Effect of sintering on the microstructural and mechanical properties of meleagris gallopova hydroxyapatite.
In this study, we obtained hydroxyapatite powders from the femur bones of meleagris gallopova at three steps and sintered at five different temperatures. The reactions, which occur during sintering of obtained powders, have been characterized by X-ray diffraction (XRD) patterns, scanning electron microscope (SEM), differential thermal analysis (DTA), thermo-gravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR) techniques. The mechanical properties of meleagris gallopova hydroxyapatite powders were determined by the measurements of density, hardness, porosity, activation energy for grain growth, variation of average grain sizes, fracture toughness and compression strength. The Fourier transform infrared spectra and the thermogravimetric analysis/differential thermal analysis thermograms of meleagris gallopova hydroxyapatite powders indicated that the presence of organic compounds were completely removed from the matrice. The X-ray diffraction patterns showed that decomposition of meleagris gallopova hydroxyapatite into tricalcium phosphate and calcium oxide was observed for the sintered samples at 1300°C. At the same temperature, formation of microcracks were also detected by scanning electron microscopy image. Mechanical tests showed that maximum hardness, fracture toughness and compression strength values were measured for the sintered samples at 1200°C.


[The problem of autolytic digestion at amniotropic and lactotropic feeding].
The review presented the results of the author, his co-workers and investigators of other laboratories about types of feeding (histotropic, hemotropic, amniotropic, lactotropic, definitive) and digestion (autolytic, native) of a fetus and an infant. The study was based on analysis of enzymes that provided hydrolysis of amniotic fluid and breast milk. The data about probable technology of abovementioned types of digestion in earlier stages of individual human advance and opportunity of hydrolase recretor origin in amniotic fluid and breast milk are shown.


Highly cis-1,4 Selective Living Polymerization of Unmasked Polar 2-(2-Methylidenebut-3-enyl)Furan and Diels-Alder Addition.
The polymerization of a new polar diene-based monomer 2-(2-methylidenebut-3-enyl)furan (MBEF) without masking is achieved by using the bis(phosphino)carbazoleide-ligated yttrium (Y) alkyl complex upon the activation of [Ph3 C][B(C6 F5 )4 ]. Under mild conditions, the polymerizations under the monomer-to-Y ratios ranging from 100:1 to 500:1 perform fluently in high yields. The afforded polydienes bearing pendant terminal furan groups have high cis-1,4-regularity up to 98.6% and molecular weights close to the theoretic values and narrow polymer dispersity index(PDI) (1.13-1.17) suggesting a livingness polymerization mode. In addition, this novel polydiene is an excellent building block for preparing functional rubber materials. For example, via Diels-Alder addition of furan groups under mild conditions, hydroxyl groups are successfully introduced on the side chains efficiently in a 75% conversion. Furthermore, the copolymerization of polar MBEF and nonpolar isoprene is also successfully realized by the bis(phosphino) carbazoleide-ligated scandium analog to access furan-modified cis-1,4 (>97%) polyisoprene with different MBEF contents (5.3%, 8.7%).


The influence of religiosity on health.
The relationship between religion and health has been a subject of interest in the past and in the latest years becoming increasingly visible in the social, behavioral, and health sciences. Among several approaches to be considered, the present work provides a briefly discuss concerning the bond between health and religiosity in the cure process and diseases treatment. Several investigations show that religious participation is related with better outcomes for persons who are recovering from physical and mental illness, also the psychology science have committed special issues to positive correlations between religious belief and practice, mental and physical health and longevity. On the other hand, religion may also be associated with negative outcomes and the inappropriate use of health services as fanaticism, asceticism, mortifications and oppressive traditionalism. The potential for both positive and negative effects of spirituality on health, combined with the high levels of engagement with spirituality suggests that this area is ripe for future sustained research. Independent of the possible mechanisms, if individuals receive health profits by the religion; those should be motivated, respecting the individual faith of each one.


Drug checking services at music festivals and events in a Canadian setting.
Drug checking is a harm reduction intervention that allows for identification of drug composition. The objective of the study was to assess drug market components and concordance between expected substance reported by clients and results from point-of-care drug checking at music festivals and events in British Columbia. From July to September 2018, we provided drug checking services at four events using combination Fourier Transform Infrared (FTIR) spectroscopy and fentanyl immunoassay strips. We measured concordance between expected substance as reported by clients to the results from the FTIR/fentanyl immunoassay strip and tracked unexpected adulterants. In total, 336 checks were completed. Most samples were expected by clients to be psychedelics (69.3%) or stimulants (19.6%). Of the 233 psychedelic samples, 169 (72.5%) contained the expected, unadulterated substance, and 27 (11.6%) contained additional contaminants. Of 66 stimulant samples, 41 (62.1%) contained expected substance, while 24 (36.4%) contained additional contaminants. Unexpected adulterants such as fentanyl, levamisole, and phenacetin were also found, in addition to several novel psychoactive substances. We found a large proportion of substances that contained unexpected adulterants. Our findings highlight the value of continued drug checking and will be helpful in designing future harm reduction interventions in similar contexts.


Nitrogen-15 and oxygen-18 characteristics of nitrous oxide: a global perspective.
The global budget of N(2)O shows a significant imbalance between the known rate of destruction in the stratosphere and the estimated rates of natural and anthropogenic production in soils and the ocean. Measurements of the (15)N/(14)N and (18)O/(16)O ratios in two major tropospheric sources of N(2)O, tropical rain forest soils and fertilized soils, show that soil N(2)O from a tropical rain forest in Costa Rica and from sugar-cane fields in Maui is strongly depleted in both (15)N and (18)O relative to mean tropospheric N(2)O. A major source of heavy N(2)O, enriched in both (15)N and (18)O, must therefore be present to balance the light N(2)O from soils. One such source is the back-mixing flux of N(2)O from the stratosphere, which is enriched in (15)N and (18)O by photolysis and chemistry. However these return fluxes of (15)N and (18)O are so great that a large oceanic flux of N(2)O is required to balance the heavy isotope-enriched stratospheric flux. All these effects will be reflected in climatically related isotopic variations in trapped N(2)O in polar ice cores.


Neighborhood Qualification of the Association Between Parenting and Problem Behavior Trajectories Among Mexican-Origin Father-Adolescent Dyads.
To address the combined importance of fathers and neighborhoods for adolescent adjustment, we examined whether associations between fathers' parenting and adolescents' problem behaviors were qualified by neighborhood adversity. We captured both mainstream (e.g., authoritative) and alternative (e.g., no-nonsense, reduced involvement) parenting styles and examined parenting and neighborhood effects on changes over time in problem behaviors among a sample of Mexican-origin father-adolescent dyads (N = 462). Compared to their counterparts in low-adversity neighborhoods, adolescents in high-adversity neighborhoods experienced greater initial benefits from authoritative fathering, greater long-term benefits from no-nonsense fathering, and fewer costs associated with reduced involvement fathering. The combined influences of alternative paternal parenting styles and neighborhood adversity may set ethnic and racial minority adolescents on different developmental pathways to competence.


Correlations between physiology and lifespan--two widely ignored problems with comparative studies.
Comparative differences between species provide a powerful source of information that may inform our understanding of the aging process. However, two problems regularly attend such analyses. The co-variation of traits with body mass is frequently ignored, along with the lack of independence of the data due to a shared phylogenetic history. These problems undermine the use of simple correlations between various factors and maximum lifespan potential (MLSP) across different species as evidence that the factors in question have causal effects on aging. Both of these problems have been widely addressed by comparative biologists working in fields other than aging research, and statistical solutions to these issues are available. Using these statistical approaches, of making analyses of residual traits with the effects of body mass removed, and deriving phylogenetically independent contrasts, will allow analyses of the relationships between physiology and maximum lifespan potential to proceed unhindered by these difficulties, potentially leading to many useful insights into the aging process.


Inhibition of adherence and cytotoxicity by circulating immune complexes formed in experimental filariasis.
Peritoneal exudate cells (PEC) from normal jirds (Meriones unguiculatus) showed adherence of Brugia pahangi microfilariae, and subsequent cytotoxicity in the presence of antimicrofilarial antisera. Heat inactivation of the antisera diminished both adherence and cytotoxicity, but readdition of fresh normal jird sera only partially restored the reactions. Macrophages were the predominant adherent cell type. Circulating immune complexes precipitated with polyethylene glycol (PEG) from the sera of jirds with an 8-month infection inhibited both of these reactions. Complement consumption by the precipitated complexes was found not to be the cause of inhibition. Blocking of adherence and cytotoxicity by circulating immune complexes may be preventing the trapping of microfilariae in vivo, and may play a role in the persistence of microfilaraemia in the jird.


Association of anxiety with subcortical amyloidosis in cognitively normal older adults.
Late-life anxiety has been associated with increased progression from normal cognition to amnestic MCI, suggesting that anxiety may be a neuropsychiatric symptom of Alzheimer's disease (AD) pathological changes and a possible marker of anatomical progression in preclinical AD. This study examined whether cortical or subcortical amyloidosis, indicating earlier or later stages of preclinical AD, was associated with greater self-reported anxiety among 118 cognitively normal volunteers, aged 65-90 years, and whether this association was stronger in APOEε4 carriers. Participants underwent Pittsburgh Compound B Positron Emission Tomography (PiB-PET) to assess fibrillar amyloid-β burden in cortical and subcortical regions, and measurement of anxiety using the Hospital Anxiety and Depression Scale-anxiety subscale. Higher PiB-PET measures in the subcortex (striatum, amygdala, and thalamus), but not in the cortex, were associated with greater anxiety, adjusting for demographics, cognition, and depression. Findings were similar using a cortico-striatal staging system and continuous PET measurements. Anxiety was highest in APOEε4 carriers with subcortical amyloidosis. This work supports in vivo staging of amyloid-β deposition in both cortical and subcortical regions as a promising approach to the study of neuropsychiatric symptoms such as anxiety in cognitively normal older individuals. Elevated anxiety symptoms in combination with high-risk biological factors such as APOEε4 and subcortical amyloid-β may identify participants closest to MCI for secondary prevention trials.


Incidence Patterns and Occupational Risk Factors of Human Brucellosis in Greece, 2004-2015.
Brucellosis is the most common bacterial zoonosis worldwide. Greece has the highest reported incidence among EU countries. However, occupational risk factors have not been well described. To determine the incidence patterns and exposure risk factors of brucellosis in Greece. We used national-level surveillance and occupational denominator data to estimate the incidence patterns and exposure risk factors of brucellosis in Greece, with particular emphasis on occupation. Between November 2003 and December 2015 a total of 2159 human brucellosis cases was reported. The mean incidence rate was 1.62 per 100 000 population per year. A large majority of cases (77.1%) reported consumption of unpasteurized milk or contact with livestock animals. Most cases occured in farmers and livestock breeders (1079 [87.7%] of 1231 cases reporting their occupation), corresponding to an annual incidence of 7.1 per 100 000. However, there were other occupations with a similar or higher risk: butchers and abattoir workers (12.7 per 100 000), laboratory personnel (3.1 per 100 000), while the highest risk was for veterinarians (53.2 per 100 000). Brucellosis incidence in specific occupational groups was much higher than in the general population. These results underline the importance of collecting information on occupation, both during the diagnostic process and in the surveillance system. Besides efforts to control brucellosis in animals, organized prevention efforts are needed within an occupational health framework, especially for the most vulnerable workers.


Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding.
We describe biochemical and structural studies of the isolated cystic fibrosis transmembrane conductance regulator (CFTR) protein. Using electron cryomicroscopy, low resolution three-dimensional structures have been obtained for the non-phosphorylated protein in the absence of nucleotide and for the phosphorylated protein with ATP. In the latter state, the cytosolic nucleotide-binding domains move closer together, forming a more compact packing arrangement. Associated with this is a reorganization within the cylindrical transmembrane domains, consistent with a shift from an inward-facing to outward-facing configuration. A region of density in the non-phosphorylated protein that extends from the bottom of the cytosolic regions up to the transmembrane domains is hypothesised to represent the unique regulatory region of CFTR. These data offer insights into the architecture of this ATP-binding cassette protein, and shed light on the global motions associated with nucleotide binding and priming of the chloride channel via phosphorylation of the regulatory region.


USE OF AN EXTRACARDIAC CONDUIT IN THE REPAIR OF l-TRANSPOSITION WITH l-LOOPING ASSOCIATED WITH SEVERE SUBVALVULAR PULMONIC STENOSIS AND A VENTRICULAR SEPTAL DEFECT.
Total correction was performed in a child with l-transposition of the great arteries, severe subpulmonic stenosis, and a ventricular septal defect. The subpulmonic obstruction was bypassed with an extra-cardiac valved conduit. This alternate method of relieving ventricular outflow obstruction should be considered when conventional techniques cannot be employed because of complex intracardiac anatomy. Proper placement of the pulmonary ventriculotomy is important in order to avoid injury to coronary arteries on the upper and lower ventricular wall and to papillary muscles in the mid-portion of the ventricle.


Role of thromboxane in control of arterial pressure and renal function in young spontaneously hypertensive rats.
As platelet and renal thromboxane (TX)A2 synthesis are increased in spontaneously hypertensive rats (SHR), we tested the hypothesis that increased renal TXA2 synthesis may cause the reduction in glomerular filtration rate (GFR), renal plasma flow (RPF), and the increase in arterial pressure in SHR of the Okamoto-Aoki strain. A selective inhibitor of TXA2 synthetase (UK 38485) was given acutely, with or without a TXA2 receptor antagonist (EP-092), to 6- to 8-wk-old SHR and age-matched Wistar-Kyoto rats (WKY) and chronically for 5.5 wk to 3.5-wk-old SHR. Inhibition of TXA2, measured by the stable metabolite TXB2, in the acute experiments was greater than 95% in serum and greater than 80% in glomeruli; in the chronic studies, it was greater than 65% in glomeruli. There was no endoperoxide shunting to vasodilatory and natriuretic prostaglandins (PGE2, PGI2) in glomeruli after TXA2 inhibition. Before drug administration, GFR and RPF were reduced and renal vascular resistance (RVR) was increased in SHR. During acute blockade of renal TXA2 synthesis, with or without a TXA2 receptor antagonist, there was no significant change in GFR, RPF, or RVR in WKY and SHR. Inhibition of TXA2 did not affect urine flow or sodium excretion in anesthetized or conscious WKY or SHR. Mean arterial pressure did not fall in treated SHR and WKY. Chronic TXA2 synthesis inhibition did not improve GFR or RPF in SHR, and systolic arterial pressure was not altered. These findings show that enhanced serum and glomerular TXA2 synthesis do not significantly contribute to the reduction in renal function and are not essential for the development of hypertension in young SHR.


Non-selective regulation of peroxide and superoxide resistance genes by PerR in Campylobacter jejuni.
Campylobacter jejuni is an important foodborne pathogen. The molecular mechanisms for the regulation of oxidative stress resistance have not yet been understood fully in this bacterium. In this study, we investigated how PerR (peroxide stress regulator) modulates the transcriptional regulation of both peroxide and superoxide resistance genes in C. jejuni, particularly under oxidative stress conditions. The transcriptional levels of ahpC, katA, and sodB were substantially increased by aeration and oxidant exposure. Interestingly, a perR mutation completely abrogated the transcriptional response of ahpC, katA and sodB to oxidants. Furthermore, we demonstrated that perR transcription was reduced by aeration and oxidant exposure. In contrast to the unique role of PerR homologs in peroxide stress regulation in other bacteria, C. jejuni PerR directly regulates the transcription of sodB, the most important gene in superoxide defense, as evidenced by the alteration of sodB transcription by the perR mutation and direct binding of rPerR to the sodB promoter. In addition, we also observed notable morphological changes in C. jejuni from spiral rods to cocoid morphology under aerobic conditions. Based on the intracellular ATP levels, C. jejuni entered a viable-but-non-culturable (VBNC) state under aerobic conditions. These findings clearly demonstrate that C. jejuni possesses a unique regulatory mechanism of oxidative stress defense that does not specifically distinguish between peroxide and superoxide defense, and PerR plays a pivotal role in this non-selective regulation of oxidative stress resistance in C. jejuni.


Regional and age-related variations in the proportions of hip fractures and major fractures among postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women.
We examined variations in proportions of hip fractures and major fractures among postmenopausal women using the Global Longitudinal Study of Osteoporosis in Women (GLOW). The proportion of major fractures that were hip fractures varied with age and region, whereas variations in the proportion of fractures that were major fractures appeared modest. In many countries, the World Health Organization fracture risk assessment tool calculates the probability of major fractures by assuming a uniform age-associated proportion of major fractures that are hip fractures in different countries. We further explored this assumption, using data from the GLOW. GLOW is an observational population-based study of 60,393 non-institutionalized women aged ≥55 years who had visited practices within the previous 2 years. Main outcome measures were self-reported prevalent fractures after the age of 45 years and incident fractures during the 2 years of follow-up. The adjusted proportion of prevalent and incident major fractures after the age of 45 years that were hip fractures was higher in North America (16%, 17%) than in northern (13%, 12%) and southern Europe (10%, 10%), respectively. The proportion of incident major fractures that were hip fractures increased more than five-fold with age, from 6.6% among 55-59-year-olds to 34% among those aged ≥85 years. Regional and age-associated variations in the proportion of all incident fractures that were major fractures were less marked, not exceeding 16% and 28%, respectively. The data suggest that there may be regional differences in the proportion of major fractures that are hip fractures in postmenopausal women. In contrast, the regional and age-related variations in the proportion of fractures that are major fractures appear to be modest. However, because of the limited number of fractures in our sample, further studies are necessary to confirm these findings.


Patient-reported outcomes from a randomized phase III trial of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis.
The phase III MONARCH randomized controlled trial (NCT02332590) demonstrated that in patients with rheumatoid arthritis (RA), sarilumab (anti-interleukin-6 receptor monoclonal antibody) monotherapy is superior to adalimumab monotherapy in reducing disease activity and signs and symptoms of RA, as well as in improving physical function, with similar rates of adverse and serious adverse events. We report the effects of sarilumab versus adalimumab on patient-reported outcomes (PROs). Patients with active RA intolerant of, or inadequate responders to, methotrexate were randomized to sarilumab 200 mg plus placebo every 2 weeks (q2w; n = 184) or adalimumab 40 mg plus placebo q2w (n = 185). Dose escalation to weekly administration of adalimumab or matching placebo was permitted at week 16. PROs assessed at baseline and weeks 12 and 24 included patient global assessment of disease activity (PtGA), pain and morning stiffness visual analogue scales (VASs), Health Assessment Questionnaire Disability Index (HAQ-DI), 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Rheumatoid Arthritis Impact of Disease (RAID), and rheumatoid arthritis-specific Work Productivity Survey (WPS-RA). Between-group differences in least-squares mean (LSM) changes from baseline were analyzed. p < 0.05 was considered significant for PROs in a predefined hierarchy. For PROs not in the hierarchy, nominal p values are provided. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) and achieving normative values were assessed. At week 24, sarilumab treatment resulted in significantly greater LSM changes from baseline than adalimumab monotherapy in HAQ-DI (p < 0.005), PtGA (p < 0.001), pain VAS (p < 0.001), and SF-36 Physical Component Summary (PCS) (p < 0.001). Greater LSM changes were reported for sarilumab than for adalimumab in RAID (nominal p < 0.001), morning stiffness VAS (nominal p < 0.05), and WPS-RA (nominal p < 0.005). Between-group differences in FACIT-F and SF-36 Mental Component Summary (MCS) were not significant. More patients reported improvements greater than or equal to the MCID in HAQ-DI (nominal p < 0.01), RAID (nominal p < 0.01), SF-36 PCS (nominal p < 0.005), and morning stiffness (nominal p < 0.05), as well as greater than or equal to the normative values in HAQ-DI (p < 0.05), with sarilumab versus adalimumab. In parallel with the clinical efficacy profile previously reported, sarilumab monotherapy resulted in greater improvements across multiple PROs than adalimumab monotherapy. ClinicalTrials.gov, NCT02332590 . Registered on 5 January 2015.


The role of viral integration in the development of cervical cancer.
The development of invasive cervical cancer is associated with human papillomavirus (HPV) infection and subsequent integration into the host epithelium. More than 99% of cervical cancers contain HPV sequences, and many of these contain a truncated HPV genome integrated into a single position within the host genome. Studies examining the role of viral integration in cervical cancer development have found that the sites of integration appear randomly distributed throughout the genome. This, and the observation that it frequently takes years after HPV infection for cervical cancer to develop, has led to the current paradigm that the site of HPV integrations is unimportant to the invasive cervical cancer that eventually develops. In our previous studies of HPV16 and HPV18 integration in cervical cancers, we also found integrations throughout the genome, but observed as well that more than half of the integrations occurred within common fragile site regions. To determine if HPV integration might play an important role in cervical cancer, we conducted two complementary studies. We first localized 40 new HPV16 integration sites from cervical tumors from women in Hong Kong; this, together with previous integration studies, provided a better picture of the distribution of integration sites throughout the genome. We then analyzed the sites of viral integration in an in vitro model of HPV integration. By comparing the sites of HPV integration in vivo (in multiple primary cervical tumors) to those obtained in vitro, the data can help to determine if HPV integrations observed in vivo are the result of random and nonselected integrations.


Vancomycin-Loaded Nanoparticles Enhance Sporicidal and Antibacterial Efficacy for Clostridium difficile Infection.
Current antibiotic treatments fail to eliminate the Clostridium difficile (C. difficile) spores and induce dysbiosis and intestinal inflammation via off-target effect, which causes refractory C. difficile infection raise an unmet need for a spore-specific antimicrobial treatment. We developed a sporicidal and antimicrobial vancomycin-loaded spore-targeting iron oxide nanoparticle (van-IONP) that selectively binds to C. difficile spores. Cryo-electron microscopy showed that vancomycin-loaded nanoparticles can target and completely cover spore surfaces. They not only successfully delayed the germination of the spores but also inhibited ∼50% of vegetative cell outgrowth after 48 h of incubation. The van-IONPs also inhibited the interaction of spores with HT-29 intestinal mucosal cells in vitro. In a murine model of C. difficile infection, the van-IONP significantly protected the mice from infected by C. difficile infection, reducing intestinal inflammation, and facilitated superior mucosal viability compared with equal doses of free vancomycin. This dual-function targeted delivery therapy showed advantages over traditional therapeutics in treating C. difficile infection.


Control of leaf and vein development by auxin.
Leaves are the main photosynthetic organs of vascular plants and show considerable diversity in their geometries, ranging from simple spoon-like forms to complex shapes with individual leaflets, as in compound leaves. Leaf vascular tissues, which act as conduits of both nutrients and signaling information, are organized in networks of different architectures that usually mirror the surrounding leaf shape. Understanding the processes that endow leaves and vein networks with ordered and closely aligned shapes has captured the attention of biologists and mathematicians since antiquity. Recent work has suggested that the growth regulator auxin has a key role in both initiation and elaboration of final morphology of both leaves and vascular networks. A key feature of auxin action is the existence of feedback loops through which auxin regulates its own transport. These feedbacks may facilitate the iterative generation of basic modules that underlies morphogenesis of both leaves and vasculature.


Compatibility of true and virtual unenhanced attenuation in rapid kV-switching dual energy CT.
We aimed to evaluate whether virtual unenhanced images (VUI) generated from nephrographic phase on rapid kV-switching dual energy CT (rsDECT) can replace true unenhanced images (TUI) by comparing attenuation values of various intraabdominal structures. In this retrospective study, 142 patients had unenhanced and nephrographic phase dual energy CT images. Attenuation values of the aorta, liver,spleen, pancreas, bilateral renal parenchyma, inferior vena cava, gallbladder and paraspinal muscle on TUI and VUI were recorded. Frequencies of organs who had more than 10 and 20 HU of attenuation difference were also calculated. A total of 1224 ROIs were sampled. No statistically significant differences were found between TUA and VUA of the aorta, spleen and pancreas. The other structures had significant differences (P < 0.001). Correlation between measurements were weak to moderate (r=0.17-0.72). 20% of organs had more than 10 HU difference and 5% had more than 20 HU difference between TUI and VUI. rsDECT based VUI does not seem to be an ideal surrogate for TUI.


In vitro macrophage manifestation of cortisone-induced decrease in resistance to mouse hepatitis virus.
Genetically resistant G3H mice routinely yielded macrophages that were resistant when grown in 90% horse serum. These mice also routinely yielded macrophages that were susceptible to the same virus, MHV (PRI), in vitro after the mice had been treated with three intraperitoneal doses, of hydrocortisone. Dexamethasone and prednisolone when similarly administered also increased the susceptibility of C3H macrophages taken from the treated animal, but progesterone and testosterone did not. In addition, spleen cells from mice treated with cortisone made the resistant C3H macrophages 100 times more susceptible in vitro. Increased in vitro susceptibility induced in this way by hydrocortisone was reversed by exposure to supernatant fluid removed from cultures of concanavalin A-treated spleen cells.


Differences in degree, differences in kind: characterizing lung injury in trauma.
Acute lung injury following trauma remains a significant source of morbidity and mortality. Although multiple trauma studies have used hypoxemia without radiographic adjudication as a surrogate for identifying adult respiratory distress syndrome (ARDS) cases, the differences between patients with hypoxemia alone and those with radiographically confirmed ARDS are not well described in the literature. We hypothesized that nonhypoxemic, hypoxemic, and ARDS patients represent distinct groups with unique characteristics and predictors. Laboratory, demographic, clinical, and outcomes data were prospectively collected from 621 intubated, critically injured patients at an urban Level 1 trauma center from 2005 to 2013. Hypoxemia was defined as PaO2/FIO2 ratio of 300 or lower. ARDS was adjudicated using Berlin criteria, with blinded two-physician consensus review of chest radiographs. Group comparisons were performed by hypoxemia and ARDS status. Logistic regression analyses were performed to separately assess predictors of hypoxemia and ARDS. Of the 621 intubated patients, 64% developed hypoxemia; 46% of these hypoxemic patients developed ARDS by chest radiograph. Across the three groups (no hypoxemia, hypoxemia, ARDS), there were no significant differences in age, sex, or comorbidities. However, there was an increase in severity of shock, injury, and chest injury by group, with corresponding trends in transfusion requirements and volume of early fluid administration. Outcomes followed a similar stepwise pattern, with pneumonia, multiorgan failure, length of intensive care unit stay, number of ventilator days, and overall mortality highest in ARDS patients. In multiple logistic regression, early plasma transfusion, delayed crystalloid administration, body mass index, and head and chest injury were independent predictors of hypoxemia, while head and chest injury, early crystalloid infusion, and delayed platelet transfusion were independent predictors of ARDS. Hypoxemia and ARDS exist on a spectrum of respiratory dysfunction following trauma, with increasing injury severity profiles and resuscitation requirements. However, they also represent distinct clinical states with unique predictors, which require directed research approaches and targeted therapeutic strategies. Prognostic and epidemiologic study, level III.


Windswept lower limb deformities in patients with hypophosphataemic rickets.
X-linked hypophosphataemic rickets is an X-linked dominant disorder that is secondary to renal phosphate-wasting. Genu varum and/or genu valgum have been described as the most common deformities in patients with hypophosphataemic rickets. Windswept deformity, which is valgus deformity in one knee and varus deformity in the other, was the most common deformity encountered in our department. We collected seven patients who had phenotypic and genotypic features consistent with the diagnosis of X-linked hypophosphataemic rickets. All presented with windswept lower limb deformity. We discuss the phenotypic and genotypic correlation, and the surgical procedures applied. Surgical interventions were scheduled to correct the triad of appearance, function and biomechanics. Re-alignment orthopaedic measures were applied to correct and to restore normal growth and development in these children. Post-operative measurements showed dramatic improvements in balance and gait. The most common deformity seen in patients with hypophosphataemic rickets is gradual anetrolateral bowing of the femur combined with tibia vara. Windswept lower limb deformity was the most common angular deformity in our patients with hypophosphataemic rickets. Baseline skeletal surveys and genotypic characterisation were subject to close scrutiny and assessment, with the aim of proper diagnosis and treatment. Nevertheless, recurrence of deformity is a common sequel and younger patients have a higher risk for recurrence.


[Morbidity of young people in the rural population].
The morbidity of rural young people is analyzed from the rate of consultations at treatment-and-prophylaxis institutions and data of comprehensive medical check-ups. The aggravation index was estimated for patients with chronic diseases in the studied population, which provided additional information. The age/sex aggravation indexes of the population extend the current methodological approaches to complex evaluation of population health and serve as additional information in evaluation of the need in different types of care.


Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families.
The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early-onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early-onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early-onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor-type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young-onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.


Neutral gas sympathetic cooling of an ion in a Paul trap.
A single ion immersed in a neutral buffer gas is studied. An analytical model is developed that gives a complete description of the dynamics and steady-state properties of the ions. An extension of this model, using techniques employed in the mathematics of economics and finance, is used to explain the recent observation of non-Maxwellian statistics for these systems. Taken together, these results offer an explanation of the long-standing issues associated with sympathetic cooling of an ion by a neutral buffer gas.


Risk indicators for severe impaired oral health among indigenous Australian young adults.
Oral health impairment comprises three conceptual domains; pain, appearance and function. This study sought to: (1) estimate the prevalence of severe oral health impairment as assessed by a summary oral health impairment measure, including aspects of dental pain, dissatisfaction with dental appearance and difficulty eating, among a birth cohort of Indigenous Australian young adults (n = 442, age range 16-20 years); (2) compare prevalence according to demographic, socio-economic, behavioural, dental service utilisation and oral health outcome risk indicators; and (3) ascertain the independent contribution of those risk indicators to severe oral health impairment in this population. Data were from the Aboriginal Birth Cohort (ABC) study, a prospective longitudinal investigation of Aboriginal individuals born 1987-1990 at an Australian regional hospital. Data for this analysis pertained to Wave-3 of the study only. Severe oral health impairment was defined as reported experience of toothache, poor dental appearance and food avoidance in the last 12 months. Logistic regression models were used to evaluate effects of demographic, socio-economic, behavioural, dental service utilisation and clinical oral disease indicators on severe oral health impairment. Effects were quantified as odds ratios (OR). The percent of participants with severe oral health impairment was 16.3 (95% CI 12.9-19.7). In the multivariate model, severe oral health impairment was associated with untreated dental decay (OR 4.0, 95% CI 1.6-9.6). In addition to that clinical indicator, greater odds of severe oral health impairment were associated with being female (OR 2.0, 95% CI 1.2-3.6), being aged 19-20 years (OR 2.1, 95% CI 1.2-3.6), soft drink consumption every day or a few days a week (OR 2.6, 95% 1.2-5.6) and non-ownership of a toothbrush (OR 1.9, 95% CI 1.1-3.4). Severe oral health impairment was prevalent among this population. The findings suggest that public health strategies that address prevention and treatment of dental disease, self-regulation of soft drink consumption and ownership of oral self-care devices are needed if severe oral health impairment among Indigenous Australian young adults is to be reduced.


Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism.
Mutations in the daf-2 gene of the conserved Insulin/Insulin-like Growth Factor (IGF-1) pathway double the lifespan of the nematode Caenorhabditis elegans. This phenotype is completely suppressed by deletion of Forkhead transcription factor daf-16. To uncover regulatory mechanisms coordinating this extension of life, we employed a quantitative proteomics strategy with daf-2 mutants in comparison with N2 and daf-16; daf-2 double mutants. This revealed a remarkable longevity-specific decrease in proteins involved in mRNA processing and transport, the translational machinery, and protein metabolism. Correspondingly, the daf-2 mutants display lower amounts of mRNA and 20S proteasome activity, despite maintaining total protein levels equal to that observed in wild types. Polyribosome profiling in the daf-2 and daf-16;daf-2 double mutants confirmed a daf-16-dependent reduction in overall translation, a phenotype reminiscent of Dietary Restriction-mediated longevity, which was independent of germline activity. RNA interference (RNAi)-mediated knockdown of proteins identified by our approach resulted in modified C. elegans lifespan confirming the importance of these processes in Insulin/IGF-1-mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF-1-mediated extension of life.


Time-resolved immunofluorometric assay for the ovarian carcinoma-associated antigenic determinant CA 125 in serum.
A time-resolved immunofluorometric assay (IFMA) is described for quantifying the ovarian carcinoma-associated antigenic determinant CA 125 in human serum. Monoclonal antibody to CA 125 is immobilized onto a microtiter well, and the same antibody labeled with a europium chelate is used as a tracer. After the immunoreaction the bound portion of the labeled antibody is quantified by dissociating the Eu3+ in a fluorescence-enhancement solution and measuring its fluorescence with a time-resolved fluorometer. The detection limit of the IFMA is 1.5 arb. units/mL, being about the same as that of a commercially available immunoradiometric assay (IRMA) for CA 125 (1.4 arb. units/mL). The analytical range of the IFMA extends to 2000 arb. units/mL, whereas the range of the IRMA is 500 arb. units/mL. For 29 serum samples from ovarian-cancer patients measured simultaneously in the IFMA and IRMA, orthogonal regression analysis gave the equation CA 125 (IFMA) = 0.9937 CA 125 (IRMA) - 1.211 arb. units/mL (Syx = 6.8681, r = 0.9932). Apparently, the IFMA for CA 125 is a convenient alternative to the IRMA for CA 125 because of short counting times, the use of nonradioactive, stable reagents, and the much-extended measuring range. Additionally, the microtiter format should lend itself to more fully automated procedures in laboratories doing many such analyses.


The role of carbapenem-resistant pathogens in cSSTI and how to manage them.
Skin and soft tissue infections (SSTIs) with a wide spectrum of disease severity ranging from uncomplicated to potentially lethal are still a leading cause of morbidity and mortality. The burden of carbapenem-resistant gram-negative bacteria (CR-GNB) in SSTIs is increasing. Luckily, the armamentarium of drugs available is recently expanding as well. The present review looks at data on the role CR-GNB in SSTIs and on the old and new drugs available for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, and Acinetobacter. The most recent information concern the availability of new antibiotics that, even if no specific clinical trials on complicated SSTIs (cSSTIs) have been performed, may play a role in clinical practice also for the treatment of cSSTIs caused by CR-GNB. Ceftolozane-tazobactam has been found to be a good option for CR Pseudomonas infections including SSTIs. Ceftazidime-avibactam is approved for several indications, including aerobic GNB infections with limited treatment options. Meropenem-vaborbactam therapy has been associated with decreased mortality in infections caused by CRE. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter for which the treatment options are limited. In the carbapenem resistance era, the physicians goal should be to stratify patients according to risk factors for CR-GNB causing SSTIs in order to minimize inappropriate initial therapies. Some recently approved drugs seem destined to become the backbone of target therapy in patients with severe infections caused by susceptible CR-GNB strains. Prompt diagnosis of cSSTIs is crucial and, when feasible, surgical debridement as source control is essential as well.


Impact of improved cookstoves on women's and child health in low and middle income countries: a systematic review and meta-analysis.
Improved biomass cookstoves may help reduce the substantial global burden of morbidity and mortality due to household air pollution (HAP) that disproportionately affects women and children in low and middle income countries (LMICs). Systematic review and meta-analysis of (quasi-)experimental studies identified from 13 electronic databases (last update: 6 April 2018), reference and citation searches and via expert consultation. LMICs PARTICIPANTS: Women and children INTERVENTIONS: Improved biomass cookstoves MAIN OUTCOME MEASURES: Low birth weight (LBW), preterm birth, perinatal mortality, paediatric acute respiratory infections (ARIs) and COPD among women. We identified 53 eligible studies, including 24 that met prespecified design criteria. Improved cookstoves had no demonstrable impact on paediatric lower ARIs (three studies; 11 560 children; incidence rate ratio (IRR)=1.02 (95% CI 0.84 to 1.24)), severe pneumonia (two studies; 11 061 children; IRR=0.88 (95% CI 0.39 to 2.01)), LBW (one study; 174 babies; OR=0.74 (95% CI 0.33 to 1.66)) or miscarriages, stillbirths and infant mortality (one study; 1176 babies; risk ratio (RR) change=15% (95% CI -13 to 43)). No (quasi-)experimental studies assessed preterm birth or COPD. In observational studies, improved cookstoves were associated with a significant reduction in COPD among women: two studies, 9757 participants; RR=0.74 (95% CI 0.61 to 0.90). Reductions in cough (four studies, 1779 participants; RR=0.72 (95% CI 0.60 to 0.87)), phlegm (four studies, 1779 participants; RR=0.65 (95% CI 0.52 to 0.80)), wheezing/breathing difficulty (four studies; 1779 participants; RR=0.41 (95% CI 0.29 to 0.59)) and conjunctivitis (three studies, 892 participants; RR=0.58 (95% CI 0.43 to 0.78)) were observed among women. Improved cookstoves provide respiratory and ocular symptom reduction and may reduce COPD risk among women, but had no demonstrable child health impact. PROSPERO: CRD42016033075.


Variations of Occipital Artery-Posterior Inferior Cerebellar Artery Bypass: Anatomic Consideration.
Advances in diagnosis of posterior inferior cerebellar artery (PICA) aneurysms have revealed the high frequency of distal and/or dissecting PICA aneurysms. Surgical treatment of such aneurysms often requires revascularization of the PICA including but not limited to its caudal loop. To examine the microsurgical anatomy involved in occipital artery (OA)-PICA anastomosis at various anatomic segments of the PICA. Twenty-eight PICAs in 15 cadaveric heads were examined with the operating microscope to take morphometric measurements and explore the specific anatomy of bypass procedures. OA bypass to the p2, p3, p4, or p5 segment was feasible with a recipient vessel of sufficient diameter. The loop wandering near the jugular foramen in the p2 segment provided sufficient length without requiring cauterization of any perforating arteries to the brainstem. Wide dissection of the cerebellomedullary fissure provided sufficient exposure for the examination of some p3 segments and all p4 segments hidden by the tonsil. OA-p5 bypass was placed at the main trunk before the bifurcation in 5 hemispheres and at the larger hemispheric trunk in others. Understanding the possible variations of OA-PICA bypass may enable revascularization of the appropriate portion of the PICA when the parent artery must be occluded. A detailed anatomic understanding of each segment clarifies important technical nuances for the bypass on each segment. Dissection of the cerebellomedullary fissure helps to achieve sufficient exposure for the bypass procedures on most of the segments.


Molecular mechanisms underlying IL-4-induced leukocyte recruitment in vivo: a critical role for the alpha 4 integrin.
IL-4 is known to induce recruitment of eosinophils and mononuclear leukocytes. In vitro this occurs in part by selective expression of VCAM-1, the ligand for the alpha 4 integrin. The objective of this study was to determine the molecular mechanisms that underlie IL-4-induced leukocyte recruitment in vivo. Mice received an intrascrotal injection of IL-4 (100 ng). Twenty-four hours later, leukocyte rolling, adhesion, and emigration in cremasteric postcapillary venules were examined via intravital microscopy, and expression of VCAM-1 and P- and E-selectin was quantitated using a radiolabeled mAb technique. IL-4 increased VCAM-1 expression, but P-selectin and E-selectin remained at constitutive levels. IL-4 induced significant increases in leukocyte adhesion and emigration, with 50% of the emigrated cells being eosinophils and the remainder being mononuclear leukocytes. Leukocyte rolling in IL-4-treated mice was >95% inhibitable using an anti-P-selectin Ab. However, IL-4-induced leukocyte recruitment was unaltered in mice treated chronically with P-selectin Ab or mice deficient in either P-selectin or P- and E-selectin, suggesting that the residual rolling supported all of the IL-4-induced recruitment. In IL-4-treated mice following P-selectin blockade, tethering and rolling were not dependent on L-selectin, but were abolished by alpha 4 integrin blockade. These findings show that the alpha 4 integrin can initiate leukocyte-endothelial cell interactions in the absence of selectins under shear conditions in vivo, and that the absence of selectins does not affect recruitment of eosinophils and mononuclear cells to IL-4-treated tissue.


Interpreting expressive performance through listener judgments of musical tension.
This study examines listener judgments of musical tension for a recording of a Schubert song and its harmonic reduction. Continuous tension ratings collected in an experiment and quantitative descriptions of the piece's musical features, include dynamics, pitch height, harmony, onset frequency, and tempo, were analyzed from two different angles. In the first part of the analysis, the different processing timescales for disparate features contributing to tension were explored through the optimization of a predictive tension model. The results revealed the optimal time windows for harmony were considerably longer (~22 s) than for any other feature (~1-4 s). In the second part of the analysis, tension ratings for the individual verses of the song and its harmonic reduction were examined and compared. The results showed that although the average tension ratings between verses were very similar, differences in how and when participants reported tension changes highlighted performance decisions made in the interpretation of the score, ambiguity in tension implications of the music, and the potential importance of contrast between verses and phrases. Analysis of the tension ratings for the harmonic reduction also provided a new perspective for better understanding how complex musical features inform listener tension judgments.


The immediate effects of a novel auditory and proprioceptive training device on gait after stroke.
This case report describes the immediate effects of a new rehabilitation tool on gait in a chronic stroke patient. Specifically, we measured step length symmetry and gait velocity in a 47 year-old male stroke patient who was currently receiving outpatient physical therapy. Objective gait measurements were taken using the GAITRite before, during, and after a 5 minute training session. Step length symmetry improved 26% during the first minute of training, 71% by the fifth minute of training, and 72% after a 5 minute rest period post-training. Gait velocity increased by 5.5% after 5 minutes of training. Clinical research is warranted to validate this new training tool as a useful adjunctive rehabilitation activity for improving spatial and temporal aspects of gait after stroke.


Effect of ethanol on muscarinic receptor-induced calcium responses in astroglia.
The effects of ethanol on muscarinic receptor-mediated calcium responses were investigated in individual primary rat astrocytes and human 132 1N1 astrocytoma cells using indo-1/AM and image cytometry. After a 30-min incubation, carbachol-induced calcium responses were inhibited only at 100 or 250 mM ethanol. The effects of ethanol were more pronounced and occurred at lower concentrations with longer exposures, with significant inhibition seen at 10 mM following a 24-hr incubation. Thapsigargin- and glutamate-induced responses were unaffected by ethanol, indicating some selectivity in this inhibition. Upon removal of ethanol, inhibition of calcium responses persisted for up to 6-12 hr, with carbachol responses returning to control levels by 24 hr after washout. Ethanol exposure did not affect muscarinic-receptor binding in astrocytoma cells, but inhibited carbachol-induced IP(3) formation. Inhibition of (3)H-thymidine incorporation by ethanol also persisted upon removal of the alcohol, with a time-dependency similar to that of the calcium responses. These results indicate that ethanol inhibits muscarinic receptor-induced calcium responses in astroglia in a concentration- and duration-dependent manner. They also show that co-incubation with ethanol is not necessary for this effect, suggesting that long-term exposure to ethanol may modify, in a reversible manner, the coupling of muscarinic receptors with its effector. This effect of ethanol may play a role in ethanol's inhibition of carbachol-induced thymidine incorporation.


Context matters when striving to promote active and lifelong learning in medical education.
WHERE DO WE STAND NOW?: In the 30 years that have passed since The Edinburgh Declaration on Medical Education, we have made tremendous progress in research on fostering 'self-directed and independent study' as propagated in this declaration, of which one prime example is research carried out on problem-based learning. However, a large portion of medical education happens outside of classrooms, in authentic clinical contexts. Therefore, this article discusses recent developments in research regarding fostering active learning in clinical contexts. Clinical contexts are much more complex and flexible than classrooms, and therefore require a modified approach when fostering active learning. Recent efforts have been increasingly focused on understanding the more complex subject of supporting active learning in clinical contexts. One way of doing this is by using theory regarding self-regulated learning (SRL), as well as situated learning, workplace affordances, self-determination theory and achievement goal theory. Combining these different perspectives provides a holistic view of active learning in clinical contexts. ENTRY TO PRACTICE, VOCATIONAL TRAINING AND CONTINUING PROFESSIONAL DEVELOPMENT: Research on SRL in clinical contexts has mostly focused on the undergraduate setting, showing that active learning in clinical contexts requires not only proficiency in metacognition and SRL, but also in reactive, opportunistic learning. These studies have also made us aware of the large influence one's social environment has on SRL, the importance of professional relationships for learners, and the role of identity development in learning in clinical contexts. Additionally, research regarding postgraduate lifelong learning also highlights the importance of learners interacting about learning in clinical contexts, as well as the difficulties that clinical contexts may pose for lifelong learning. However, stimulating self-regulated learning in undergraduate medical education may also make postgraduate lifelong learning easier for learners in clinical contexts.


HLA-B∗44 Is Associated with Dengue Severity Caused by DENV-3 in a Brazilian Population.
Human leukocyte antigen (HLA) alleles have been correlated with susceptibility or resistance to severe dengue; however, few immunogenetic studies have been performed in Latin American (LA) populations. We have conducted immunogenetic studies of HLA class I and II alleles in a cohort of 187 patients with DENV-3 infection and confirmed clinical diagnosis of either severe dengue, known as dengue hemorrhagic fever (DHF), or the less severe form, dengue fever (DF), in Recife, Pernambuco, Brazil. An association analysis was performed using Fisher's association test, with odds ratios (ORs) calculated using conditional maximum likelihood estimates. HLA-B∗44 (P = 0.047, OR = 2.025, 95% CI = 0.97-4.24) was found to be associated with increased susceptibility to DHF in response to DENV-3 infection. In addition, HLA-B∗07 (P = 0.048, OR = 0.501, one-sided 95% CI = 0-0.99) and HLA-DR∗13 (P = 0.028, OR = 0.511, one-sided 95% CI = 0-0.91) were found to be associated with resistance to secondary dengue infection by DENV-3. These results suggest that HLA-B∗44 supertype alleles and their respective T-cell responses might be involved in susceptibility to severe dengue infections, whereas the HLA-B∗07 supertype alleles and DR∗13 might be involved in cross-dengue serotype immunity.


Unraveling public perceptions of the Sustainable Development Goals for better policy implementation.
Public participation is crucial for policy-making and can contribute to strengthening democracies and decision-making. Public participation can help to address sustainability challenges and plays a key role in attaining the Sustainable Development Goals (SDGs). While the SDGs are policy concepts, there has been limited research conducted on how the public perceives the SDGs. Public participation in scientific research has been carried out through citizen science (CS). This paper analyzes the public's perception of the SDGs through CS and how the public can participate in their implementation. The paper uses the OSDG community platform, a citizen science platform with >2000 participants, to analyze public perception of the SDGs. A set of 40,062 excerpts of text (v2023-01-01), a topic modeling and agreement scores by using CorTexT Manager software, was analyzed. The results show that some SDGs, e.g. health (SDG3) or life below water (SDG14), have higher levels of agreement from the public, whilst for other SDGs the public disagree on their perception, (e.g. zero hunger). The paper shows that issues affecting citizens' daily lives (e.g. in People related goals) tend to have a higher level of agreement among volunteers, while economic issues and directives have greater discrepancies. The results provide an overview of the differences in public perception on the SDGs and their implementation. The misperceptions regarding the SDGs should be reduced to achieve a better implementation, improve public participation, and help policy-making processes.


Nitric oxide inhibits isoproterenol-stimulated adipocyte lipolysis through oxidative inactivation of the beta-agonist.
Nitric oxide has been implicated in the inhibition of catecholamine-stimulated lipolysis in adipose tissue by as yet unknown mechanisms. In the present study, it is shown that the nitric oxide donor, 2,2-diethyl-1-nitroso-oxyhydrazine, antagonized isoproterenol (isoprenaline)-induced lipolysis in rat adipocytes, freshly isolated from white adipose tissue, by decreasing the potency of the beta-agonist without affecting its efficacy. These data suggest that nitric oxide did not act downstream of the beta-adrenoceptor but reduced the effective concentration of isoproterenol. In support of the latter hypothesis, we found that pre-treatment of isoproterenol with nitric oxide abolished the lipolytic activity of the catecholamine. Spectroscopic data and HPLC analysis confirmed that the nitric oxide-mediated inactivation of isoproterenol was in fact because of the modification of the catecholamine through a sequence of oxidation reactions, which apparently involved the generation of an aminochrome. Similarly, aminochrome was found to be the primary product of isoproterenol oxidation by 3-morpholinosydnonimine and peroxynitrite. Finally, it was shown that nitric oxide released from cytokine-stimulated adipocytes attenuated the lipolytic effect of isoproterenol by inactivating the catecholamine. In contrast with very recent findings, which suggest that nitric oxide impairs the beta-adrenergic action of isoproterenol through intracellular mechanisms and not through a chemical reaction between NO and the catecholamine, we showed that nitric oxide was able to attenuate the pharmacological activity of isoproterenol in vitro as well as in a nitric oxide-generating cellular system through oxidation of the beta-agonist. These findings should be taken into account in both the design and interpretation of studies used to investigate the role of nitric oxide as a modulator of isoproterenol-stimulated signal transduction pathways.


Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies.
A study from five hepatology units documenting 157 cases of drug-induced hepatitis and a second study from a laboratory of immunology which tested more than 100,000 sera permitted us to establish the frequency of antiorganelle antibodies and their diagnostic value in drug-induced hepatitis. In drug-induced hepatitis caused by a heterogenous group of drugs consisting of ajmaline, aminopterine, isaxonine, isoniazid, perhexiline, phenylbutazone and troleandromycine, antiorganelle antibodies were absent or rare. In drug-induced hepatitis caused by another heterogenous group of drugs, including clometacin, fenofibrate, oxyphenisatin and papaverine, antismooth muscle, antinucleus and antimitochondria antibodies were found in isolation or in different combinations in 70% of cases. From the presence of antismooth muscle antibodies in sera, we could trace 30 cases of clometacin-induced hepatitis. The third group included drug-induced hepatitis with special antibody:iproniazid-induced hepatitis with antimitochondrial antibody 6 and tienilic acid (ticrynafen)-induced hepatitis with antiliver/kidney microsome antibody 2 (anti-LKM2). These two antibodies are rare in routine sera and were absent in patients who received the drug and had no liver damage. From the presence of corresponding antibodies, we detected six cases of iproniazid-induced hepatitis and 67 cases of tienilic acid-induced hepatitis. Antiorganelle antibodies found in high titers disappeared in 2 to 24 months following withdrawal of the offending drug. The fourth group was represented by halothane-induced hepatitis; antiliver/kidney microsome antibody 1 was weak and infrequent. Similarities between drug-induced hepatitis of the second group and lupoïd hepatitis suggest that drugs may reveal this spontaneous disorder.(ABSTRACT TRUNCATED AT 250 WORDS)


W value measurements for 241Am alpha particles in various gases.
Measurements of W, the mean energy expended per ion pair formed, have been performed for 241Am alpha particles stopping in a number of the gases commonly used in ionisation chambers. Both absolute and relative measurements were made with nitrogen used as the reference gas for the relative measurements. The absolute method entailed a simultaneous measurement of a quantity of charge and the number of alpha particles which produced that charge, whilst the relative approach simply required a determination of the ratio of ion currents. Results were obtained for methane-based tissue-equivalent gas, for its constituents, i.e. methane, carbon dioxide and nitrogen, for argon, and also for a gas mixture with a composition approximately equivalent to A-150 plastic.


Identification of a linear epitope on the fusion glycoprotein of respiratory syncytial virus.
The fusion glycoprotein of the Edinburgh strain of respiratory syncytial (RS) virus was cloned from infected cell mRNA. A full-length clone was subjected to sequence analysis, and compared with other strains of RS virus. The inferred primary amino acid sequence was used to generate a nested set of overlapping peptides spanning the mature protein. Peptides were synthesized on polyethylene pins and examined for their reactivity towards high titre human antisera. Decameric peptides spanning the highly conserved region between amino acids Lys and Ala (positions 470 to 490), reacted strongly with the sera and a detailed study with hexameric peptides located the epitope to FPSDEF, at positions 483 to 488. Replacement synthesis analysis revealed that Pro at position 484 and Glu at 487 were critical components of the binding site and could not be substituted.


Automated review of electronic health records to assess quality of care for outpatients with heart failure.
Electronic health records (EHRs) may be used to assess quality of care. To evaluate the accuracy of automated review of EHR data to measure quality of care for outpatients with heart failure. Observational study of quality of care for heart failure comparing automated review of EHR data with automated review followed by manual review of electronic notes for patients with apparent quality deficits (hybrid review). An academic general internal medicine clinic with several years' experience using a commercial EHR. 517 adults with a qualifying International Classification of Diseases, Ninth Revision, diagnosis of heart failure in their EHR data and 2 or more clinic visits over the past 18 months. Left ventricular ejection fraction (LVEF), prescription of a beta-blocker and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) for patients with left ventricular systolic dysfunction (LVEF <0.40) and prescription of warfarin for patients with comorbid atrial fibrillation. Performance based on automated review of EHR data was similar to that based on hybrid review for assessing LVEF measurement (94.6% vs. 97.3%), prescription of beta-blockers (90.9% vs. 92.8%), and prescription of ACE inhibitors or ARBs (93.9% vs. 98.7%). However, performance based on automated review was lower than that based on hybrid review for prescription of warfarin for atrial fibrillation (70.4% vs. 93.6%), primarily because automated review did not detect documentation of accepted reasons for not prescribing warfarin. The findings may not be applicable to other practices and other EHRs. The authors used EHR data to identify eligible patients, so the study may have excluded some patients with heart failure. Patient charts were manually reviewed only if a provider appeared to fail a quality measure on automated review and did not determine the sensitivity and specificity of automated review according to standard definitions. Automated review of EHR data to measure the quality of care of outpatients with heart failure missed many exclusion criteria for medications documented only in providers' notes. As a result, it sometimes underestimated performance on medication-based quality measures.


Nanoscale resolution for fluorescence microscopy via adiabatic passage.
We propose the use of the subwavelength localization via adiabatic passage technique for fluorescence microscopy with nanoscale resolution in the far field. This technique uses a Λ-type medium coherently coupled to two laser pulses: the pump, with a node in its spatial profile, and the Stokes. The population of the Λ system is adiabatically transferred from one ground state to the other except at the node position, yielding a narrow population peak. This coherent localization allows fluorescence imaging with nanometer lateral resolution. We derive an analytical expression to asses the resolution and perform a comparison with the coherent population trapping and the stimulated-emission-depletion techniques.


Learning social attitudes: children's sensitivity to the nonverbal behaviors of adult models during interracial interactions.
White children show marked ingroup race preferences and a relative devaluation of Black people. The origin of these early interracial attitudes is to a large extent still unclear. The studies here test the possibility that preschool-aged children are particularly sensitive to the nonverbal behaviors performed by White adults during interracial interactions. In Study 1, children were shown a video displaying an interaction between a White and a Black adult. Across conditions, the White adult's verbal behaviors were either friendly or neutral, whereas his nonverbal behaviors showed either easiness (e.g., closeness, high eye contact) or uneasiness (e.g., distance, avoidance of eye contact). Results revealed that participants shaped their attitudes toward the Black target accordingly, independently from the White adults' verbal behaviors. Study 2 replicated the basic findings and demonstrated that the observed effects generalized to other Black targets. Results are discussed in relation to current approaches to understanding the formation of racial attitudes among children.


Tremella-Like ZnO@Col-I-Decorated Titanium Surfaces with Dual-Light-Defined Broad-Spectrum Antibacterial and Triple Osteogenic Properties.
The growing population of peri-implant diseases (PIDs) has become a public obsession, mainly due to the lack of antibacterial ability and osteogenic promotion of titanium (Ti) implants. Herein, inspired by tremella, we reported zinc oxide (ZnO)@collagen type I (Col-I)-decorated Ti for PIDs treatments. Compared with pure Ti implants, ZnO@Col-I-decorated Ti could be activated by a safe visible yellow light and showed excellent broad-spectrum antibacterial properties. The proliferation and osteogenic gene expression of bone marrow mesenchymal stem cells (BMSCs) indicated that the triple osseointegration of implants was realized through (I) the remarkedly improved surface hydrophilicity of ZnO@Col-I-decorated Ti, (II) the function of Col-I, and (III) the excellent near-infrared (NIR)-induced photothermal performance of ZnO. Collectively, the proposed dual-light-defined ZnO@Col-I coating was a promising implant surface modification system to provide customized treatments for each PID patient.


Multi-walled carbon nanotube-graphene-polyaniline multiphase nanocomposite with superior electromagnetic shielding effectiveness.
The multiphase approach was adapted to enhance the electromagnetic interference (EMI) shielding effectiveness (SE) of polyaniline (PANI) based nanocomposites. The natural graphite flakes (NGF) incorporated modified PANI was used for the development of multi-walled carbon nanotubes (MWCNTs) based nanocomposites. In PANINGF-MWCNTs composites, multilayer graphene was synthesized in situ by ball milling. The resultant PANINGF-MWCNTs nanocomposites were characterized by different techniques. It was revealed from the transmission electron microscope (TEM) observation that in situ derived multilayer graphene acts as a bridge between PANI and MWCNTs, and plays a significant role for improving the properties of multiphase nanocomposites. It was observed that EMI-SE increases with increasing the MWCNTs content from 1 to 10 wt% in the multiphase nanocomposites. The maximum value of total EMI-SE was -98 dB of nanocomposite with 10 wt% of MWCNTs content. The high value of EMI-SE is dominated by the absorption phenomenon which is due to the collective effect of increase in space charge polarization and decrease in carrier mobility. The decrease in carrier mobility has a positive effect on the shore hardness value due to the strong interaction between the reinforcing constituent in multiphase nanocomposites. As a consequence, shore hardness increases from 56 to 91 at 10 wt% of MWCNTs.


Treatment of mandibular cherubism.
A case of cherubism of the mandible with an atypical history and with the onset of the facial deformity delayed until after puberty has been reported. The patient was treated during a relatively inactive stage, which followed a year of rather active growth. The distinct facial deformities were treated by a combination of curettage and recontouring, which resulted in an improved facial appearance and elimination of the fibro-osseous lesions of the mandible.


[Reciprocal homology of the preotic mesodermal segments of representatives of different classes of vertebrates].
The data of the literature and those of the author on the origin of preotic mesodermal segments are discussed. Only in Cyclostomata all preotic segments are formed from the wall of archenteron and are larval segments. In all the gnathos tomata, the primary gastral segments are substituted, to different degrees, by postlarval peristonal mesoderm. The preotic mesomeres of Cyclostomata are homologous to II--IV mesomeres of Branchiostoma lanceolata. The anterior cephalic cavity and the premandibular segment of the elasmobranchia are homologous to I and II segments of Branchiostoma lanceolata. The mandibular mesoderm of the elasmobranchia includes the gastral mesoderm (homologous to III and some subsequent segments of Brachiostoma lanceolata) and peristomal mesoderm. The mandibular mesoderm in higher vertebrates has the same composition, but their anterior larval segments disappear and are substituted by gastral part of the mandibular mesoderm.


The role of the pediatrician in transitioning children and adolescents with developmental disabilities and chronic illnesses from school to work or college. American Academy of Pediatrics. Committee on Children With Disabilities.
The role of the pediatrician in transitioning children with disabilities and chronic illnesses from school to work or college is to provide anticipatory guidance and to promote self-advocacy and self-determination. Knowledge of the provisions of the key federal laws affecting vocational education is essential for the pediatrician's successful advocacy for patients.


[Blattabacterium in the fat body of the Maritime Territory relic roach, Cryptocercus relictus].
Rod-like symbiotic bacteria in the fat body of the cockroach Cryptocercus relictus have a thin cell wall of the Gram-positive type; the nucleoplasm in "diffuse". The septum connected with a massive mesosome is formed during cell division. The bacteria in the host cells are surrounded will several host membranes. For tens of millions of years. Cryptocercus relictus has been developing in the conditions of entire geographical isolation, but the morphology of its Blattabacterium is similar to that of the symbionts of other cockroaches examined. This gives evidence to the conservative nature of the cockroach--bacterial symbiosis.


MAXIMUM LIKELIHOOD ESTIMATION USING EXPECTATION MAXIMIZATION APPLIED TO AMBIENT DOSE EQUIVALENT MEASUREMENTS.
The use of spectrometric detectors for ambient dose equivalent measurements requires the development of calculation procedures to obtain the incident photon fluence spectra from the measured pulse-height spectra. In this work, the implementation of a methodology based on the maximum likelihood estimation using expectation maximization is described. The method has been validated using simulated and reference photon beams. The results are in excellent agreement with the reference values in the framework of the involved uncertainties. The presented method allows the consideration of the detector resolution, improving thus the energy resolution of the obtained incident photon spectra.


Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population.
To compare estimates of serum bilirubin as determined by a transcutaneous device (BiliChek [BC]) with laboratory-measured total serum bilirubin (TSB) in a predominately Hispanic population in which a significant number of TSB values > or =15 mg/dL was anticipated. A total of 248 Hispanic and 56 non-Hispanic neonates were studied. Transcutaneous measurements were performed by 1 investigator within 30 minutes of blood sampling for TSB; TSB was determined in a large clinical laboratory using the diazo Jendrassik-Grof with blank method. Agreement between BC and TSB determinations was assessed using Bland-Altman plots and the Bradley-Blackwood test. Interdevice comparisons were made among the BC devices. Predictive indices for TSB >10 mg/dL and >15 mg/dL were determined using various BC cutoff values. TSB was > or =15 mg/dL in 31% of the Hispanic neonates. BC generally tended to underestimate TSB determinations, and this trend was more pronounced when TSB was >10 mg/dL. Very high sensitivities were observed only when relatively low BC cutoff values were used to predict TSB >10 mg/dL or >15 mg/L. Relatively small numbers of infants had BC values in these low ranges. The tendency of BC to underestimate TSB limits its usefulness in neonates with relatively high TSB. In this population, most infants would have required additional evaluation to ensure that TSB was not >10 mg/dL or >15 mg/dL. It seems that the discrepancy between this study and previous studies of BC is related to our relatively large number of TSB values > or =15 mg/dL.


Relationship Between Difficulties Encountered in School Life or Daily Life by Professional Training College Students and Their Sources of Advice.
This study attempted to clarify issues regarding difficulties in school life perceived by professional training college students and educational support systems for students including possible developmental disabilities. We surveyed 953 students enrolled at 9 professional training colleges in Japan by using an anonymous self-administered questionnaire to investigate difficulties during school life, help-seeking preferences, and self-esteem. Difficulties were investigated by using the Self-Cognitive Difficulties Scale, help-seeking preferences were assessed with the Help-Seeking Preferences Scale, and self-esteem was assessed by the Rosenberg Self-Esteem Scale. We also investigated the relationship between the Self-Cognitive Difficulties Scale and the sources of advice used by students. Responses were obtained from 863 students, and those of 775 students were considered to be valid. In terms of learning scenarios, 271 students (35.0%) responded that written examinations caused the most difficulties. The Rosenberg Self-Esteem Scale and Help-Seeking Preferences Scale were negatively correlated with the Self-Cognitive Difficulties Scale. With respect to the relationship between sub-factors of the Self-Cognitive Difficulties Scale and sources of advice, the students who asked specialists for advice had significantly higher scores for the factors of interpersonal relationships and reading/writing, as well as significantly higher scores for impulsivity and learning-related difficulties. The students who asked their previous high school teachers for advice had significantly higher scores for inattention and reading/writing. Furthermore, the students who asked senior students in the same department for advice had a significantly higher score for learning-related difficulties. Our results suggested that professional training college students with a high Self-Cognitive Difficulties Scale score are more likely to choose a specialist as the source of advice. When providing educational support to professional training college students, it is important to consider the possibility that their sources of advice might differ depending on their individual self-perceived difficulty characteristics.


Effects of antibiotic treatment and phagocyte infiltration on development of Pseudomonas aeruginosa biofilm-Insights from the application of a novel PF hydrogel model in vitro and in vivo.
Bacterial biofilm infections are major health issues as the infections are highly tolerant to antibiotics and host immune defenses. Appropriate biofilm models are important to develop and improve to make progress in future biofilm research. Here, we investigated the ability of PF hydrogel material to facilitate the development and study of Pseudomonas aeruginosa biofilms in vitro and in vivo. Wild-type P. aeruginosa PAO1 bacteria were embedded in PF hydrogel situated in vitro or in vivo, and the following aspects were investigated: 1) biofilm development; 2) host immune response and its effect on the bacteria; and 3) efficacy of antibiotic treatment. Microscopy demonstrated that P. aeruginosa developed typical biofilms inside the PF hydrogels in vitro and in mouse peritoneal cavities where the PF hydrogels were infiltrated excessively by polymorphonuclear leukocytes (PMNs). The bacteria remained at a level of ~106 colony-forming unit (CFU)/hydrogel for 7 days, indicating that the PMNs could not eradicate the biofilm bacteria. β-Lactam or aminoglycoside mono treatment at 64× minimal inhibitory concentration (MIC) killed all bacteria in day 0 in vitro biofilms, but not in day 1 and older biofilms, even at a concentration of 256× MIC. Combination treatment with the antibiotics at 256× MIC completely killed the bacteria in day 1 in vitro biofilms, and combination treatment in most of the cases showed significantly better bactericidal effects than monotherapies. However, in the case of the established in vivo biofilms, the mono and combination antibiotic treatments did not efficiently kill the bacteria. Our results indicate that the bacteria formed typical biofilms in PF hydrogel in vitro and in vivo and that the biofilm bacteria were tolerant against antibiotics and host immunity. The PF hydrogel biofilm model is simple and easy to fabricate and highly reproducible with various application possibilities. We conclude that the PF hydrogel biofilm model is a new platform that will facilitate progress in future biofilm investigations, as well as studies of the efficacy of new potential medicine against biofilm infections.


Uterine perivascular adipose tissue is a novel mediator of uterine artery blood flow and reactivity in rat pregnancy.
In vivo, uterine perivascular adipose tissue (PVAT) potentiates uterine artery blood flow in pregnant rats, although not in non-pregnant rats. In isolated preparations, uterine PVAT has pro-contractile and anti-dilatory effects on uterine arteries. Pregnancy induces changes in uterine arteries that makes them responsive to uterine PVAT signalling. An increase in uterine artery blood flow (UtBF) is a common and necessary feature of a healthy pregnancy. In the present study, we tested the hypothesis that adipose tissue surrounding uterine arteries (uterine perivascular adipose tissue; PVAT) is a novel local mediator of UtBF and uterine artery tone during pregnancy. In vivo experiments in anaesthetized Sprague-Dawley rats showed that pregnant animals (gestational day 16, term = 22--23 days) had a three-fold higher UtBF compared to non-pregnant animals. Surgical removal of uterine PVAT reduced UtBF only in pregnant rats. In a series of ex vivo bioassays, we demonstrated that uterine PVAT had pro-contractile and anti-dilatory effects on rat uterine arteries. In the presence of PVAT-conditioned media, isolated uterine arteries from both pregnant and non-pregnant rats had reduced vasodilatory responses. In non-pregnant rats, these responses were mediated at the level of uterine vascular smooth muscle, whereas, in pregnant rats, PVAT-media reduced endothelium-dependent relaxation. Pregnancy increased adipocyte size in ovarian adipose tissue but had no effect on uterine PVAT adipocyte morphology. In addition, pregnancy down-regulated the gene expression of metabolic adipokines in uterine but not in aortic PVAT. In conclusion, this is the first study to demonstrate that uterine PVAT plays a regulatory role in UtBF, at least in part, as a result of its actions on uterine artery tone. We propose that the interaction between the uterine vascular wall and its adjacent adipose tissue may provide new insights for interventions in pregnancies with adipose tissue dysfunction and abnormal UtBF.


The Effect of Cognitive Rest as Part of Postconcussion Management for Adolescent Athletes: A Critically Appraised Topic.
Clinical Scenario: It is hypothesized that cognitive activity following a concussion may potentially hinder patient recovery. While the recommendation of cognitive rest is often maintained and rationalized, a causal relationship between cognitive activity and symptom duration has yet to be established. Does the implementation of cognitive rest as part of the postconcussion management plan reduce the number of days until the concussed adolescent patient is symptom free compared to a postconcussion management plan that does not incorporate cognitive rest? Summary of Key Findings: A thorough literature search returned 7 possible studies; 5 studies met the inclusion criteria and were included. Three studies indicated that increased cognitive activity is associated with longer recovery from a concussion, and, therefore, supported the use of cognitive rest. One study indicated that the recommendation for cognitive rest was not significantly associated with time to concussion symptom resolution. One study indicated that strict rest, defined as 5 days of no school, work, or physical activity; might prolong symptom duration. Clinical Bottom Line: There is moderate evidence to support the prescription of moderate cognitive rest for concussed patients. Clinicians who intend on implementing cognitive rest in their concussion protocols should be aware of inconsistencies and be open-minded to alternative treatment progressions while taking into consideration each individual patient and maintaining adequate patient-centered care principles. Strength of Recommendation: Grade B evidence exists that prescription of moderate cognitive rest for concussed patients may be beneficial as a supplement to physical rest as treatment for symptom reduction in adolescents.


Chemical markers for the quality control of herbal medicines: an overview.
Selection of chemical markers is crucial for the quality control of herbal medicines, including authentication of genuine species, harvesting the best quality raw materials, evaluation of post-harvesting handling, assessment of intermediates and finished products, and detection of harmful or toxic ingredients. Ideal chemical markers should be the therapeutic components of herbal medicines. However, for most herbal medicines, the therapeutic components have not been fully elucidated or easily monitored. Bioactive, characteristic, main, synergistic, correlative, toxic and general components may be selected. This article reviews the effective use of chemical markers in the quality control of herbal medicines including the selection criteria considering the roles and physicochemical factors which may affect the effective use of chemical markers.


Future Challenges in Cancer Resistance to Immunotherapy.
Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.


UNDERSTANDING THE ADAPTATION AND SENSITIVITY OF THE MICROBIOME: MICROBIAL RESILIENT AND HUMAN WELL-BEING.
The term microbiome describes the assortment of microbes that dwell in and on a person's body, particularly in the gut, comprising fungi, bacteria, infectious agents and additional microbes. According to research, numerous elements of human well-being, such as digestion, immunological response and psychological well-being, have been linked to the microbiome. Preserving human wellness requires knowledge of the microbiome's stability and how it reacts to perturbations. According to preliminary research, adults' microbial ecosystems are considered stable with no signs of significant disturbances. This stability is not preserved by inertia and the system's interaction with restorative forces keeps the processes stable. Short antibiotic doses can result in quick and substantial microbiome alterations. However, there is confirmation that the taxonomic structure of the microbiome has at least recovered after such disruptions. The effect of antibiotics is individualized and can be altered by earlier exposure to a similar drug, which is a crucial aspect to remember. These results suggest that the individual's microbiome has adaptable qualities. Examining the microbiome's reactions to perturbations might be helpful in the prediction of potential instabilities and illness by revealing important features of function, microbial connections, and important species in the native microbiota. This information can benefit the management of the individual microbial community and the promotion of better health conditions.


CD4+ T cells from peripheral blood of a melanoma patient recognize peptides derived from nonmutated tyrosinase.
Tyrosinase is an antigen that is expressed by normal melanocytes as well as melanoma cells, against which responses by autologous T cells have been detected. Although CD4+ T cells play an important role in tumor immunity in animal tumor models, little information about CD4+ T-cell immunity against human tumors exists. Here, we report that CD4+ T cells from the peripheral blood of a patient with melanoma respond to synthetic peptides derived from nonmutated tyrosinase. T-cell clones were generated that recognized the tyrosinase p386-406 peptide when it was presented by the HLA-DR15 (DRB1*1501) molecule. The CD4+ T-cell clone also recognized autologous EBV-transformed B-lymphoblastoid cell lines that had been pulsed with the lysate of melanoma cells. The synthetic tyrosinase p386-406 peptide was capable of binding to HLA-DR15 (DRB1*1501) molecules on cell surface of DR15 homozygous cells. Thus, the finding that nonmutated tyrosinase peptides are immunogenic in a melanoma patient may provide the basis for the development of cancer immunotherapy, based on knowledge of synthetic tumor-associated peptide antigens.


[Hemosiderin-laden macrophages count in sputum in diagnosis of dyspnea of heart origin].
The respiratory or heart origin of dyspnea is not always easy to find out using the available diagnostic tools. Many patients present both heart and lung diseases that cause dyspnea. The role of hemosiderin-laden macrophages count (HC) in sputum in this context has not been well settled so far. The objective was to describe the prediction usefulness of HC in patients suffering from dyspnea of heart origin, and to find out if HC changed after administering treatment. HC was analyzed in 61 patients whose main symptom was dyspnea in the emergency department, and it was evaluated by means of clinical history, clinical course and performance of lung function tests and echocardiography. 35 patients were classified as having dyspnea of heart origin, 17 as having dyspnea of lung origin and 9 had dyspnea of both origins. The HC was higher in patients with dyspnea of heart origin 37% (95% CI, 26-47) or cardiopulmonary origin 30% (95% CI, 8-52) than in patients with dyspnea of lung origin 15% (95% CI, 4-27), and it remained higher despite administering treatment. The sensitivity (52%), specificity (88%), positive predictive value (92%) and negative predictive value (58%) was established for a 30% HC cutoff. The prediction model of heart origin dyspnea presented an area under the ROC curve of 0.978 (95% CI, 0.95-1). HC reflects the severity of pulmonary venocapillar disturbance, identifies the majority of patients suffering from current or past heart failure or severe cardiac dysfunction, and is useful for the prediction of dyspnea of heart origin. HC utility should focus on selected patients.


Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro.
The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.


ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.
The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that ST6 β-galactoside α2,6 sialyltransferase 1 (ST6GAL1), which adds α2,6-linked sialic acids to N-glycosylated proteins, was upregulated in patients with early-stage PDAC and was further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells. Additionally, we developed a genetically engineered mouse (GEM) model with transgenic expression of ST6GAL1 in the pancreas and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D had greatly accelerated PDAC progression compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1's role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We verified ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.


A low-cost uniaxial cell stretcher for six parallel wells.
Cells in the lungs, the heart, and numerous other organs, are constantly exposed to dynamic forces and deformations. To mimic these dynamic mechanical loading conditions and to study the resulting cellular responses such as morphological changes or the activation of biochemical signaling pathways, cells are typically seeded on flexible 2D substrates that are uniaxially or biaxially stretched. Here, we present an open-source cell stretcher built from parts of an Anet A8 3D printer. The cell stretcher is controlled by a fully programmable open-source software using GCode and Python. Up to six flexible optically clear substrates can be stretched simultaneously, allowing for comparative multi-batch biological studies including microscopic image analysis. The cell yield from the cell culture area of 4 cm2 per substrate is sufficient for Western-blot protein analysis. As a proof-of-concept, we study the activation of the Yes-associated protein (YAP) mechanotransduction pathway in response to increased cytoskeletal tension induced by uniaxial stretching of epithelial cells. Our data support the previously observed activation of the YAP transcription pathway by stretch-induced increase in cytoskeletal tension and demonstrate the suitability of the cell stretcher to study complex mechano-biological processes.


[Lights and shadows for public health: A critical analysis of the tobacco legislation in Spain].
Tobacco smoking is a chronic disease that is the leading preventable cause of death in developed countries. In Spain, the prevalence of tobacco use has decreased driven by the implementation of tobacco control policies; however, current legislation does not establish a harmonized regulation for all tobacco products. The aim of this article is to review the current legislation and critically analyze its limitations in relation to the principles of good administration now defined in the Law 39/2015. Spanish in force tobacco control policies main limitations can be divided into four areas: the lack of specific regulation for new tobacco products; the differences in their regulation; the lack of information to the general population on their harmful effects and the new developments in the regulation of smoke-free spaces; and the lack of adaptation of the regulation to the most recent scientific evidence. All in all, the quality of tobacco control regulations in Spain, despite the successes achieved with the Law 28/2005, has been compromised by the State's laxity in the legislative, regulatory, and administrative spheres, which has led to a regulatory stagnation that runs counter to the principles of good regulation. This review should encourage scientific organizations and civil society associations to call for an actualization of the tobacco legislation, with determined and coordinated prevention and control policies to promote a tobacco-free Spain.