fish stock exploited in two fishing zones.
This work presents a specific stock-effort dynamical model. The stocks correspond to two populations of fish moving and growing between two fishery zones. They are harvested by two different fleets. The effort represents the number of fishing boats of the two fleets that operate in the two fishing zones. The bioeconomical model is a set of four ODE's governing the fishing efforts and the stocks in the two fishing areas. Furthermore, the migration of the fish between the two patches is assumed to be faster than the growth of the harvested stock. The displacement of the fleets is also faster than the variation in the number of fishing boats resulting from the investment of the fishing income. So, there are two time scales: a fast one corresponding to the migration between the two patches, and a slow time scale corresponding to growth. We use aggregation methods that allow us to reduce the dimension of the model and to obtain an aggregated model for the total fishing effort and fish stock of the two fishing zones. The mathematical analysis of the model is shown. Under some conditions, we obtain a stable equilibrium, which is a desired situation, as it leads to a sustainable harvesting equilibrium, keeping the stock at exploitable densities.


Pest categorisation of Penthimiola bella.
The EFSA Panel on Plant Health performed a pest categorisation of Penthimiola bella (Hemiptera: Cicadellidae), the citrus leafhopper, for the European Union (EU). P. bella is native to the Afrotropical region; it has spread to Israel (first reported in 1974), Lebanon, and was reported from Morocco in 2018. Within the EU, P. bella is established in Portugal (Algarve) where it was first found on sweet oranges in 2012, and then in Spain in 2020, also on sweet oranges. P. bella is not listed in Annex II of Commission Implementing Regulation (EU) 2019/2072. It is a polyphagous species reported, among cultivated hosts, on sweet orange, grapefruit and avocado. It is also described as being found on unspecified trees and bushes in savannahs, mountain forests and rain forests in Africa. Climatic conditions in some parts of southern EU countries are favourable and host plants are available in those areas to support establishment and spread. Despite being present in Portugal for over 10 years, there is a lack of evidence of impacts; hence, the magnitude of impact following introduction is uncertain. Nevertheless, in South Africa, P. bella was reported as being an economically important pest of citrus and to cause damage to avocado fruit during the early stages of development. Phytosanitary measures are available to reduce the likelihood of entry and further spread. Except for having uncertain economic or environmental impacts as a result of its introduction, P. bella satisfies all the other criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union quarantine pest.


Curve location influences spinal balance in coronal and sagittal planes but not transversal trunk motion in adolescents with idiopathic scoliosis: a prospective observational study.
In adolescent idiopathic scoliosis (AIS), spinal deformity can be seen in the thoracic or in the lumbar area. Although differences according to curve location are well described on standard radiographs, dynamic consequences of such difference remain unclear. Our objective was to explore the differences in dynamic spinal balance according to curve location in AIS patients using gait analysis METHODS: We prospectively included 22 females with AIS planned for surgical correction (16.3 years old, 81% Risser ≥ 4). Patients were divided into two matched cohorts, according to major curve location [right thoracic (Lenke 1) or left lumbar (Lenke 5)]. Gait analysis was performed the day before surgery. Global balance was analyzed as the primary outcome. Local curves parameters (dynamic Cobb angles) were defined as the secondary outcome. In coronal plane, Lenke 5 patients had a left trunk shift, whereas trunk was shifted to the right in Lenke 1 patients (- 20.7 vs 6.3, p = 0.001). In the sagittal plane, the main difference between the two groups was T12 position that remained over the pelvis during gait in Lenke 5 patients, whereas it was anterior to the pelvis in Lenke 1 patients. In the transversal plane, Lenke 5 and Lenke 1 patients presented the same gait abnormalities, with a global trunk rotation to the left (- 4.8 vs - 7.6, p = 0,165). This is the first study to provide the results of a direct comparison between Lenke 1 and Lenke 5 patients during gait. Curve location influenced coronal and sagittal balance, but abnormalities of transversal trunk motion were the same, wherever the curve was located. These slides can be retrieved under Electronic Supplementary Material.


Granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB-/- mice.
Granzyme (grz) AB(-/-) H2(b) mice generate numerically normal cytotoxic T lymphocyte (CTL) responses to the prominent influenza A virus D(b) NP(366) and D(b) PA(224) epitopes and terminate the infectious process in the pneumonic lung with the same kinetics as the WT controls. Though grz B protein expression is fully compromised, there is only a partial effect on the level of CTL activity measured in a classical, short-term (51)Cr release assay. Single-cell polymerase chain reaction (PCR) analysis of both highly activated effector and "resting" memory CD8(+) T cells from influenza A virus-infected grzAB(-/-) mice showed a high prevalence of grzK mRNA(+) expression in tetramer (tet)(+) CTLs as was found in WT mice. However, a marked reduction in cytotoxicity present in the primary splenic CTLs of grzAB(-/-) mice correlated with decreased grzK expression, as measured by real-time PCR. This suggests that grzK plays an important role in CD8(+) T-cell cytotoxicity both in the presence and absence of grzA and B.


Observation of light dragging in a rubidium vapor cell.
We report on the experimental demonstration of the light dragging effect due to atomic motion in a rubidium vapor cell. We find that the minimum group velocity is achieved for light redshifted from the center of the atomic resonance and that the value of this shift increases with decreasing group velocity, in agreement with the theoretical predictions by Kocharovskaya, Rostovtsev, and Scully [Phys. Rev. Lett. 86, 628 (2001)].


Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide.
The aim of this study was to assess the efficacy of new agents in patients with malignant glioma in a neoadjuvant setting not confounded by surgery. The first study of neoadjuvant temozolomide aimed to provide a benchmark for future evaluation of new treatments. This was a multicentre phase II study of chemotherapy in patients with histologically verified glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) who had undergone biopsy alone. Patients were planned to receive two cycles of temozolomide at 200 mg/m(2) orally daily for 5 days at a 28-day interval prior to radiotherapy. Response was assessed by two central observers on pre- and post-chemotherapy enhanced scans using bi-dimensional criteria and as progression-free survival (PFS) at the time of second assessment prior to radiotherapy. Withdrawal from the study due to worsening clinical condition was, in the absence of second imaging, assessed as progressive disease. Survival and quality of life (QOL) were secondary endpoints. Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study and 187 were analysed. Overall, 162 patients were assessable for response; seven had partial and 25 had minimal response. The objective response rate was 20% [95% confidence interval (CI) 14-26%] and PFS prior to commencing radiotherapy was 64% (95% CI 57-72%). The median survival was 10 months, and 1-year survival 41%. The median survival of responders was 16 months compared to 3 months in patients with progressive disease (P <0.001 on multivariate analysis). The phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide provide a benchmark for assessment of efficacy of other agents and combinations.


Folate: a functional food constituent.
Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Mammalian cells cannot synthesize folate and its deficiency has been implicated in a wide variety of disorders. A number of reviews have dwelt up on the health benefits associated with increased folate intakes and many countries possess mandatory folate enrichment programs. Lately, a number of studies have shown that high intakes of folic acid, the chemically synthesized form, but not natural folates, can cause adverse effects in some individuals such as the masking of the hematological manifestations of vitamin B(12) deficiency, leukemia, arthritis, bowel cancer, and ectopic pregnancies. As fermented milk products are reported to contain even higher amounts of folate produced by the food-grade bacteria, primarily lactic acid bacteria (LAB), the focus has primarily shifted toward the natural folate, that is, folate produced by LAB and levels of folate present in foods fermented by/or containing these valuable microorganisms. The proper selection and use of folate-producing microorganisms is an interesting strategy to increase "natural" folate levels in foods. An attempt has been made through this review to share information available in the literature on wide ranging aspects of folate, namely, bioavailability, analysis, deficiency, dietary requirements, and health effects of synthetic and natural folate, dairy and nondairy products as a potential source of folate, microorganisms with special reference to Streptococcus thermophilus as prolific folate producer, and recent insight on modulation of folate production levels in LAB by metabolic engineering.


Increased frequency of asymptomatic bronchial hyperresponsiveness in nonasthmatic patients with food allergy.
Subclinical inflammation in gut mucosa has been demonstrated in bronchial asthma suggesting the whole mucosal system is involved in allergic diseases. The presence of subclinical bronchial involvement was assessed by nonspecific bronchial hyperresponsiveness (BHR) in nonasthmatic patients with food allergy (FA). BHR was studied in 35 patients with various manifestations of FA without food-induced asthma. Sixteen had a previous history of asthma and/or rhinitis to aeroallergens (group A), whereas 19 patients (group B) did not. BHR was defined by a provocative dose causing a 20% fall in forced expiratory volume in one second of (PC20) <8 mg.mL(-1) of methacholine. Asymptomatic BHR occurred frequently in nonasthmatic patients with FA (10 of 19, 53%); this did not significantly differ from patients with FA and a previous history of asthma and/or rhinitis to aeroallergens (13 of 16, 81%). PC20 was significantly lower in group A (1.84+/-0.53 mg.mL(-1)) than in group B (3.35+/-0.74 mg.mL(-1); p<0.05). The number of patients with positive skin tests to aeroallergens was similar between groups. Sequential evaluation, performed 1 year after initial evaluation, in 7 nonasthmatic patients (group B) demonstrated a similar level of BHR. The present study demonstrated that BHR is a frequent finding in nonasthmatic patients with food allergy which may be due, at least in part, to a subclinical inflammatory process in the bronchi.


CT-auto exposure control on cerebral 3D-CT angiography: dose reduction and optimized image SD for inspection purposes.
It is a fact that image noise influences for image qualities of the brain CT are known widely. The same principle applies to 3D-CTA, image noise significantly influences the depiction of blood vessels. So we evaluated the use of CT-AEC for 3D-CTA to optimize the scan dose and control the depiction of cerebral vessels by CT-AEC. We decided to optimize the noise index (NI) for cerebral 3D-CTA through the use of an imitation blood phantom. In the evaluation of the depiction of the anterior choroidal artery that was able to be confirmed with DSA, the detection rate in high resolution mode: NI 6.0 was 70%. The depiction of the anterior choroidal artery became defective in the detailed exam mode: NI 7.0, low dose mode: NI 9.0 because of the noise. As for the existence of cerebral aneurysms, the sensitivities were 100% with DSA and 94.3% with 3D-CTA in detailed exam mode, and there was no statistical difference. The specificities of 3D-CTA had lowered to 92.6% and 97.2% in DSA. In low dose mode and detailed exam mode, DLP had decreased by 55.2% and 18.1% on the average compared to a fixed tube current (P<0.05). However, in high resolution mode, DLP increased by 5.9% on the average. It was necessary to limit the scan range to the region of interest when we used a fixed tube current. This clinical research verified that CT-AEC on cerebral 3D-CTA was useful for dose reduction and control of the depiction ability for inspection purposes.


Temperature-dependent spin crossover in neuronal nitric oxide synthase bound with the heme-coordinating thioether inhibitors.
A series of L-arginine analogue nitric oxide synthase inhibitors with a thioether tail have been shown to form an Fe-S thioether interaction as evidenced by continuous electron density between the Fe and S atoms. Even so, the Fe-S thioether interaction was found to be far less important for inhibitor binding than the hydrophobic interactions between the alkyl group in the thioether tail and surrounding protein (Martell et al. J. Am. Chem. Soc. 2010 , 132 , 798). However, among the few thioether inhibitors that showed Fe-S thioether interaction in crystal structures, variations in spin state (high-spin or low-spin) were observed dependent upon the heme iron oxidation state and temperature. Since modern synchrotron X-ray data collection is typically carried out at cryogenic temperatures, we reasoned that some of the discrepancies between cryo-crystal structures and room-temperature UV-visible spectroscopy could be the result of temperature-dependent spin-state changes. We, therefore, have characterized some of these neuronal nitric oxide synthase (nNOS)-thioether inhibitor complexes in both crystal and solution using EPR and UV-visible absorption spectrometry as a function of temperature and the heme iron redox state. We found that some thioether inhibitors switch from high to low spin at lower temperatures similar to the "spin crossover" phenomenon observed in many transition metal complexes.


[Necrotizing enterocolitis in the preterm infant: etiopathogenic considerations].
Necrotizing enterocolitis (NE) represents the most frequent gastrointestinal emergency encountered in neonatal intensive care units. This necrotic-inflammatory bowel disease affects primarily premature patients and it is recorded as an important cause of neonatal morbidity and mortality. The NE aetiology seems to be multifactorial: prematurity, enteral feeding, hypoxia and micro-organisms toxicity are registered as the most important risk factors, able to trigger the phlogistic and necrotic way at the basis of necrotizing enterocolitis. Despite the NE first report was in the past century, the correct pathogenic sequence of this neonatal disease is still hypothetical.


Anthocyanins: Molecular Aspects on Their Neuroprotective Activity.
Anthocyanins are a type of flavonoids that give plants and fruits their vibrant colors. They are known for their potent antioxidant properties and have been linked to various health benefits. Upon consumption, anthocyanins are quickly absorbed and can penetrate the blood-brain barrier (BBB). Research based on population studies suggests that including anthocyanin-rich sources in the diet lower the risk of neurodegenerative diseases. Anthocyanins exhibit neuroprotective effects that could potentially alleviate symptoms associated with such diseases. In this review, we compiled and discussed a large body of evidence supporting the neuroprotective role of anthocyanins. Our examination encompasses human studies, animal models, and cell cultures. We delve into the connection between anthocyanin bioactivities and the mechanisms underlying neurodegeneration. Our findings highlight how anthocyanins' antioxidant, anti-inflammatory, and anti-apoptotic properties contribute to their neuroprotective effects. These effects are particularly relevant to key signaling pathways implicated in the development of Alzheimer's and Parkinson's diseases. In conclusion, the outcome of this review suggests that integrating anthocyanin-rich foods into human diets could potentially serve as a therapeutic approach for neurological conditions, and we identify promising avenues for further exploration in this area.


Tight links between adenine and guanine nucleotide pools in mouse pancreatic islets: a study with mycophenolic acid.
Glucose metabolism in pancreatic B-cells leads to an increase in the ATP/ADP ratio that might participate in the regulation of insulin secretion. Good correlations have also been observed between guanine nucleotide levels in isolated pancreatic islets and insulin secretion. To assess whether guanine nucleotides have a specific role in stimulus-secretion coupling, their concentration should be modified selectively. This was attempted by culturing mouse islets overnight in the presence of mycophenolic acid (MPA), an inhibitor of GMP synthesis at the level of IMP dehydrogenase. The drug (25-50 microg/ml) did not affect the insulin content but decreased the GTP content of the islets and inhibited insulin secretion during subsequent incubation in the presence of 15 mM glucose. However, MPA also decreased the ATP/ADP ratio in the islets. The addition of guanine to the culture medium (to stimulate the salvage pathway of GTP synthesis) restored normal GTP levels, corrected the ATP/ADP ratio and partly prevented the inhibition of insulin release. In contrast, attempts to stimulate ATP synthesis specifically (by provision of adenine or adenosine) failed to reverse any of the effects of MPA. It is concluded that guanine and adenine nucleotide pools are tightly linked and cannot be specifically affected by MPA in pancreatic islet cells, probably because of the activity of nucleoside diphosphate kinase and because of the role of GTP in several reactions leading to adenine nucleotide generation. Contrary to previous claims, MPA is not an adequate tool for evaluating a specific role of guanine nucleotides in the control of insulin secretion.


An acoustic/thermo-responsive hybrid system for advanced doxorubicin delivery in tumor treatment.
The efficiency of drug delivery and bioavailability to tumor cells are crucial for effective cancer chemotherapy. Herein, a doxorubicin (DOX) encapsulated lysolipid-based thermosensitive liposome decorated with cRGD peptide (RTSL) is conjugated on the surface of an IR780-loaded microbubble (IMB) to synthesize RTSL-IMBs. Sequentially taking advantage of acoustic-assisted early extravasation and thermo-triggered interstitium ultrafast drug release, RTSL-IMBs combine with ultrasound (US) and laser irradiation can advance drug delivery and bioavailability. In vitro experiments demonstrate that RTSL-IMBs associated with a two-step protocol (subsequently US irradiation for 1 min and laser irradiation for 5 min) can dramatically enhance the cellular uptake and bioavailability of DOX. In vivo fluorescence imaging studies reveal that the combination of RTSL-IMBs and US shows a 2.8-fold intratumoral drug accumulation increase at 0.5 h post-injection, while it will take 48 h to reach the same level of intratumoral drug accumulation for the RTSL-IMB group alone. Interestingly, the following localized application of a laser can further increase drug accumulation and slow tumor clearance. Histological analysis demonstrates that the combinational RTSL-IMBs, US and laser significantly improve the drug penetration distance and delivery efficiency in the tumor core. In this study, the acoustic/thermo-responsive hybrid system shows potential for advancing DOX chemotherapy in breast cancer cell MCF-7 xenograft nude mice.


The AP-2 complex interacts with γ-TuRC and regulates the proliferative capacity of neural progenitors.
Centrosomes are organelles that nucleate microtubules via the activity of gamma-tubulin ring complexes (γ-TuRC). In the developing brain, centrosome integrity is central to the progression of the neural progenitor cell cycle, and its loss leads to microcephaly. We show that NPCs maintain centrosome integrity via the endocytic adaptor protein complex-2 (AP-2). NPCs lacking AP-2 exhibit defects in centrosome formation and mitotic progression, accompanied by DNA damage and accumulation of p53. This function of AP-2 in regulating the proliferative capacity of NPCs is independent of its role in clathrin-mediated endocytosis and is coupled to its association with the GCP2, GCP3, and GCP4 components of γ-TuRC. We find that AP-2 maintains γ-TuRC organization and regulates centrosome function at the level of MT nucleation. Taken together, our data reveal a novel, noncanonical function of AP-2 in regulating the proliferative capacity of NPCs and open new avenues for the identification of novel therapeutic strategies for the treatment of neurodevelopmental and neurodegenerative disorders with AP-2 complex dysfunction.


Estradiol valerate/dienogest: a novel combined oral contraceptive.
Estradiol valerate/dienogest (E2V/DNG) is a combined oral contraceptive (COC) with 2 new hormonal entities and a unique 4-phasic dosing regimen indicated for women to prevent pregnancy. The purpose of this article is to review the pharmacology, pharmacokinetics, clinical efficacy, tolerability, and cost of E2V/DNG. MEDLINE (1966-June 2011) and EMBASE (1966-June 2011) were searched for original research and review articles published in the English language using the terms Natazia or Qlaira or estradiol valerate and dienogest. The reference lists of identified articles were reviewed for additional pertinent publications. Abstracts from the 2005 to 2011 American Society of Reproductive Medicine and American College of Obstetricians and Gynecologists meetings were searched using the same terms. The search provided 56 articles that addressed the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of E2V/DNG in women of reproductive age. Articles reporting efficacy or tolerability in the setting of menopause were excluded. The initial efficacy of E2V/DNG on ovulation inhibition was investigated in 2 prospective, randomized, open-label, Phase II dose-finding studies. The dose that was approved by the Food and Drug Administration resulted in 3.13% of women ovulating in the second cycle of treatment (90% CI, 0.2%-6.05%). Rate of pregnancy prevention with this agent was reported with a Pearl Index ranging from 0.73 to 1.27 (unadjusted) to 0.34 to 0.72 (adjusted for method failure only). The mean duration of withdrawal bleeding was 4.3 days (range, 4.0-4.6 days) among 2266 women receiving 13 treatment cycles. Adverse events reported in >1% of patients included abdominal pain, acne, breast pain, dysmenorrhea, emotional lability, headache, nausea, and weight increase. Estradiol valerate/dienogest is a new contraceptive formulation. It offers efficacy, tolerability, and an acceptable safety profile with a potentially better bleeding pattern than levonorgestrel-containing COCs. This COC may be especially useful for older women of reproductive age who are adherent to therapy and looking for shorter and/or lighter menstrual cycles. Studies will need to be performed to determine whether clinically significant differences in outcomes exist among E2V/DNG and other available COCs.


[Fangotherapy in chronic degenerative rheumatic diseases].
The authors remind the historical role of the mud-therapy in the care of chronic degenerative rheumoartrhopaties, namely osteoarthritis. The main researches belong activity of muds on plasmatic hormones, cytokines, endorphins; a great deal of care is devoted to evaluation of efficacy of mud therapy and relating end points. The clinic outcomes of mud therapy, namely in osteoarthritis patients, were referred. Altogether the studies stress the employ of mud therapy in the treatment of osteoarthritis, the consequences of traumas, some dismetabolic chronic arthropaties, and fibromyalgic syndromes.


Medical conditions in autism spectrum disorders.
Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio-pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development.


Diagnosis of diaphragm injuries using modern 256-slice CT scanners: too early to abandon operative exploration.
Missed injury of the diaphragm may result in hernia formation, enteric strangulation, and death. Compounding the problem, diaphragmatic injuries are rare and difficult to diagnose with standard imaging. As such, for patients with high suspicion of injury, operative exploration remains the gold standard for diagnosis. As no current data currently exist, we sought to perform a pragmatic evaluation of the diagnostic ability of 256-slice multidetector CT scanners for diagnosing diaphragmatic injuries after trauma. A retrospective review of trauma patients from 2011 to 2018 was performed at an American College of Surgeons-verified level 1 trauma center to identify the diagnostic accuracy of CT scan for acute diaphragm injury. All patients undergoing abdominal operation were eligible for inclusion. Two separate levels of CT scan technology, 64-slice and 256-slice, were used during this time period. The prospective imaging reports were reviewed for the diagnosis of diaphragm injury and the results confirmed with the operative record. Injuries were graded using operative description per the American Association for the Surgery of Trauma guidelines. One thousand and sixty-eight patients underwent operation after preoperative CT scan. Acute diaphragm injury was identified intraoperatively in 14.7%. Most with diaphragmatic injury underwent 64-slice CT (134 of 157, 85.4%). Comparing patients receiving 64-slice or 256-slice CT scan, there was no difference in the side of injury (left side 57.5% vs. 69.6%, p=0.43) or median injury grade (3 (3, 3) vs. 3 (2, 3), p=0.65). Overall sensitivity, specificity, and diagnostic accuracy of the 256-slice CT were similar to the 64-slice CT (56.5% vs. 45.5%, 93.7% vs. 98.1%, and 89.0% vs. 90.2%). The new 256-slice multidetector CT scanner fails to sufficiently improve diagnostic accuracy over the previous technology. Patients with suspicion of diaphragm injury should undergo operative intervention. I, diagnostic test or criteria.


Cancer chemoprevention by natural-products (review).
Cancer chemoprevention is based on a number of experimental and epidemiological evidence that our environment could contain not only carcinogenic compounds but also natural or synthetic substances able to inhibit or reverse the process of carcinogenesis. More than 600 potential chemopreventives have been identified and approximately 30 of them have been or are being tested in humans. These include naturally occurring substances present in human foods and synthetic chemicals. In this review natural products possessing chemopreventive potential are introduced with experimental evidence of their mechanisms of action, although other natural chemopreventives are under investigation with regard to their spectra of activity and their possible relevance to prophylaxis of human cancer.


Regulation of endothelial nitric oxide synthase by protein kinase C.
Endothelial nitric oxide synthase (eNOS) is a key enzyme in nitric oxide-mediated signal transduction in mammalian cells. Its catalytic activity is regulated both by regulatory proteins, such as calmodulin and caveolin, and by a variety of post-translational modifications including phosphorylation and acylation. We have previously shown that the calmodulin-binding domain peptide is a good substrate for protein kinase C [Matsubara, M., Titani, K., and Taniguchi, H. (1996) Biochemistry 35, 14651-14658]. Here we report that bovine eNOS protein is phosphorylated at Thr497 in the calmodulin-binding domain by PKC both in vitro and in vivo, and that the phosphorylation negatively regulates eNOS activity. A specific antibody that recognizes only the phosphorylated form of the enzyme was raised against a synthetic phosphopeptide corresponding to the phosphorylated domain. The antibody recognized eNOS immunoprecipitated with anti-eNOS antibody from the soluble fraction of bovine aortic endothelial cells, and the immunoreactivity increased markedly when the cells were treated with phorbol 12-myristate 13-acetate. PKC phosphorylated eNOS specifically at Thr497 with a concomitant decrease in the NOS activity. Furthermore, the phosphorylated eNOS showed reduced affinity to calmodulin. Therefore, PKC regulates eNOS activity by changing the binding of calmodulin, an eNOS activator, to the enzyme.


Thrombotic thrombocytopenic purpura associated with multiple myeloma.
Thrombotic thrombocytopenic purpura is a thrombotic microangiopathic disease. Associations with collagen vascular diseases, pregnancy, some drugs, surgical intervention, and infections are documented (known). Malignancy is also one of the known factors associated with thrombotic thrombocytopenic purpura. These malignancies are usually the disseminated solid organ tumors. Hematological malignancies constitute a rare association. Here, we present a patient with thrombotic thrombocytopenic purpura associated with multiple myeloma and discuss the pathogenesis. To our knowledge, this is the first case report of thrombotic thrombocytopenic purpura associated with multiple myeloma.


Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5.
RIG-I, MDA5 and LGP2 are cytosolic pattern recognition receptors detecting single-stranded or double-stranded RNA in virally infected cells. The activation of RIG-I or MDA5 stimulates the secretion of type I interferons that play key roles in antiviral immune responses. The C-terminal domains (CTD) of RIG-I and LGP2 are responsible for RNA binding; however, it is not clear how MDA5 binds RNA. To understand the structural basis of dsRNA recognition by MDA5, we have determined the 1.45A resolution structure of the C-terminal domain of human MDA5. The structure revealed a highly conserved fold similar to the structures of RIG-I and LGP2 CTDs. NMR titration of MDA5 CTD with dsRNA demonstrated that a positively charged surface is involved in dsRNA binding. Mutagenesis and RNA binding studies showed that electrostatic interactions play primary roles in dsRNA recognition by MDA5. Like RIG-I and LGP2, MDA5 CTD preferentially binds dsRNA with blunt ends, but does not associate with dsRNA with either 5' or 3' overhangs. Molecular modeling of MDA5 CTD/dsRNA complex suggests that MDA5 CTD may recognize the first turn of blunt-ended dsRNA in a similar manner as LGP2.


Purification and properties of Drosophila heat shock activator protein.
Drosophila heat shock activator protein, a rare transacting factor which is induced upon heat shock to bind specifically to the heat shock regulatory sequence in vivo, has been purified from shocked cells to more than 95 percent homogeneity by sequence-specific duplex oligonucleotide affinity chromatography. The purified protein has a relative molecular mass of 110 kilodaltons, binds to the regulatory sequence with great affinity and specificity, and strongly stimulates transcription of the Drosophila hsp70 gene. Studies with this regulatory protein should lead to an understanding of the biochemical pathway underlying the heat shock phenomenon.


How are adverse childhood experiences and women's mental health associated? A latent class analysis.
Adverse childhood experiences (ACEs) have a cumulative effect on adult mental health; however, the effect of such combinations is less well known. The purpose of this study is to assess the association between specific combinations of early adversities and women's mental health. A total of 378 women (Myears = 41.4; SDyears = 13) receiving support from mental health and social services participated in this cross-sectional study. Latent class analysis was performed to classify participants based on the number of ACEs types. Our results provided support for four latent classes which differed in ACEs types reported: class 1 range of maltreatment but no family disruption (16.40 %; n = 62), class 2 range of maltreatment with family disruption (24.87 %; n = 94), class 3 few ACEs (44.71 %; n = 169), class 4 high maltreatment/high family disruption (14.02 %; n = 53). Differences in psychological functioning (presence of psychopathology, attachment, emotion dysregulation, and coping strategies) were found between the classes, especially between few ACEs and high maltreatment/high family disruption classes. In addition, women who lived in a low-adversity home and those who lived in a home with maltreatment, but no family disruption, differed in their desire for closeness, problem-solving and emotional expression strategies. This study highlights that the probability of exposure to different combinations of ACEs is associated with differences in adult psychological functioning. Deeper insight into this association may contribute to a better understanding of mental health problems and to improved prevention and intervention strategies in public support systems.


Child maltreatment: variation in trends and policies in six developed countries.
We explored trends in six developed countries in three types of indicators of child maltreatment for children younger than 11 years, since the inception of modern child protection systems in the 1970s. Despite several policy initiatives for child protection, we recorded no consistent evidence for a decrease in all types of indicators of child maltreatment. We noted falling rates of violent death in a few age and country groups, but these decreases coincided with reductions in admissions to hospital for maltreatment-related injury only in Sweden and Manitoba (Canada). One or more child protection agency indicators increased in five of six countries, particularly in infants, possibly as a result of early intervention policies. Comparisons of mean rates between countries showed five-fold to ten-fold differences in rates of agency indicators, but less than two-fold variation in violent deaths or maltreatment-related injury, apart from high rates of violent child death in the USA. These analyses draw attention to the need for robust research to establish whether the high and rising rates of agency contacts and out-of-home care in some settings are effectively reducing child maltreatment.


Comparison of cardiac troponin T versus creatine kinase-MB for risk stratification in a chest pain evaluation unit.
We evaluated cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) for risk stratification of chest pain unit (CPU) patients. We studied 383 consecutive patients with chest pain assigned to our CPU by emergency department physicians. At baseline all had normal or nondiagnostic electrocardiograms, no high-risk clinical features, and negative CK/CK-MB. CK-MB and electrocardiograms were taken at 0, 4, 8, and 12 hours and cTnT at 0, 4, and 8 hours. Eight patients (2.1%) were CK-MB positive and 39 (10.2%) were cTnT positive, including all but 1 CK-MB-positive patient. All marker-positive patients were detected by 8 hours. Seven cTnT-positive patients and 1 cTnT-negative patient had myocardial infarction (p <0.0001). cTnT-positive patients were older, less likely to be women or smokers, and more often had diabetes mellitus or known coronary disease (CAD). Seventy-one percent of patients underwent diagnostic testing. cTnT-positive patients more often underwent angiography (46% vs 20%) and underwent stress testing less often (28% vs 57%) than cTnT-negative patients. When performed, their stress tests were more often positive (46% vs 14%) and they more often had angiographically significant lesions (89% vs 49%) and multivessel disease (67% vs 29%). There were no short-term deaths. Long-term mortality was higher in cTnT-positive patients (27% vs 7%, p <0.0001). Thus, cTnT identified more CPU patients with myocardial necrosis and multivessel CAD than CK-MB and a population with high long-term mortality risk. Routine use of cTnT in CPUs could facilitate risk stratification and management.


Clinical, Neurophysiological, and MRI Markers of Fampridine Responsiveness in Multiple Sclerosis-An Explorative Study.
Objective: Persons with multiple sclerosis (PwMS), already established as responders or non-responders to Fampridine treatment, were compared in terms of disability measures, physical and cognitive performance tests, neurophysiology, and magnetic resonance imaging (MRI) outcomes in a 1-year explorative longitudinal study. Materials and Methods: Data from a 1-year longitudinal study were analyzed. Examinations consisted of the timed 25-foot walk test (T25FW), six spot step test (SSST), nine-hole peg test (9-HPT), five times sit-to-stand test (5-STS), symbol digit modalities test (SDMT), transcranial magnetic stimulation (TMS) elicited motor evoked potentials (MEP) examining central motor conduction times (CMCT), peripheral motor conduction times (PMCT) and their amplitudes, electroneuronography (ENG) of the lower extremities, and brain structural MRI measures. Results: Forty-one responders and eight non-responders to Fampridine treatment were examined. There were no intergroup differences except for the PMCT, where non-responders had prolonged conduction times compared to responders to Fampridine. Six spot step test was associated with CMCT throughout the study. After 1 year, CMCT was further prolonged and cortical MEP amplitudes decreased in both groups, while PMCT and ENG did not change. Throughout the study, CMCT was associated with the expanded disability status scale (EDSS) and 12-item multiple sclerosis walking scale (MSWS-12), while SDMT was associated with number of T2-weighted lesions, lesion load, and lesion load normalized to brain volume. Conclusions: Peripheral motor conduction time is prolonged in non-responders to Fampridine when compared to responders. Transcranial magnetic stimulation-elicited MEPs and SDMT can be used as markers of disability progression and lesion activity visualized by MRI, respectively. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03401307.


Hip arthroscopic capsulotomy techniques and capsular management strategies: a systematic review.
Hip arthroscopy is increasingly used to address hip joint pathology. Iatrogenic instability has been reported as a potential complication, leading to the evaluation of various capsular management strategies. The purpose of this review was to (1) report the techniques used for capsulotomy in hip arthroscopy, (2) understand techniques and indications for capsular closure, and (3) report outcomes based on capsular management strategy. MEDLINE, EMBASE, and PubMed were searched and screened in duplicate for relevant studies. Data regarding patient demographics, indications, surgical technique, rehabilitation strategies, and complication rates were obtained. Study quality was assessed in duplicate using the Methodological Index for Non-Randomized Studies (MINORS) Criteria. Eighty-two studies of primarily level IV evidence (80 %) and of fair quality involving 4504 patients with a mean age of 35 years old (range 1.2-82 years) were included. Fifty percent of patients were male. Mean follow-up was 24.9 months (range 5 days to 13 years). Of 68 studies reporting capsulotomy technique (only 7 % of all otherwise eligible studies), 55 % performed an interportal capsulotomy while 24 % performed a T-capsulotomy. Of 36 studies reporting capsular management strategy post-arthroscopy, 22 % did not repair the capsulotomy, 6 % routinely performed partial repair, and 50 % performed complete repair. Of three studies (206 patients) directly comparing capsular management strategies, only one study found a statistically significant difference between complete and partial repair on the Hip Outcome Score-Sport Specific Subscale, though this difference was less than the minimal clinically important difference (83.6 versus 87.3). The total rate of reported post-operative dislocation, instability, or instability was 0.3 % (5 patients). Technical details regarding capsulotomy and capsular management post-hip arthroscopy are not consistently reported in the literature. Capsulotomies are most often performed using an interportal technique, and more recent studies report routine closure. Overall, post-operative instability is rare and there is no consistent trend for capsular management strategy. Given current evidence, there is little basis on which to establish the relationship between surgical technique and post-operative instability or long-term consequences (e.g., kinematic changes). Thus, while capsular closure/plication may be suitable for specific populations (i.e., dysplasia or laxity), evidence-based indications for capsular repair remain unclear. Level IV, systematic review of level I-IV Studies.


[Meteoadaptogenic properties of antihypoxic drugs].
The meteoadaptogenic properties of antihypoxic drugs (citoflavin, reamberin, hypoxen, mexidol) have been studied in climate thermobarocomplex Tabai (Japan) on a group of healthy volunteers aged 20 - 24. It is established that all these drugs produce a meteoadaptogenic effect, the degree of which depends on the environment conditions (overcooling, overheating, hypobaric hypoxia). Citoflavin optimized the functional state in both cold and hot climate as well as under hypobaric hypoxia conditions. Mexidol can be classified as an adaptogen and both menthal and physical actoprotector under overcooling or hypobaric hypoxia conditions (highlands). Hypoxen, which positively affects the psychological component of the functional state and enhances psychomotor activity, can be used for rapid adaptation to a hot climate. Reamberine significantly increases the physical component of the functional state under cold conditions and can be considered as a psychomotor enhancer and adaptogen for the regions of cold climate. Therefore, all the drugs studied (citoflavin, reamberin, hypoxen, mexidol) can be recommended as the means of activation, support, and recovery of physical and psychological efficiency under rapidly changing environment conditions.


The Auger process in multilayer WSe2 crystals.
Multilayer WSe2 with a larger optical density of states and absorbance is regarded as a better candidate than its monolayer counterpart for next generation optoelectronic devices, however insight into carrier dynamics is still lacking. Herein, we experimentally observed an anomalous PL quenching with decreasing temperature for multilayer WSe2. At a low temperature (77 K), the Auger processes govern carrier recombination in multilayer WSe2, which are induced by a phonon bottleneck effect and strong photon absorption, and lead to PL quenching. From transient absorption spectroscopy, two distinct Auger processes are observed: a fast one (1-2 ps) and a slow one (>190 ps), which are caused by two different deep midgap defect-levels in WSe2. Based on the Auger recombination model, these two Auger rates are quantitatively estimated at ∼6.69 (±0.05) × 10-2 and 1.22 (±0.04) × 10-3 cm2 s-1, respectively. Our current observations provide an important supplement for optimizing the optical and electric behaviors in multilayer WSe2 based devices.


Molecular Dynamics Simulation of Oxygen Ion Conduction in Orthorhombic Perovskite Ba-Doped LaInO3 Using Cubic and Orthorhombic Model.
The oxygen ion conduction behavior of an orthorhombic perovskite oxide Ba-doped LaInO3 was evaluated by molecular dynamics simulation. Comparative calculations for cubic and the orthorhombic models show that the orthorhombic model was in better agreement with the experimental results with respect to both ionic conductivity and activation energy. The results of the radial distribution function for O-O pair provided and explanation for why the ionic conductivity of cubic perovskite is higher than that of orthorhombic perovskite. The orthorhombic model has a higher peak intensity of O-O pair than the cubic model, it means that the orthorhombic model has a smaller number of oxygen-vacancy pairs in the lattice structure. Consequently, the ionic conductivity of orthorhombic perovskite is lower than that of cubic perovskite due to less conduction path.


Occupational accident indicators among Social Security beneficiaries: temporal trend and magnitude in Brazil and its regions, 2009-2019.
To evaluate the temporal trend and magnitude of occupational accident indicators among Social Security beneficiaries in Brazil and its regions from 2009 to 2019. A time series study was conducted on occupational accident indicators in the regions of Brazil, from 2009 to 2019. Data were retrieved from the Statistical Yearbook of Occupational Accidents and the Statistical Yearbook of Social Security. Prais-Winsten generalized linear regression models were used to estimate trends, and annual percentage change and their respective 95% confidence intervals were obtained. There were 7,253,923 occupational accidents during the study period. The average incidence rate was 16.3 per 1,000 employment relationships, with a decreasing trend (APC = 4.3%; 95%CI -5.63;-3.26). Brazil and its regions showed an overall decreasing trend in indicators representing morbidity burden and the magnitude of occupational accidents. In Brazil, despite regional inequalities, there has been a decrease in occupational accident rates reported to Social Security. The results suggest improvements in working conditions, control and prevention of occupational accidents among these workers and contribute to targeting measures to prevent and control these diseases in the regions with the highest incidence. Further research could explore trends according to professional category and economic activity sector, aimed at improving the monitoring of safety conditions and the wellbeing of workers in the regions of Brazil.


A subpopulation of cerebral B cluster neurones of Aplysia californica is involved in defensive head withdrawal but not appetitive head movements.
The cerebral B cluster neurones of Aplysia californica were studied under experimental conditions designed to evoke head movements in a selective fashion: either to approach an appetitive stimulus, or to withdraw from an aversive one. Intracellular recordings indicated the presence of two types of B cluster neurones: Bn cells that had fast (narrow) spikes, and Bb cells that had slow (broad) spikes. Tactile stimulation of the tentacles, rhinophores and lips excited Bn neurones, but inhibited Bb neurones. Intracellular stimulation of Bn cells evoked contractions of body wall muscles. No contractions were observed when Bb cells were fired, indicating that it is unlikely that the Bb neurones are motor neurones. Several lines of evidence indicated that the Bn type neurones are involved in withdrawal responses but not in appetitive head turning. (1) Elimination of the descending axons of the Bn cells by lesioning the cerebropleural connectives (C-Pl connectives) did not affect the head-turning response. This lesion significantly altered the head-withdrawal response by selectively eliminating an initial fast component of the withdrawal movement. (2) In chronic recordings from the C-Pl connective, unit activity was obtained which was correlated with the presentation of an appetitive stimulus rather than with evoked or spontaneous turning movements. A substantial increase in activity also occurred during head withdrawal of the animal. On the basis of these data, we postulate that separate populations of motor neurones are responsible for the aversive withdrawal of the head, and for the directed turning response towards a stimulus.


Structural and functional analysis of cationic transfection lipids: the hydrophobic domain.
Cationic lipids (cytofectins) have gained widespread acceptance as pharmaceutical polynucleotide delivery agents for both cultured cell and in vivo transfection, and the cytofectins DOTAP and DC-Cholesterol are being tested in clinical human gene therapy trials. This study reports the effects of modifications in the hydrophobic domain of a prototypic cytofectin (DORI), including modifications in lipid side-chain length, saturation, and symmetry. A panel of related compounds was prepared and analyzed using DNA transfection, electron microscopy, and differential scanning calorimetry (DSC). Lipid formulations were prepared with dioleoylphosphatidylethanolamine (DOPE) as unsonicated preparations and sonicated preparations. Transfection analyses were performed using cultured fibroblasts, human bronchial epithelial, and Chinese hamster ovarian cells as well as a mouse model for pulmonary gene delivery. In general, cytofectins containing dissymmetric hydrophobic domains were found to work as well or better than the best symmetric analogs. Optimal side-chain length and symmetry varied with cell type. Compounds with phase transitions (Tc) above and below physiological temperature (37 degrees C) were tested for DNA transfection activity. In contrast to previous reports, cytofectin Tc was not found to be predictive of transfection efficacy. Pulmonary treatment with free DNA was found to be at least as effective as treatment with commonly used cytofectin:DNA complexes. However, cytofectins that incorporate a hydroxyethylammonium moiety in the polar domain were found to enhance in vivo gene delivery relative to free DNA.


Reversal of the potassium entry mechanism in red cells, with and without reversal of the entire pump cycle.
1. (42)K has been used to study the ouabain-sensitive component of potassium efflux from intact human red cells.2. Ouabain-sensitive efflux of potassium was observed only in media containing either sodium ions in moderate or high concentration or potassium ions.3. The effects of sodium and potassium in the medium were not additive. Potassium ions always increased the ouabain-sensitive potassium efflux, but in media containing 4.2 mM-K an increase in sodium concentration from 4.5 to 131 mM had little effect.4. In potassium-free media, ouabain-sensitive potassium efflux increased roughly linearly as the external sodium concentration was increased from 35 to 155 mM.5. The sensitivity of potassium efflux to external potassium depended on the concentration of sodium in the medium. In a 5 mM-Na (choline) medium, ouabain-sensitive potassium efflux was half-maximal at about 0.27 mM-K. In a 150 mM-Na medium the effect of potassium was half-maximal at about 1 mM-K. The relation between external potassium concentration and ouabain-sensitive sodium efflux was similarly influenced by the concentration of sodium ions in the medium.6. Inosine greatly reduced the ouabain-sensitive efflux of potassium into both 5 mM-K and potassium-free media. It probably acted by reducing the intracellular phosphate concentration to a low level.7. Ouabain-sensitive potassium efflux was not affected by the concentration of inorganic phosphate outside the cells and was not associated with a ouabain-sensitive efflux of phosphate of comparable magnitude. A small associated efflux could not be excluded.8. Simultaneous measurements of sodium efflux and of potassium efflux from identical batches of cells incubated in potassium-free media showed that inosine reduced ouabain-sensitive potassium efflux at the same time as it increased ouabain-sensitive sodium efflux.9. When cells that had been largely depleted of energy stores by pre-incubation with 2-deoxyglucose were incubated in high-sodium media, with and without potassium, it was observed that potassium in the medium increased the ouabain-sensitive potassium efflux but reduced the ouabain-sensitive efflux of sodium.10. Simultaneous measurements of the ouabain-sensitive efflux of potassium and influx and efflux of sodium across the membranes of starved cells incubated in potassium-free media, with and without inosine, suggested that ouabain-sensitive potassium efflux was associated with a net ouabain-sensitive entry of sodium.11. The results are best explained by supposing that the ouabain-sensitive efflux of potassium does not reflect lack of discrimination by the mechanism responsible for sodium expulsion, but is brought about by the reversal of steps in the pump cycle normally responsible for potassium entry.


Pubertal exposure to anabolic androgenic steroids increases spine densities on neurons in the limbic system of male rats.
Human studies show that the number of teenagers abusing anabolic androgenic steroids (AAS) is increasing. During adolescence, brain development is altered by androgen exposure, which suggests that AAS may potentially alter central nervous system (CNS) development. The goal of the present study was to determine whether pubertal AAS exposure increased dendritic spine densities on neurons within the medial amygdala and the dorsal hippocampus. Pubertal gonadally intact male rats received the AAS testosterone propionate (5 mg/kg) or vehicle for 5 days/week for 4 weeks. To determine the long-term implications of pubertal AAS use, another set of males received the same AAS treatment and was then withdrawn from AAS exposure for 4 weeks. Results showed that pubertal AAS exposure significantly increased spine densities on neurons in the anterior medial amygdala, posterodorsal medial amygdala, and the cornu ammonis region 1 (CA1) of the hippocampus compared with gonadally intact control males. Spine densities returned to control levels within the anterior medial amygdala and the posterodorsal medial amygdala 4 weeks after withdrawal. However, spine densities remained significantly elevated after AAS withdrawal in the CA1 region of the hippocampus, suggesting that pubertal AAS exposure may have a long-lasting impact on CA1 hippocampal neuroanatomy. Since pubertal AAS exposure increased spine densities and most excitatory synapses in the CNS occur on dendritic spines, AAS may increase neuronal excitation. It is proposed that this increase in excitation may underlie the behavioral responses seen in pubertal AAS-treated male rats.


Amblyopia: etiology, detection, and treatment.
Amblyopia is a preventable cause of visual loss in children that may be permanent unless it is detected and treated early. It may be caused by strabismus, refractive errors, or cataracts. Primary strabismus may lead to loss of vision from amblyopia and the loss of binocularity. Secondary strabismus may be a sign of primary visual loss in one or both eyes. The most serious disorder that may present as secondary strabismus is retinoblastoma. It is imperative to detect retinoblastoma early because of its morbidity and mortality. Amblyopia is detected by assessing the visual acuity of each eye. Strabismus is detected by using the corneal light reflex test and the cover test. Focusing problems are detected by assessing the visual acuity and the red reflex. Cataracts and retinoblastoma may be detected by examining the red reflex of the eye. Treatment of amblyopia consists of correcting the amblyogenic factor with appropriate glasses and surgery. The preferred eye is patched with an adhesive patch to stimulate visual development in the amblyopic eye. The pediatrician plays a crucial role in the early detection of amblyopia, strabismus, and cataracts. The key to successful visual outcome is early recognition by the pediatrician, referral to the pediatric ophthalmologist, and prompt treatment.


Predictors of Post-Exercise Energy Intake in Adolescents Ranging in Weight Status from Overweight to Severe Obesity.
Exercise may sensitize individuals with overweight and obesity to appetitive signals (e.g., hunger and fullness cues), overriding trait eating behaviors that contribute to overeating and obesity, such as uncontrolled eating. The objective of the current study was to measure predictors of objective ad libitum energy intake at a laboratory-based, post-exercise test-meal in adolescents ranging in weight status from overweight to severe obesity. We hypothesized that appetitive states, rather than appetitive traits, would be the strongest predictors of energy intake at a post-exercise test-meal, after controlling for body size. At Baseline, 30 adolescents (ages 10-16 years, 50% female (F), 43% non-Hispanic white (NHW), 83% with obesity (OB)) completed state and trait appetite measures and an ad libitum dinner meal following intensive exercise. Nineteen of those participants (47% F, 32% NHW, 79% OB) completed identical assessments two years later (Year 2). Energy intake (kcal) at each time point was adjusted for fat-free mass index (i.e., body size). Adjusted energy intake was reliable from Baseline to Year 2 (ICC = 0.84). Multiple pre-meal appetite ratings were associated with test-meal energy intake. In stepwise linear regression models, pre-meal prospective food consumption was the strongest and only significant predictor of test-meal energy intake at both Baseline (R2 = 0.25, p = 0.005) and Year 2 (R2 = 0.41, p = 0.003). Baseline post-exercise energy intake was associated with weight change over two years (R2 = 0.24, p = 0.04), but not with change in fat mass (p = 0.11). Appetitive traits were not associated with weight or body composition change (p > 0.22). State appetite cues were the strongest predictors of post-exercise energy intake, independent of body size. Future studies should examine whether long-term exercise programs enhance responsiveness to homeostatic appetite signals in youth with overweight and obesity, with a goal to reduce excess energy intake and risk for weight gain over time.


Hollow mesoporous carbon nanospheres for imaging-guided light-activated synergistic thermo-chemotherapy.
Carbon-based light-activated materials can absorb optical energy to generate photoacoustic (PA) signals for imaging or transduce optical photons to thermal energy, which holds great promise for biomedical applications. Herein, we synthesize hollow and mesoporous carbon nanospheres (HMCNs) with uniform size on a large scale. The properties of hollow cavity and mesoporous structures make the HMCNs achieve high drug loading (480 mg DOX per g HMCNs). The present intense near infrared (NIR) absorbance achieves excellent photoacoustic imaging ability and photothermal conversion efficacy (32.0%). More interestingly, the encapsulated drugs can have a triggered release under NIR irradiation. The investigations in vitro and in vivo demonstrate that HMCNs have excellent biocompatibility, and accumulate in tumors by the enhanced permeability and retention (EPR) effect. Moreover, under NIR irradiation, in vivo evaluation shows that HMCNs can perform strong PA imaging, and induce great tumor inhibition by the combination of chemotherapy and PTT under the guidance of photoacoustic imaging. The present study provides new insight for design of novel biocompatible light-activated carbons for cancer nanotheranostics.


Association of thyroid function with non-alcoholic fatty liver disease in recent-onset diabetes.
Non-alcoholic fatty liver disease (NAFLD) has been linked to type 2 diabetes (T2D), but also to hypothyroidism. Nevertheless, the relationship between thyroid function and NAFLD in diabetes is less clear. This study investigated associations between free thyroxine (fT4) or thyroid-stimulating hormone (TSH) and NAFLD in recent-onset diabetes. Participants with recent-onset type 1 diabetes (T1D, n = 358), T2D (n = 596) or without diabetes (CON, n = 175) of the German Diabetes Study (GDS), a prospective longitudinal cohort study, underwent Botnia clamp tests and assessment of fT4, TSH, fatty liver index (FLI) and in a representative subcohort 1 H-magnetic resonance spectroscopy. First, fT4 levels were similar between T1D and T2D (p = .55), but higher than in CON (T1D: p < .01; T2D: p < .001), while TSH concentrations were not different between all groups. Next, fT4 correlated negatively with FLI and positively with insulin sensitivity only in T2D (ß = -.110, p < .01; ß = .126, p < .05), specifically in males (ß = -.117, p < .05; ß = .162; p < .01) upon adjustments for age, sex and BMI. However, correlations between fT4 and FLI lost statistical significance after adjustment for insulin sensitivity (T2D: ß = -.021, p = 0.67; males with T2D: ß = -.033; p = .56). TSH was associated positively with FLI only in male T2D before (ß = .116, p < .05), but not after adjustments for age and BMI (ß = .052; p = .30). Steatosis risk correlates with lower thyroid function in T2D, which is mediated by insulin resistance and body mass, specifically in men, whereas no such relationship is present in T1D.


Phosphonium ylide catalysis: a divergent diastereoselective approach to synthesize cyclic ketene acetals [thia(zolidines/zinanes)] from β-ketothioamides and dihaloalkanes.
Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from β-ketothioamides (which act as a three atom N, C, and S synthon) with dihaloalkanes via [3 + 2] and [3 + 3] annulations under metal-free conditions. An N,C,S-centred chemoselective dihaloalkane-controlled cascade process has been identified for the preparation of cyclic N,S-heterocycles (thiazolidines and 1,3-thiazinanes) from identical β-ketothioamides. The reaction proceeds via consecutive sulfur and nitrogen nucleophilic attack of the thioamide on dihaloalkanes enabling the formation of S-C and N-C bonds. The ring size of the skeletally distinct N,S-heterocycles has been efficiently tuned by switching the use of 1,2- and 1,3-dihaloalkanes as α,β- and α,γ-dielectrophiles. It is noteworthy that the products possess Z-stereochemistry with regard to the exocyclic C[double bond, length as m-dash]C double bond at the 2-position of the ring, revealing exclusive diastereoselectivity. Since phosphorus ylides have found limited use as catalysts, control experiments revealed their behaviour as a catalyst, which not only increase the catalyst tool box, but also would contribute to the field of ylide chemistry.


Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer.
Identification of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of colonoscopy and polypectomies. We evaluated the efficacy of screening in a controlled trial over 15 years. Incidence of CRC and survival were compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic screening at 3-year intervals was arranged for 133 subjects; 119 control subjects had no screening. Genetic testing was offered to subjects in whose families the causative mutation was known. CRC developed in 8 screened subjects (6%) compared with 19 control subjects (16 %; P = 0.014). The CRC rate was reduced by 62%. In mutation-positive subjects alone, the CRC rates were 18% in screened subjects and 41% in controls (P = 0.02). The decrease resulted from the removal of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with unknown mutation status (40%). All CRCs in the study group were local, causing no deaths, compared with 9 deaths caused by CRC in the controls. The overall death rates were 10 vs. 26 subjects in the study and control groups (P = 0.003), 4 vs. 12 in mutation-positive subjects (P = 0.05). Colonoscopic screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families.


Shape matching by integral invariants on eccentricity transformed images.
Matching occluded and noisy shapes is a frequently encountered problem in vision and medical image analysis and more generally in computer vision. To keep track of changes inside breast, it is important for a computer aided diagnosis system (CAD) to establish correspondences between regions of interest. Shape transformations, computed both with integral invariants and geodesic distance yield signatures that are invariant to isometric deformations, such as bending and articulations. Integral invariants are used on 2D planar shapes to describe the shape boundary. However, they provide no information about where a particular feature on the boundary lies with regard to overall shape structure. On the other hand, eccentricity transforms can be used to match shapes by signatures of geodesic distance histograms based on information from inside the shape; but they ignore the boundary information. We describe a method that combines both the boundary signature of shape obtained from integral invariants and structural information from the eccentricity transform to yield improved results.


Biodegradeable temporising matrix use in a traumatic chest wound.
The Welsh Centre for Burns and Plastic Surgery is responsible for a population of 10 million people in Wales and England. We describe the use of biodegradable temporising matrix (BTM) in a large traumatic chest wound in a 23-year-old woman. BTM is a synthetic dermal substitute and has been utilised to achieve soft tissue coverage in complex wounds. This wound was sustained after the patient fell from a tractor into a large silage rake, resulting in injuries to her chest and limbs. Following meticulous debridement, her resulting full thickness skin defect measured 30 × 30 cm extending from the sternal notch to the upper abdomen, with bone, muscle and breast tissue exposure. The central chest area is complex to reconstruct due to the contours of the breasts and tendency to contracture following skin graft reconstruction. We demonstrate the first reported use of BTM for breast reconstruction, as far as we are aware.


The role of eye movements in decision making and the prospect of exposure effects.
The aim of the current study was to follow on from previous findings that eye movements can have a causal influence on preference formation. Shimojo et al. (2003) previously found that faces that were presented for a longer duration in a two alternative forced choice task were more likely to be judged as more attractive. This effect only occurred when an eye movement was made towards the faces (with no effect when faces were centrally presented). The current study replicated Shimojo et al.'s (2003) design, whilst controlling for potential inter-stimuli interference in central presentations. As per previous findings, when eye movements were made towards the stimuli, faces that were presented for longer durations were preferred. However, faces that were centrally presented (thus not requiring an eye movement) were also preferred in the current study. The presence of an exposure duration effect for centrally presented faces casts doubt on the necessity of the eye movement in this decision making process and has implications for decision theories that place an emphasis on the role of eye movements in decision making.


Influence of obesity on the metabolism of apolipoprotein B in humans.
The influence of obesity on the metabolism of apolipoprotein B (apo B) in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) was investigated in nine obese and seven nonobese Pima Indian men. Kinetics of VLDL-apo B (VLDL-B), VLDL-triglycerides, IDL-B and LDL-B were studied after injection of autologous 131I-VLDL, [3H]glycerol, and autologous 125I-LDL. Specific activities were measured in apo B isolated from all lipoprotein fractions and in triglyceride isolated from VLDL. Transport rates and fractional catabolic rates for apo B in VLDL, IDL, and LDL and triglyceride in VLDL were determined by multicompartmental analysis. This method also allowed the estimation of rates of interconversions of the lipoproteins. The two groups had similar mean ages and heights, but the obese group had a higher total body weight (131 +/- 14 vs. 66 +/- 3 kg +/- SEM) and fat free mass (81 +/- 5 vs. 54 +/- 2 kg) than lean controls. Plasma total lipids were similar for the two groups, and apo B concentrations in VLDL, IDL, and LDL were similar in obese and lean subjects. In spite of similarity in concentrations, obese subjects compared to lean subjects had higher synthetic rates of VLDL-triglyceride (62.6 +/- 15 vs. 26.2 +/- 7 g/d, P less than 0.01), VLDL-B (2,241 +/- 215 vs. 1,113 +/- 72 mg/d, P less than 0.001), and LDL-B (1,234 +/- 87 vs. 802 +/- 83 mg/d, P less than 0.01). Furthermore, in obese subjects, significantly higher amounts of VLDL-B were removed from the circulation without conversion to LDL-B (1,078 +/- 159 vs. 460 +/- 34 mg/d, P less than 0.05), and obese subjects had a higher fractional catabolic rate for LDL than the lean controls (0.48 +/- 0.02 vs. 0.41 +/- 0.02 d-1, P less than 0.05). The rapid catabolism of LDL and increased metabolism of VLDL without conversion to LDL in obese individuals may be mechanisms for maintenance of LDL at normal levels despite the overproduction of its precursor.


Abnormally high risk of stroke in Brugada syndrome.
The present study sought to evaluate the incidence of cerebrovascular events in a large cohort of patients with Brugada syndrome (BrS) analysing possible predictors, clinical characteristics and prognosis of cardioembolic events secondary to atrial fibrillation. A total of 671 consecutive patients (age 42.1 ± 17.0 years; men 63%) with a diagnosis of BrS were retrospectively analysed over a mean follow-up period of 10.8 ± 5.5 years. The diagnosis of ischemic stroke was made according to the AHA/ASA guidelines using computed tomography (CT) and angio-CT in the emergency department. Among 671 patients with BrS, 79 (11.8%) had atrial fibrillation. The incidence of cardioembolic stroke in patients with BrS and atrial fibrillation was 13.9% (11 events). These patients had a low CHA2DS2Vasc score (82%, 0 and 1). Patients with transient ischemic attack/stroke were more frequently asymptomatic (91 vs. 25%; P < 0.0001) and older (59.4 ± 11.2 vs. 43.9 ± 16.7; P = 0.004) as compared with those without cerebrovascular events. The incidence of cardioembolic stroke in patients with BrS and atrial fibrillation was unexpectedly high. The cerebrovascular accidents were often the presenting clinical manifestation and were significantly associated with asymptomatic atrial fibrillation and older age. CHADS2 and CHA2DS2Vasc scores did not predict the unexpectedly high risk of thromboembolic events in this group of patients. The use of more invasive diagnostic tools might be useful in order to increase the rate of atrial fibrillation detection.


Mammalian odorant receptor tuning breadth persists across distinct odorant panels.
The molecular receptive range (MRR) of a mammalian odorant receptor (OR) is the set of odorant structures that activate the OR, while the distribution of these odorant structures across odor space is the tuning breadth of the OR. Variation in tuning breadth is thought to be an important property of ORs, with the MRRs of these receptors varying from narrowly to broadly tuned. However, defining the tuning breadth of an OR is a technical challenge. For practical reasons, a screening panel that broadly covers odor space must be limited to sparse coverage of the many potential structures in that space. When screened with such a panel, ORs with different odorant specificities, but equal tuning breadths, might appear to have different tuning breadths due to chance. We hypothesized that ORs would maintain their tuning breadths across distinct odorant panels. We constructed a new screening panel that was broadly distributed across an estimated odor space and contained compounds distinct from previous panels. We used this new screening panel to test several murine ORs that were previously characterized as having different tuning breadths. ORs were expressed in Xenopus laevis oocytes and assayed by two-electrode voltage clamp electrophysiology. MOR256-17, an OR previously characterized as broadly tuned, responded to nine novel compounds from our new screening panel that were structurally diverse and broadly dispersed across an estimated odor space. MOR256-22, an OR previously characterized as narrowly tuned, responded to a single novel compound that was structurally similar to a previously known ligand for this receptor. MOR174-9, a well-characterized receptor with a narrowly tuned MRR, did not respond to any novel compounds in our new panel. These results support the idea that variation in tuning breadth among these three ORs is not an artifact of the screening protocol, but is an intrinsic property of the receptors.


Beneficial effects of white wine polyphenols-enriched diet on Alzheimer's disease-like pathology.
The development of effective medicines to break or delay the progressive brain degeneration underlying cognitive decline and dementia that characterize Alzheimer's disease (AD) is one of the greatest challenges of our time. In the present work, a selective pool of polyphenols, obtained from the white wine by adsorption to polyvinylpyrrolidone polymer (PVPP), was used to prepare a polyphenols-enriched diet, supplementing the drinking water with 100 mg/L (expressed as gallic acid equivalent) of wine polyphenolic extract. The impact of the daily consumption of water supplemented with polyphenols for 2 months on brain of 10-month-old 3xTg-AD and NonTg mice was evaluated, considering effects on the redox state of cells, levels of amyloid-β peptides, mitochondrial bioenergetics and fatty acid profile of whole membrane phospholipids. The polyphenols-enriched diet promotes brain accumulation of catechin and hydroxybenzoic acid derivatives, and modulates the redox state of 3xTg-AD brain cells, increasing both glutathione/glutathione disulfide ratio and catalase activity and decreasing membrane lipids oxidation. Additionally, the functional diet decreases the 3xTg-AD brain levels of both amyloid-β peptides, Aβ1-40 and Aβ1-42. However, the brain mitochondrial bioenergetic dysfunction of 3xTg-AD animals was not attenuated by the polyphenols-enriched diet. Lipidomic studies showed that this functional diet modulates membrane lipid composition of brain cells, increasing C22:6n-3 (docosahexanoic acid) and decreasing C20:4n-6 (arachidonic acid) levels, which may have beneficial impact on the chronic inflammatory process associated with AD pathology. Altogether, these results indicate that the oral administration of this polyphenols-enriched diet promotes significant benefits in multiple aspects of the pathophysiological cascade associated with the neuropathology developed by 3xTg-AD mice.


Homology and functional similarity of an hrp-linked pathogenicity locus, dspEF, of Erwinia amylovora and the avirulence locus avrE of Pseudomonas syringae pathovar tomato.
The "disease-specific" (dsp) region next to the hrp gene cluster of Erwinia amylovora is required for pathogenicity but not for elicitation of the hypersensitive reaction. A 6.6-kb apparent operon, dspEF, was found responsible for this phenotype. The operon contains genes dspE and dspF and is positively regulated by hrpL. A BLAST search revealed similarity in the dspE gene to a partial sequence of the avrE locus of Pseudomonas syringae pathovar tomato. The entire avrE locus was sequenced. Homologs of dspE and dspF were found in juxtaposed operons and were designated avrE and avrF. Introduced on a plasmid, the dspEF locus rendered P. syringae pv. glycinea race 4 avirulent on soybean. An E. amylovora dspE mutant, however, elicited a hypersensitive reaction in soybean. The avrE locus in trans restored pathogenicity to dspE strains of E. amylovora, although restored strains were low in virulence. DspE and AvrE are large (198 kDa and 195 kDa) and hydrophilic. DspF and AvrF are small (16 kDa and 14 kDa) and acidic with predicted amphipathic alpha helices in their C termini; they resemble chaperones for virulence factors secreted by type III secretion systems of animal pathogens.


The relationship between tear meniscus regularity and conjunctival folds.
To investigate the capability of a new portable digital meniscometer (PDM) to measure tear meniscus radius (TMR) and tear meniscus height (TMH) at different locations along the lower lid and to evaluate relationships between tear meniscus regularity and the degree of lid-parallel conjunctival folds (LIPCOFs). Using the PDM, the TMR and TMH of 42 subjects were measured at three locations along the lower lid of one eye: central, perpendicularly below the pupil center (TMR-C, TMH-C), and temporal (TMR-T, TMH-T) and nasal (TMR-N, TMH-N), perpendicularly below the limbus. Nasal and temporal LIPCOF grades were recorded. Correlations between the measurements were analyzed using the Pearson coefficient (or Spearman rank in nonparametric data), and the differences were evaluated by paired t tests or analysis of variance and post hoc Fisher least significant difference test. Temporal TMR was 0.041 mm flatter (p = 0.002) and TMH-T was 0.063 mm higher (p < 0.001), whereas TMR-N was 0.026 mm flatter (p = 0.038) and TMH-N was 0.046 mm higher (p < 0.001) than TMR-C and TMH-C. Temporal LIPCOF grades were significantly correlated to temporal alterations in TMH (r = 0.590; p < 0.001) and TMR (r = 0.530; p < 0.001), and nasal LIPCOF grades were significantly correlated to nasal alterations in TMH (r = 0.492; p = 0.001) and TMR (r = 0.350; p = 0.023). The PDM is able to noninvasively detect significant differences in TMR and TMH along the lower lid. The flatter TMR and higher TMH at the nasal and temporal locations are associated with increased LIPCOF. Because increased LIPCOF scores may affect tear film disruption along the lower lid, measuring TMR and TMH at the central position below the pupil may provide the best intersubject reliability.


Ischemic tolerance and cardiac repair in the spiny mouse (Acomys).
Ischemic heart disease and by extension myocardial infarction is the primary cause of death worldwide, warranting regenerative therapies to restore heart function. Current models of natural heart regeneration are restricted in that they are not of adult mammalian origin, precluding the study of class-specific traits that have emerged throughout evolution, and reducing translatability of research findings to humans. Here, we present the spiny mouse (Acomys spp.), a murid rodent that exhibits bona fide regeneration of the back skin and ear pinna, as a model to study heart repair. By comparing them to ordinary mice (Mus musculus), we show that the acute injury response in spiny mice is similar, but with an associated tolerance to infarction through superior survivability, improved ventricular conduction, and near-absence of pathological remodeling. Critically, spiny mice display increased vascularization, altered scar organization, and a more immature phenotype of cardiomyocytes, with a corresponding improvement in heart function. These findings present new avenues for mammalian heart research by leveraging unique tissue properties of the spiny mouse.


T cell expansion is the limiting factor of virus control in mice with attenuated TCR signaling: implications for human immunodeficiency.
Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV). Twp CD8(+) T cells showed impaired polyfunctional cytokine production, whereas cytotoxicity as the crucial antiviral effector function for LCMV control was normal. The main limiting factor in the antiviral response of twp mice was impaired T cell proliferation and survival, leading to a 5- to 10-fold reduction of antiviral T cells at the peak of the immune response. This was still sufficient to control infection with the LCMV Armstrong strain, but the more rapidly replicating LCMV-WE induced T cell exhaustion and viral persistence. Thus, under conditions of impaired TCR signaling, reduced T cell expansion was the limiting factor in antiviral immunity. These findings have implications for understanding antiviral immunity in patients with T cell deficiencies.


Myalgic encephalomyelitis--report of an epidemic.
The relationship between the group B Coxsackieviruses and a wide variety of illnesses, particularly pleurodynia and myo/pericarditis, is already well established. The detection of raised levels of neutralizing antibody to these viruses in a group of patients in a rural practice presenting with an illness resembling myalgic encephalomyelitis (ME) was therefore unexpected. This is a most distressing and debilitating illness for the patient and the affected family. What is the immunological failure in these patients which apparently allows this virus to persist causing such unusual and bizarre illness? At present ME is probably much commoner than is realized, the majority of patients being given the dismissive diagnosis of psychoneurosis.


Mutagenesis and O6-ethylguanine levels in DNA from N-nitroso-N-ethylurea-treated Salmonella typhimurium: evidence for a high mutational efficiency of O6-ethylguanine.
The dose-responses for N-nitroso-N-ethylurea (NEU)-induced mutagenesis in the hisG46 mutant, Salmonella typhimurium TA1535, and for the formation of O6-ethylguanine (O6-EtGua) and 7-ethylguanine in the DNA isolated from these cells were measured. Mutagenesis and O6-EtGua formation exhibited threshold-like behavior, whereas the formation of 7-ethylguanine was linear with dose. These results are consistent with a dependence of mutagenesis on O6-EtGua. There was no threshold in the production of O6-EtGua in isolated DNA treated with NEU. The failure of O6-EtGua to appreciably accumulate in the cellular DNA at low doses of NEU was attributed to a saturable, constitutive repair activity in the bacteria. Based on (i) the ratio of O6-EtGua in DNA to revertant fraction, (ii) published values for the size of the Salmonella genome and (iii) the target size and target bases (guanine-cytosine base pairs) for reversion of the hisG46 (missense) mutation, it was calculated that about 1/3 of the O6-EtGua's in the DNA led to mutations. Using the same calculations and data from previous experiments, a mutational efficiency for O6-methylguanine of 2/3 was obtained. Threshold-type responses in NEU-induced mutagenesis were observed in the other hisG46 mutants, TA100 and TA1975, but not in the frameshift mutant, TA98 where the dose response was linear. As TA98 contains the same DNA repair systems as TA100, frameshift mutations induced by NEU may result from DNA adducts produced linearly with dose.


Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms.
Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.


Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury.
Diabetic nephropathy is one of the most devastating complications of diabetes, and growing evidence implicates podocyte dysfunction in disease pathogenesis. The objective of this study was to investigate the contribution of protein tyrosine phosphatase 1B (PTP1B) in podocytes to hyperglycemia-induced renal injury. To determine the in vivo function of PTP1B in podocytes we generated mice with podocyte-specific PTP1B disruption (hereafter termed pod-PTP1B KO). Kidney functions were determined in control and pod-PTP1B KO mice under normoglycemia and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia. PTP1B expression increased in murine kidneys following HFD and STZ challenges. Under normoglycemia control and pod-PTP1B KO mice exhibited comparable renal functions. However, podocyte PTP1B disruption attenuated hyperglycemia-induced albuminuria and renal injury and preserved glucose control. Also, podocyte PTP1B disruption was accompanied with improved renal insulin signaling and enhanced autophagy with decreased inflammation and fibrosis. Moreover, the beneficial effects of podocyte PTP1B disruption in vivo were recapitulated in E11 murine podocytes with lentiviral-mediated PTP1B knockdown. Reconstitution of PTP1B in knockdown podocytes reversed the enhanced insulin signaling and autophagy suggesting that they were likely a consequence of PTP1B deficiency. Further, pharmacological attenuation of autophagy in PTP1B knockdown podocytes mitigated the protective effects of PTP1B deficiency. These findings demonstrate that podocyte PTP1B deficiency attenuates hyperglycemia-induced renal damage and suggest that PTP1B may present a therapeutic target in renal injury.


[Specificity of interaction of hexokinase isozyme II with mitochondrial membranes].
Study on the mechanism of hexokinase isozyme II adsorption on mitochondrial membranes in the presence of 10 mM MgCl2 demonstrated that 0.16% of the total proteins of the soluble fraction and the total hexokinase pool are capable of reversible binding to the membrane. The plot for the dependence of the degree of enzyme adsorption on Mg2+ concentration is hyperbolic. Under these conditions, hexokinase competes favourably for the binding sites with lactate dehydrogenase and creatine kinase. Analysis of the adsorption capacity of natural and artificial phospholipid membranes showed that hexokinase isozyme II is adsorbed in much the same way on inner and outer mitochondrial membranes as well as on a mixture of membranes obtained from various sources and on lecithin liposomes. The adsorption properties of hexokinase isozyme II and of its functional analog--isozyme I--point to marked differences in the mechanism of their interaction with the membrane. In contrast with isozyme I, isozyme II of hexokinase undergoes kinetic alterations. Besides, it was found that mild autolysis of isozyme II is accompanied by a loss of the enzyme ability to bind to mitochondrial membranes. The data obtained suggest that the specificity of hexokinase isozyme II adsorption depends on the structural peculiarities of the protein but not on those of the mitochondrial membrane.


Remote transport of high-dimensional orbital angular momentum states and ghost images via spatial-mode-engineered frequency conversion.
The efficient transport and engineering of photonic orbital angular momentum (OAM) lie at the heart of various related classical and quantum applications. Here, by leveraging the spatial-mode-engineered frequency conversion, we realize the remote transport of high-dimensional orbital angular momentum (OAM) states between two distant parties without direct transmission of information carriers. We exploit perfect vortices for preparing high-dimensional yet maximal O AM entanglement. Based on nonlinear sum-frequency generation working with a strong coherent wave packet and a single photon, we conduct the Bell-like state measurements for high-dimensional perfect vortices. We experimentally achieve an average transport fidelity 0.879 ± 0.048 and 0.796 ± 0.066 for a complete set of 3-dimensional and 5-dimensional OAM mutually unbiased bases, respectively. Furthermore, by exploring the full transverse entanglement, we construct another strategy of quantum imaging with interaction-free light. It is expected that, with the future advances in nonlinear frequency conversion, our scheme will pave the way for realizing truly secure high-dimensional quantum teleportation in the upcoming quantum network.


Donor Skeletal Muscle Quality Affects Graft Mortality After Living Donor Liver Transplantation- A Single Center, Retrospective Study.
The recipient muscle status is closely associated with postoperative poor survival in recipients of living donor liver transplantation (LDLT). However, it is uncertain whether LDLT donor muscle quality and quantity affect graft quality. Hence, we analyzed the correlation between donor muscle status and graft function. We measured the skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) of 380 LDLT donors. We examined the correlation between donor SMI or IMAC and graft mortality, the occurrence rates of small-for-size graft (SFSG) syndrome, and 6-month graft survival rates. The donor SMI had no effect on the occurrence of SFSG syndrome and graft survival, while a high IMAC in both male and female donors was significantly correlated with the rate of SFSG syndrome [high vs low: (male donors) 15.8% vs. 2.5%, p = 0.0003; (female donors) 12.8% vs. 3.1%, p = 0.0234] and 6-month graft survival rates [(male donors) 87.7% vs 95.9%, p = 0.02; (female donors) 83.0% vs. 99.0%, p < 0.0001]. Multivariate analysis revealed that a high donor IMAC (HR; 5.42, CI; 2.13-13.8, p = 0.0004) was an independent risk factor for 6-month graft survival, and the donor IMAC is useful for donor selection for high-risk recipients.