Uterine artery embolization: reduced radiation with refined technique.
To determine the estimated absorbed ovarian dose (EAOD) and absorbed skin dose (ASD) that occurs during uterine artery embolization (UAE) using pulsed fluoroscopy and a refined procedure protocol. The absorbed dose was measured in 20 patients who underwent UAE procedures. Radiation was limited by using low frequency pulsed fluoroscopy, bilateral catheter technique with simultaneous injections for embolization as well as pre-and postembolization exposures and focus on limitation of magnified and oblique fluoroscopy. Lithium fluoride dosimeters were placed both in the posterior vaginal fornix and on the skin at the beam entrance site. The vaginal dose was used to approximate the EAOD. Fluoroscopy time and exposures were recorded. The mean values for all patients were calculated and compared to our previous results obtained with conventional fluoroscopy and to threshold doses for the induction of deterministic skin injury. Mean fluoroscopy time was 10.95 min. (range 6-21.3 min.) and the mean number of angiographic exposures was 20.9 (range 14-53). The mean EAOD was 9.5 cGy (range 2.21-23.21 cGy) and the mean ASD was 47.69 cGy (range 10.83-110.14 cGy). This compares to previous results with non-pulsed fluoroscopy of an EAOD of 22.34 cGy (range 4.25-65.08 cGy) and an ASD of 162.32 cGy (range 66.01-303.89 cGy) as well as threshold doses for induction of deterministic radiation injury to the skin (400-500 cGy). When pulsed fluoroscopy is used with emphasis on dose reduction techniques, the EAOD and ASD can be substantially reduced to less than 1/2 (P = .017) and 1/3 (P < .0001) when compared to UAE performed with nonpulsed fluoroscopy. These radiation reduction tools should therefore be applied whenever possible.


Invasive aspergillosis in AIDS.
Invasive aspergillosis (IA) is a rare infection in patients with the Acquired Immune Deficiency Syndrome (AIDS). We report the first Australian cases of histologically and microbiologically proven IA diagnosed antemortem in AIDS patients. We also describe the first case of laryngeal involvement and the unusual case of a pneumothorax due to IA. These three cases illustrate the varied clinical and pathological features of IA in AIDS and highlight some of the difficulties in diagnosis and treatment. The infections occurred in the setting of advanced immunodeficiency and multiple opportunistic infections and responded poorly to treatment.


Cognitive control signals in posterior cingulate cortex.
Efficiently shifting between tasks is a central function of cognitive control. The role of the default network - a constellation of areas with high baseline activity that declines during task performance - in cognitive control remains poorly understood. We hypothesized that task switching demands cognitive control to shift the balance of processing toward the external world, and therefore predicted that switching between the two tasks would require suppression of activity of neurons within the posterior cingulate cortex (CGp). To test this idea, we recorded the activity of single neurons in CGp, a central node in the default network, in monkeys performing two interleaved tasks. As predicted, we found that basal levels of neuronal activity were reduced following a switch from one task to another and gradually returned to pre-switch baseline on subsequent trials. We failed to observe these effects in lateral intraparietal cortex, part of the dorsal fronto-parietal cortical attention network directly connected to CGp. These findings indicate that suppression of neuronal activity in CGp facilitates cognitive control, and suggest that activity in the default network reflects processes that directly compete with control processes elsewhere in the brain.


Treatment of Invasive Candidiasis: A Narrative Review.
Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients.


Effects of mud-bath therapy in psoriatic arthritis patients treated with TNF inhibitors. Clinical evaluation and assessment of synovial inflammation by contrast-enhanced ultrasound (CEUS).
Despite the efficacy of TNF inhibitors, most patients with psoriatic arthritis maintain a residual synovial inflammation. The main aim of the study was to evaluate the effects of mud-bath therapy on clinical picture of PsA patients treated with TNF inhibitors. The secondary outcome was to assess synovial inflammation in hand joints detected by contrast-enhanced ultrasound. Other aims were to verify the risk of arthritis flare and to evaluate the effects of spa treatment on functional ability and on quality of life. Thirty-six patients with psoriatic arthritis, treated in the last 6 months with TNF inhibitors, were enrolled. After 1:1 randomisation, 18 patients (group A) underwent mud-bath therapy (12 mudpacks and 12 thermal baths), maintaining treatment with TNF inhibitors; 18 patients (group B) continued pharmacological therapy alone. CRP, PASI, DAS28, swollen and tender joint count, VAS pain, HAQ and SF-36 were evaluated at baseline (T0) and after 45 days (T1). Synovial inflammation detected by contrast-enhanced ultrasound, analysed by a software system, was also assessed. A significant improvement in PASI (P<0.005), DAS28 (P<0.05), swollen joint count and tender joint count (P<0.001), and HAQ (P<0.001) between T0 and T1 was observed in group A. No patient underwent a flare-up of arthritis. Ultrasound videos demonstrated a significant appearance delay (P<0.05) and faster washout (P<0.02) of contrast dye in group A patients with respect to group B. These data suggest a decrease of residual synovial inflammation and a beneficial clinical effect of spa therapy in psoriatic arthritis patients treated with TNF inhibitors.


Neural bases of social anxiety disorder: emotional reactivity and cognitive regulation during social and physical threat.
Social anxiety disorder is thought to involve emotional hyperreactivity, cognitive distortions, and ineffective emotion regulation. While the neural bases of emotional reactivity to social stimuli have been described, the neural bases of emotional reactivity and cognitive regulation during social and physical threat, and their relationship to social anxiety symptom severity, have yet to be investigated. To investigate behavioral and neural correlates of emotional reactivity and cognitive regulation in patients and controls during processing of social and physical threat stimuli. Participants were trained to implement cognitive-linguistic regulation of emotional reactivity induced by social (harsh facial expressions) and physical (violent scenes) threat while undergoing functional magnetic resonance imaging and providing behavioral ratings of negative emotion experience. Academic psychology department. Fifteen adults with social anxiety disorder and 17 demographically matched healthy controls. Blood oxygen level-dependent signal and negative emotion ratings. Behaviorally, patients reported greater negative emotion than controls during social and physical threat but showed equivalent reduction in negative emotion following cognitive regulation. Neurally, viewing social threat resulted in greater emotion-related neural responses in patients than controls, with social anxiety symptom severity related to activity in a network of emotion- and attention-processing regions in patients only. Viewing physical threat produced no between-group differences. Regulation during social threat resulted in greater cognitive and attention regulation-related brain activation in controls compared with patients. Regulation during physical threat produced greater cognitive control-related response (ie, right dorsolateral prefrontal cortex) in patients compared with controls. Compared with controls, patients demonstrated exaggerated negative emotion reactivity and reduced cognitive regulation-related neural activation, specifically for social threat stimuli. These findings help to elucidate potential neural mechanisms of emotion regulation that might serve as biomarkers for interventions for social anxiety disorder.


Hibernating myocardium: an incomplete adaptation to ischemia.
We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.


Projecting the future diabetes population size and related costs for the U.S.
We developed a novel population-level model for projecting future direct spending on diabetes. The model can be used in the federal budget process to estimate the cost implications of alternative policies. We constructed a Markov model simulating individuals' movement across different BMI categories, the incidence of diabetes and screening, and the natural history of diabetes and its complications over the next 25 years. Prevalence and incidence of obesity and diabetes and the direct spending on diabetes care and complications are projected. The study population is 24- to 85-year-old patients characterized by the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey and National Health Interview Survey. Between 2009 and 2034, the number of people with diagnosed and undiagnosed diabetes will increase from 23.7 million to 44.1 million. The obesity distribution in the population without diabetes will remain stable over time with approximately 65% of individuals of the population being overweight or obese. During the same period, annual diabetes-related spending is expected to increase from $113 billion to $336 billion (2007 dollars). For the Medicare-eligible population, the diabetes population is expected to rise from 8.2 million in 2009 to 14.6 million in 2034; associated spending is estimated to rise from $45 billion to $171 billion. The diabetes population and the related costs are expected to at least double in the next 25 years. Without significant changes in public or private strategies, this population and cost growth are expected to add a significant strain to an overburdened health care system.


Does an ear deformity bring an adverse impact on quality of life of Treacher Collins syndrome individuals?
Treacher Collins syndrome (TCS) is an autosomal dominant disorder with variable expression in which the ear may or may not be absent or with a malformation. Individuals with TCS suffer social stigma that may affect interaction with their peers. Quality of life instruments obtained through self-perception questionnaires are stigma identification tools and can enable social adjustment of these individuals. This study aims to assess the quality of life of individuals with TCS and to gauge the impacts of ear deformity on the quality of life. Twelve volunteers with a clinical and genetic diagnosis of TCS answered the WHO quality of life questionnaire and were divided into groups with normal ears (n = 6) versus affected ears (n = 6), and their results were compared. Siviero's scale was used to stratify the quality of life scores as satisfactory, intermediate and unsatisfactory. The overall score of the normal ears group was 73.13 and 71.81 for the affected ears group, and both were classified as an intermediate quality of life, with no statistically significant differences between them. Ear deformity is not a burden to the quality of life of these individuals, who already show other deformities and overall intermediate quality of life scores.


Infectious Maize rayado fino virus from Cloned cDNA.
A full-length cDNA clone was produced from a U.S. isolate of Maize rayado fino virus (MRFV), the type member of the genus Marafivirus within the family Tymoviridae. Infectivity of transcripts derived from cDNA clones was demonstrated by infection of maize plants and protoplasts, as well as by transmission via the known leafhopper vectors Dalbulus maidis and Graminella nigrifrons that transmit the virus in a persistent-propagative manner. Infection of maize plants through vascular puncture inoculation of seed with transcript RNA resulted in the induction of fine stipple stripe symptoms typical of those produced by wild-type MRFV and a frequency of infection comparable with that of the wild type. Northern and Western blotting confirmed the production of MRFV-specific RNAs and proteins in infected plants and protoplasts. An unanticipated increase in subgenomic RNA synthesis over levels in infected plants was observed in protoplasts infected with either wild-type or cloned virus. A conserved cleavage site motif previously demonstrated to function in both Oat blue dwarf virus capsid protein and tymoviral nonstructural protein processing was identified near the amino terminus of the MRFV replicase polyprotein, suggesting that cleavage at this site also may occur.


Can functional genomic diversity provide novel insights into mechanisms of community assembly? A pilot study from an invaded alpine streambed.
An important focus of community ecology, including invasion biology, is to investigate functional trait diversity patterns to disentangle the effects of environmental and biotic interactions. However, a notable limitation is that studies usually rely on a small and easy-to-measure set of functional traits, which might not immediately reflect ongoing ecological responses to changing abiotic or biotic conditions, including those that occur at a molecular or physiological level. We explored the potential of using the diversity of expressed genes-functional genomic diversity (FGD)-to understand ecological dynamics of a recent and ongoing alpine invasion. We quantified FGD based on transcriptomic data measured for 26 plant species occurring along adjacent invaded and pristine streambeds. We used an RNA-seq approach to summarize the overall number of expressed transcripts and their annotations to functional categories, and contrasted this with functional trait diversity (FTD) measured from a suite of characters that have been traditionally considered in plant ecology. We found greater FGD and FTD in the invaded community, independent of differences in species richness. However, the magnitude of functional dispersion was greater from the perspective of FGD than from FTD. Comparing FGD between congeneric alien-native species pairs, we did not find many significant differences in the proportion of genes whose annotations matched functional categories. Still, native species with a greater relative abundance in the invaded community compared with the pristine tended to express a greater fraction of genes at significant levels in the invaded community, suggesting that changes in FGD may relate to shifts in community composition. Comparisons of diversity patterns from the community to the species level offer complementary insights into processes and mechanisms driving invasion dynamics. FGD has the potential to illuminate cryptic changes in ecological diversity, and we foresee promising avenues for future extensions across taxonomic levels and macro-ecosystems.


Quo vadis source tracking? Towards a strategic framework for environmental monitoring of fecal pollution.
Advances in microbial source tracking (MST) have largely been driven by the need to comply with water quality standards based on traditional indicator bacteria. Recently, a number of culture-independent, and library-independent methods based on polymerase chain reaction (PCR) have been gaining popularity among source trackers. However, only a limited number of these methods have been successfully used in field applications, primarily due to the fact that many of them are still being developed. In this critical outlook, we examine different viewpoints associated with the practical use of MST to identify critical research gaps, propose a priority-based timeline to address them, and outline emerging technologies that will likely impact the future of source tracking. We propose that it is necessary to consider each of these aspects in order to advance towards a unifying framework in source identification, so that fecal pollution monitoring can be reliably used for comprehensive environmental microbial monitoring, to develop risk assessment models, and to implement and validate adequate management practices.


The differential fate of mesonephric tubular-derived efferent ductules in estrogen receptor-alpha knockout versus wild-type female mice.
We investigated mesonephric tubular-derived efferent ductules in female wild-type (WT) and estrogen receptor-alpha knockout (ERalphaKO) mice from late fetal to adult life. On gestational day 17, efferent ductules in both fetal WT and ERalphaKO females were well developed and morphologically similar, although one third the size of the male counterpart. Unexpectedly, efferent ductules with a ciliated epithelium were still present on postnatal day 10 in WT and ERalphaKO females. By day 23, however, marked phenotypic differences occurred in efferent ductules of WT and ERbetaKO vs. ERalphaKO female mice. In the latter, efferent ductules became hypertrophied and dilated, whereas only small tubules remained in WT and ERbetaKO adult mice. The serum testosterone concentrations were similar in 21- to 25-day-old ERalphaKO, heterozygous, and WT female mice, suggesting that increased testosterone was not inducing enlargement of efferent ductules in ERalphaKO females. In conclusion, remnants of efferent ductules persisted in normal adult female mice, although these structures were greatly reduced in size compared with efferent ductules in ERalphaKO female mice. The underlying mechanism inducing hypertrophy and dilation of efferent ductules in ERalphaKO females is not clear, but secretory and/or reabsorptive function of female efferent ductules may involve ERalpha.


Stakeholder participation in IPBES: connecting local environmental work with global decision making.
The Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services(IPBES) strengthens the science-policy interface by producing scientific assessments on biodiversity and ecosystem services to inform policy. IPBES fosters knowledge exchange across disciplines, between researchers and other knowledge holders, practitioners, societal actors and decision makers working at different geographic scales. A number of avenues for participation of stakeholders across the four functions if IPBES exist. Stakeholders come from diverse backgrounds, including Indigenous Peoples and local communities, businesses, and non-governmental organization. They represent multiple sources of information, data, knowledge, and perspectives on biodiversity. Stakeholder engagement in IPBES seeks to 1. communicate, disseminate, and implement the findings of IPBES products; 2. Develop guidelines for biodiversity conservation within member countries; and 3. create linkages between global policy and local actors - all key to the implementation of global agreements on biodiversity. This paper reflects on the role of stakeholders in the first work programme of IPBES (2014-2018). It provides an overview of IPBES processes and products relevant to stakeholders, examines the motivation of stakeholders to engage with IPBES, and explores reflections by the authors (all active participants on the platform) for improved stakeholder engagement and contributions to future work of the platform.


Neurovestibular Compensation following Ototoxic Lesion and Labyrinthectomy.
Introduction Unilateral labyrinthectomy and intra-tympanic gentamycin have been employed in the treatment of Ménière's disease, but the efficacy of these techniques has not been well established. Objective The objective of this study is to measure the time course of recovery from a unilateral labyrinthectomy either after ipsilateral topical treatment with gentamicin to the inner ear or without the previous insult. Methods Twenty-nine adult Mongolian gerbils were randomized into two experimental groups. Group 1 (n = 17) received a right ear gentamicin drug-induced lesion by unilateral labyrinthectomy (UL). Group 2 (n = 12) only received a right unilateral labyrinthectomy lesion. We measured the horizontal vestibulo-ocular responses in gerbils before and after the lesion. The gerbils received an angular acceleration stimulus and their eye movements were recorded. Results The gentamicin lesion resulted in a quicker recovery. Experimental groups underwent a similar time course of recovery. Statistical analysis showed no significant difference between the two groups. Both groups displayed adaptation to the lesion by day 21, but long-term compensation did not completely revert to the original pre-lesion state. Conclusions In a lesion requiring both static and dynamic compensation as in UL, the need for a static compensation may alter pre-existing compensation from a previous dynamic insult and require a new compensation. A previous lesion and adaptation is not preserved for a second lesion and the subject has to re-compensate. Therefore, surgical treatment in Meniere's disease such as UL can be considered without prior gentamicin treatment. Static and dynamic compensations do not appear to be as independent as previous studies have suggested.


Genetics of triple-negative breast cancer: Implications for patient care.
Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.


Psychometric properties of the PTSD Checklist for DSM-5: a pilot study.
To date there is a lack of studies assessing the psychometric properties of the recently revised PTSD Checklist (PCL), the PTSD Checklist for DSM-5 (PCL-5). The aim of this pilot study was to examine the psychometric properties of the PCL-5 in parents of children with burns. The participating parents (N=62, mean age=38) completed self-report questionnaires, 0.8-5.6 years after their child's burn. Measures were the PCL-5, the Impact of Event Scale-Revised (IES-R), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Perceived Stress Scale (PSS). Burn severity of the child and sociodemographic variables was obtained. The parents' average PCL-5 scores were low to moderate. The internal consistency of the PCL-5 was satisfactory, with Cronbach's alpha ranging from 0.56 to 0.77 and mean inter-item correlations ranging from 0.22 to 0.73 for the four PCL-5 subscales and the PCL-5 total. The PCL-5 subscales were moderately to highly correlated with the corresponding IES-R subscales as well as MADRS and PSS (p<0.05), whereas associations with sociodemographics and burn severity were low to moderate. This study provides preliminary support for the use of PCL-5. The results indicate satisfactory psychometric properties of the PCL-5 as measured with internal consistency, test-retest reliability, and aspects of convergent validity.


The 2CAN Score.
Background and Purpose- A quarter of acute strokes occur in patients hospitalized for another reason. A stroke recognition instrument may be useful for non-neurologists to discern strokes from mimics such as seizures or delirium. We aimed to derive and validate a clinical score to distinguish stroke from mimics among inhospital suspected strokes. Methods- We reviewed consecutive inpatient stroke alerts in a single academic center from January 9, 2014, to December 7, 2016. Data points, including demographics, stroke risk factors, stroke alert reason, postoperative status, neurological examination, vital signs and laboratory values, and final diagnosis, were collected. Using multivariate logistic regression, we derived a weighted scoring system in the first half of patients (derivation cohort) and validated it in the remaining half of patients (validation cohort) using receiver operating characteristics testing. Results- Among 330 subjects, 116 (35.2%) had confirmed stroke, 43 (13.0%) had a neurological mimic (eg, seizure), and 171 (51.8%) had a non-neurological mimic (eg, encephalopathy). Four risk factors independently predicted stroke: clinical deficit score (clinical deficit score 1: 1 point; clinical deficit score ≥2: 3 points), recent cardiac procedure (1 point), history of atrial fibrillation (1 point), and being a new patient (<24 hours from admission: 1 point). The score showed excellent discrimination in the first 165 patients (derivation cohort, area under the curve=0.93) and remaining 165 patients (validation cohort, area under the curve=0.88). A score of ≥2 had 92.2% sensitivity, 69.6% specificity, 62.2% positive predictive value, and 94.3% negative predictive value for identifying stroke. Conclusions- The 2CAN score for recognizing inpatient stroke performs well in a single-center study. A future prospective multicenter study would help validate this score.


Enteroviruses and type 1 diabetes: towards a better understanding of the relationship.
Environmental factors, especially viruses, are involved in the initiation or the acceleration of type 1 diabetes (T1D) pathogenesis. Epidemiological data strongly suggest that enteroviruses, such as coxsackievirus B4 (CV-B4), can be associated with T1D. It has been demonstrated that enterovirus infections were significantly more prevalent in at risk individuals, such as siblings of diabetic patients, when they developed anti-beta-cell autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects. The isolation of CV-B4 from the pancreas of diabetic patients strengthened the hypothesis of a relationship between the virus and the disease. Studies performed in vitro and in vivo in animal models helped to discover mechanisms of the infection of pancreas and other tissues, potentially able to play a role in the pathogenesis of T1D. Interestingly, it cannot be excluded that enteroviruses behave as half-devil half-angel since experimental studies suggest that, in certain conditions, these agents would be able to protect individuals against the disease. All of the plausible mechanisms by which enterovirus may be related to T1D will be reviewed here.


European society of Clinical Microbiology and Infectious Diseases guidelines on diagnosis and treatment of brain abscess in children and adults.
These European Society of Clinical Microbiology and Infectious Diseases guidelines are intended for clinicians involved in diagnosis and treatment of brain abscess in children and adults. Key questions were developed, and a systematic review was carried out of all studies published since 1 January 1996, using the search terms 'brain abscess' OR 'cerebral abscess' as Mesh terms or text in electronic databases of PubMed, Embase, and the Cochrane registry. The search was updated on 29 September 2022. Exclusion criteria were a sample size <10 patients or publication in non-English language. Extracted data was summarized as narrative reviews and tables. Meta-analysis was carried out using a random effects model and heterogeneity was examined by I2 tests as well as funnel and Galbraith plots. Risk of bias was assessed using Risk Of Bias in Non-randomised Studies - of Interventions (ROBINS-I) (observational studies) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (diagnostic studies). The Grading of Recommendations Assessment, Development and Evaluation approach was applied to classify strength of recommendations (strong or conditional) and quality of evidence (high, moderate, low, or very low). Magnetic resonance imaging is recommended for diagnosis of brain abscess (strong and high). Antimicrobials may be withheld until aspiration or excision of brain abscess in patients without severe disease if neurosurgery can be carried out within reasonable time, preferably within 24 hours (conditional and low). Molecular-based diagnostics are recommended, if available, in patients with negative cultures (conditional and moderate). Aspiration or excision of brain abscess is recommended whenever feasible, except for cases with toxoplasmosis (strong and low). Recommended empirical antimicrobial treatment for community-acquired brain abscess in immuno-competent individuals is a 3rd-generation cephalosporin and metronidazole (strong and moderate) with the addition of trimethoprim-sulfamethoxazole and voriconazole in patients with severe immuno-compromise (conditional and low). Recommended empirical treatment of post-neurosurgical brain abscess is a carbapenem combined with vancomycin or linezolid (conditional and low). The recommended duration of antimicrobial treatment is 6-8 weeks (conditional and low). No recommendation is offered for early transition to oral antimicrobials because of a lack of data, and oral consolidation treatment after ≥6 weeks of intravenous antimicrobials is not routinely recommended (conditional and very low). Adjunctive glucocorticoid treatment is recommended for treatment of severe symptoms because of perifocal oedema or impending herniation (strong and low). Primary prophylaxis with antiepileptics is not recommended (conditional and very low). Research needs are addressed.


The production of mammary carcinomas in rats by 9,10-dimethyl-1,2-benzanthracene and its relationship to the oestrous cycle.
Sprague-Dawley rats aged 50 days were given single oral doses of the carcinogen, DMBA.Rats receiving the carcinogen at the same stage of the oestrous cycle were grouped together and mammary tumour production was compared between these groups.When the carcinogen was given during di-oestrus the mean number of tumours per animal was significantly greater than when it was given at other stages in the oestrous cycle. There was considerable variation in total tumour yield from one batch of animals to another.


The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy.
Of 217 patients in whom anterior ischemic optic neuropathy (AION) was diagnosed during the period from 1975 to 1985, verifiable medical information was obtained for 212 (98%). Over a median follow-up period of three years, no group of patients had an increased mortality rate over that of age-, sex-, and race-matched controls; however, patients with "idiopathic" AION and patients with systemic hypertension who developed nonarteritic AION had a statistically significant increased risk of experiencing cerebrovascular events and myocardial infarctions compared with appropriately matched control groups. In view of the findings of our study, we suggest that patients with idiopathic AION and hypertensive patients who develop nonarteritic AION undergo a complete physical examination, cardiac evaluation, tests of carotid artery patency, and careful medical follow-up to attempt to prevent subsequent cerebrovascular or cardiovascular events.


Magnetic Hysteresis at 10 K in Single Molecule Magnet Self-Assembled on Gold.
Tremendous progress in the development of single molecule magnets (SMMs) raises the question of their device integration. On this route, understanding the properties of low-dimensional assemblies of SMMs, in particular in contact with electrodes, is a necessary but difficult step. Here, it is shown that fullerene SMM self-assembled on metal substrate from solution retains magnetic hysteresis up to 10 K. Fullerene-SMM DySc2N@C80 and Dy2ScN@C80 are derivatized to introduce a thioacetate group, which is used to graft SMMs on gold. Magnetic properties of grafted SMMs are studied by X-ray magnetic circular dichroism and compared to the films of nonderivatized fullerenes prepared by sublimation. In self-assembled films, the magnetic moments of the Dy ions are preferentially aligned parallel to the surface, which is different from the disordered orientation of endohedral clusters in nonfunctionalized fullerenes. Whereas chemical derivatization reduces the blocking temperature of magnetization and narrows the hysteresis of Dy2ScN@C80, for DySc2N@C80 equally broad hysteresis is observed as in the fullerene multilayer. Magnetic bistability in the DySc2N@C80 grafted on gold is sustained up to 10 K. This study demonstrates that self-assembly of fullerene-SMM derivatives offers a facile solution-based procedure for the preparation of functional magnetic sub-monolayers with excellent SMM performance.


Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo.
In sickle cell disease (SCD), adhesion of sickle red blood cells (SSRBCs) and activated leukocytes in inflamed venules affects blood rheology, causing vaso-occlusive manifestations and vital reduction in microvascular blood flow. Recently, we found that NADPH oxidases (NOXs) create a vicious feedback loop within SSRBCs. This positive feedback loop mediates SSRBC adhesion to the endothelium. We show for the first time the therapeutic effectiveness of the redox-active manganese (Mn) porphyrins MnTnBuOE-2-PyP5+ (MnBuOE; BMX-001) and MnTE-2-PyP5+ (MnE; BMX-010, AEOL10113) to treat established vaso-occlusion in a humanized sickle mouse model of an acute vaso-occlusive crisis using intravital microscopy. These Mn porphyrins can suppress SSRBC NOX activity. Subcutaneous administration of only 1 dose of MnBuOE or MnE at 0.1 to 2 mg/kg after the inflammatory trigger of vaso-occlusion, or simultaneously, reversed and reduced leukocyte and SSRBC adhesion, diminished leukocyte rolling, restored blood flow, and increased survival rate. Furthermore, MnBuOE and MnE administered to sickle mice subcutaneously at 0.1 to 1 mg/kg for 28 days (except on weekends) did not exacerbate anemia, which seemed to be due to downregulation of both SSRBC reactive oxygen species production and exposure of the eryptotic marker phosphatidylserine. In addition, Mn porphyrins ameliorated leukocytosis, venous blood gases, endothelial activation, and organ oxidative damage. Our data suggest that Mn porphyrins, likely by repressing NOX-mediated adhesive function of SSRBCs and activated leukocytes, could represent a novel, safe therapeutic intervention to treat or prevent the establishment of acute pain crises. These NOX-targeted antioxidants merit further assessment in SCD clinical trials.


Immune Correlates of GM-CSF and Melanoma Peptide Vaccination in a Randomized Trial for the Adjuvant Therapy of Resected High-Risk Melanoma (E4697).
Purpose: E4697 was a multicenter intergroup randomized placebo-controlled phase III trial of adjuvant GM-CSF and/or a multiepitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma.Experimental Design: A total of 815 patients were enrolled from December 1999 to October 2006 into this six-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase368-376 (370D), gp100209-217 (210M), MART-127-35) in montanide was designed to promote melanoma-specific CD8+ T-cell responses.Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. A total of 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8+ T-cell responses. HLA-A2+ patients who had any peptide-specific CD8+ T-cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF-neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.Conclusions: The assessment of cellular and humoral responses identified counterintuitive immune system changes correlating with clinical outcome. Clin Cancer Res; 23(17); 5034-43. ©2017 AACR.


Enhanced transmission of transverse electric waves through periodic arrays of structured subwavelength apertures.
Transmission through sub-wavelength apertures in perfect metals is expected to be strongly suppressed. However, by structural engineering of the apertures, we numerically demonstrate that the transmission of transverse electric waves through periodic arrays of subwavelength apertures in a thin metallic film can be significantly enhanced. Based on equivalent circuit theory analysis, periodic arrays of square structured subwavelength apertures are obtained with a 1900-fold transmission enhancement factor when the side length a of the apertures is 10 times smaller than the wavelength (a/lambda =0.1). By examining the induced surface currents and investigating the influence of the lattice constant and the incident angle to the resonant frequency, we show that the enhancement is due to the excitation of the strong localized resonant modes of the structured apertures.


A Pro-Metastatic Derivatives Eliminator for In Vivo Dual-Removal of Circulating Tumor Cells and Tumor-Derived Exosomes Impedes their Biodistribution into Distant Organs.
Circulating tumor cells (CTCs) and tumor-derived exosomes (TDEs) play an irreplaceable role in the metastatic cascade and preventing them from reaching distant organs via blood circulation helps to reduce the probability of cancer recurrence and metastasis. However, technologies that can simultaneously prevent CTCs and TDEs from reaching distant organs have not been thoroughly developed until now. Here, inspired by hemoperfusion, a pro-metastatic derivative eliminator (PMDE) is developed for the removal of both CTCs and TDEs from the peripheral blood, which also inhibits their biodistribution in distant organs. This device is designed with a dual antibody-modified immunosorbent filled into a capture column that draws peripheral blood out of the body to flow through the column to specifically capture CTCs and TDEs, followed by retransfusing the purified blood into the body. The PMDE can efficiently remove CTCs and TDEs from the peripheral blood and has excellent biocompatibility. Interestingly, the PMDE device can significantly inhibit the biodistribution of CTCs and TDEs in the lung and liver by scavenging them. This work provides a new perspective on anti-metastatic therapy and has broad prospects in clinical applications to prevent metastasis and recurrence.


Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays.
We have established highly sensitive and specific androgen and estrogen reporter cell lines which we have named AR (androgen receptor) and ERalpha (estrogen receptor alpha) CALUX (Chemically Activated LUciferase eXpression), respectively. Both bioassays are member of a panel of CALUX reporter cell lines derived from the human U2-OS osteosarcoma cell line, all using highly selective reporter constructs based with a basal promoter element linked to multimerized response elements, allowing efficient and specific measurement of compounds interfering with androgen, estrogen, progesterone, and glucocorticoid receptors. The AR CALUX bioassay contains the human androgen receptor and a luciferase reporter construct containing three androgen-responsive elements coupled to a minimal TATA promoter. This cell line was characterized by its stable expression of AR protein, its highly selective response to low levels of different natural and synthetic androgens, and its insignificant response to other nuclear hormone receptor ligands such as estrogens, progestins, and glucocorticoids. The EC50 of dihydrotestosterone (DHT) was found to be 0.13 nM, consistent with the high affinity of this ligand to the human AR. Flutamide, cyproterone acetate, and the environmental contaminants vinclozolin, DDT, methoxychlor, its metabolite HPTE, and penta-BFR showed clear antagonistic activity in the AR CALUX bioassay, competitively inhibiting DHT-mediated transactivation. The established AR CALUX bioassay proved to excel in terms of easy cell line maintenance, high fold induction range (typical 30 times over solvent control), low minimal detection limit (3.6 pM), and high androgen selectivity. Potential applications such as testing the androgenic or estrogenic activity of pure chemicals and pharmaceuticals and complex mixtures (environmental, food, feed, and clinical) are discussed.


Update on Predicting Severe Hyperbilirubinemia and Bilirubin Neurotoxicity Risks in Neonates.
Extreme hyperbilirubinemia and kernicterus, though rare, continue to occur despite the adoption of universal screening. Unless they are known to have glucose-6-phosphate dehydrogenase deficiency, infants who currently develop kernicterus in high resource countries are often otherwise healthy newborns discharged from the well-baby nursery. In this review, we highlight risk factors that increase the risk of a newborn ≥35 weeks gestational age developing severe hyperbilirubinemia, as well as the risk factors that increase the hyperbilirubinemic infant's risk of kernicterus.


Childbirth and fertility preservation in childhood and adolescent cancer patients: a second national survey of Japanese pediatric endocrinologists.
Although existing guidelines recommend long-term follow-up of childhood cancer survivors (CCSs), their fertility has not been fully investigated in Japan. To address this issue, we organized a working panel consisting of medical specialists in foundation hospitals. We conducted questionnaire surveys targeting pediatric endocrinologists regarding reproduction in pediatric and adolescent cancer patients in collaboration with the CCS committee of the Japanese Society for Pediatric Endocrinology (JSPE). The first questionnaire was sent to 178 directors or councilors of the JSPE, and the second was sent to those who had provided answers on their experience with childbirth or fertility preservation. A total of 151 responses (84.8%) were obtained in the first survey. In the second survey, the response rate was 100% (39 respondents). There were 27 answers describing experiences with childbirth (16 from partners of male CCSs, 22 from female CCSs). A few cases of premature birth and low birth weight were reported. There were 25 answers describing experiences with fertility preservation; 21 were from male and 17 from female CCSs. It was mainly physicians who recommended fertility preservation. This nationwide questionnaire survey revealed that a limited number of Japanese pediatric endocrinologists had experience with childbirth and fertility preservation in CCSs. A further long-term follow-up study of their fertility is needed.


Prognostic Value of the New Prostate Cancer International Society of Urological Pathology Grade Groups.
Gleason grading is the best independent predictor for prostate cancer (PCa) progression. Recently, a new PCa grading system has been introduced by the International Society of Urological Pathology (ISUP) and is recommended by the World Health Organization (WHO). Following studies observed more accurate and simplified grade stratification of the new system. Aim of this study was to compare the prognostic value of the new grade groups compared to the former Gleason Grading and to determine whether re-definition of Gleason Pattern 4 might reduce upgrading from prostate biopsy to radical prostatectomy (RP) specimen. A cohort of men undergoing RP from 2002 to 2015 at the Hospital of Goeppingen (Goeppingen, Germany) was used for this study. In total, 339 pre-operative prostatic biopsies and corresponding RP specimens, as well as additional 203 RP specimens were re-reviewed for Grade Groups according to the ISUP. Biochemical recurrence-free survival (BFS) after surgery was used as endpoint to analyze prognostic significance. Other clinicopathological data included TNM-stage and pre-operative PSA level. Kaplan-Meier analysis revealed risk stratification of patients based on both former Gleason Grading and ISUP Grade Groups, and was statistically significant using the log-rank test (p < 0.001). Both grading systems significantly correlated with TNM-stage and pre-operative PSA level (p < 0.001). Higher tumor grade in RP specimen compared to corresponding pre-operative biopsy was observed in 44 and 34.5% of cases considering former Gleason Grading and ISUP Grade Groups, respectively. Both, former Gleason Grading and ISUP Grade Groups predict survival when applied on tumors in prostatic biopsies as well as RP specimens. This is the first validation study on a large representative German community-based cohort to compare the former Gleason Grading with the recently introduced ISUP Grade Groups. Our data indicate that the ISUP Grade Groups do not improve predictive value of PCa grading and might be less sensitive in deciphering tumors with 3 + 4 and 4 + 3 pattern on RP specimen. However, the Grade Group system results less frequently in an upgrading from biopsy to the corresponding RP specimens, indicating a lower risk to miss potentially aggressive tumors not represented on biopsies.


Consumer Decision-Making Abilities and Long-Term Care Insurance Purchase.
To determine the impact of consumer decision-making abilities on making a long-term care insurance (LTCi) purchasing decision that is consistent with normative economic predictions regarding policy ownership. Using data from the Health and Retirement Study, multivariate analyses are implemented to estimate the effect of decision-making ability factors on owning LTCi. Stratified multivariate analyses are used to examine the effect of decision-making abilities on the likelihood of adhering to economic predictions of LTCi ownership. In the full sample, better cognitive capacity was found to significantly increase the odds of ownership. When the sample was stratified based on expected LTCi ownership status, cognitive capacity was positively associated with ownership among those predicted to own and negatively associated with ownership among those predicted not to own who could likely afford a policy. Consumer decision-making abilities, specifically cognitive capacity, are an important determinant of LTCi decision outcomes. Deficits in this ability may prevent individuals from successfully preparing for future long-term care expenses. Policy makers should consider changes that reduce the cognitive burden of this choice, including the standardization of the LTCi market, the provision of consumer decision aids, and alternatives to voluntary and private insuring mechanisms.


Common coding of expected value and value uncertainty memories in the prefrontal cortex and basal ganglia output.
Recent evidence implicates both basal ganglia and ventrolateral prefrontal cortex (vlPFC) in encoding value memories. However, comparative roles of cortical and basal nodes in value memory are not well understood. Here, single-unit recordings in vlPFC and substantia nigra reticulata (SNr), within macaque monkeys, revealed a larger value signal in SNr that was nevertheless correlated with and had a comparable onset to the vlPFC value signal. The value signal was maintained for many objects (>90) many weeks after reward learning and was resistant to extinction in both regions and to repetition suppression in vlPFC. Both regions showed comparable granularity in encoding expected value and value uncertainty, which was paralleled by enhanced gaze bias during free viewing. The value signal dynamics in SNr could be predicted by combining responses of vlPFC neurons according to their value preferences consistent with a scheme in which cortical neurons reached SNr via direct and indirect pathways.


Endoscopic ultrasonography-guided gastroenterostomy versus uncovered duodenal metal stenting for unresectable malignant gastric outlet obstruction (DRA-GOO): a multicentre randomised controlled trial.
Endoscopic ultrasonography-guided gastroenterostomy (EUS-GE) is a novel endoscopic method to palliate malignant gastric outlet obstruction. We aimed to assess whether the use of EUS-GE with a double balloon occluder for malignant gastric outlet obstruction could reduce the need for reintervention within 6 months compared with conventional duodenal stenting. The was an international, multicentre, randomised, controlled trial conducted at seven sites in Hong Kong, Belgium, Brazil, India, Italy, and Spain. Consecutive patients (aged ≥18 years) with malignant gastric outlet obstruction due to unresectable primary gastroduodenal or pancreatobiliary malignancies, a gastric outlet obstruction score (GOOS) of 0 (indicating an inability in intake food or liquids orally), and an Eastern Cooperative Oncology Group performance status score of 3 or lower were included and randomly allocated (1:1) to receive either EUS-GE or duodenal stenting. The primary outcome was the 6-month reintervention rate, defined as the percentage of patients requiring additional endoscopic intervention due to stent dysfunction (ie, restenosis of the stent due to tumour ingrowth, tumour overgrowth, or food residue; stent migration; or stent fracture) within 6 months, analysed in the intention-to-treat population. Prespecified secondary outcomes were technical success (successful placement of a stent), clinical success (1-point improvement in gastric outlet obstruction score [GOOS] within 3 days), adverse events within 30 days, death within 30 days, duration of stent patency, GOOS at 1 month, and quality-of-life scores. This study is registered with ClinicalTrials.gov (NCT03823690) and is completed. Between Dec 1, 2020, and Feb 28, 2022, 185 patients were screened and 97 (46 men and 51 women) were recruited and randomly allocated (48 to the EUS-GE group and 49 to the duodenal stent group). Mean age was 69·5 years (SD 12·6) in the EUS-GE group and 64·8 years (13·0) in the duodenal stent group. All randomly allocated patients completed follow-up and were analysed. Reintervention within 6 months was required in two (4%) patients in the EUS-GE group and 14 (29%) in the duodenal stent group [p=0·0020; risk ratio 0·15 [95% CI 0·04-0·61]). Stent patency was longer in the EUS-GE group (median not reached in either group; HR 0·13 [95% CI 0·08-0·22], log-rank p<0·0001). 1-month GOOS was significantly better in the EUS-GE group (mean 2·41 [SD 0·7]) than the duodenal stent group (1·91 [0·9], p=0·012). There were no statistically significant differences between the EUS-GE and duodenal stent groups in death within 30 days (ten [21%] vs six [12%] patients, respectively, p=0·286), technical success, clinical success, or quality-of-life scores at 1 month. Adverse events occurred 11 (23%) patients in the EUS-GE group and 12 (24%) in the duodenal stent group within 30 days (p=1·00); three cases of pneumonia (two in the EUS-GE group and one in the duodenal stent group) were considered to be procedure related. In patients with malignant gastric outlet obstruction, EUS-GE can reduce the frequency of reintervention, improve stent patency, and result in better patient-reported eating habits compared with duodenal stenting, and the procedure should be used preferentially over duodenal stenting when expertise and required devices are available. Research Grants Council (Hong Kong Special Administrative Region, China) and Sociedad Española de Endoscopia Digestiva.


Plant Strategies along Resource Gradients.
Plants present a variety of defensive strategies against herbivores, broadly classified into tolerance and resistance. Since resource availability can also limit plant growth, we expect plant allocation to resource acquisition and defense to vary along resource gradients. Yet, the conditions under which one defensive strategy is favored over the other are unclear. Here, we use an eco-evolutionary model to investigate plant adaptive allocation to resource acquisition, tolerance, and resistance along a resource gradient in a simple food web module inspired by plankton communities where plants compete for a single resource and are grazed on by a shared herbivore. We show that undefended, acquisition-specialist strategies dominate under low resource supplies. Conversely, high resource supplies, which lead to high herbivore abundance because of trophic transfers, result in either the dominance of very resistant strategies or coexistence between a completely resistant strategy and a fast-growing, tolerant one. We also explore the consequences of this adaptive allocation on species biomasses. Finally, we compare our predictions to a more traditional, density-independent optimization model. We show that density dependence mediated by resources and herbivores is the cause of the increase in plant resistance along the resource gradient, as the optimization model would instead have favored tolerance.


Transparency and accountability in mass media campaigns about organ donation: a response to Morgan and Feeley.
We respond to Morgan and Feeley's critique on our article "Mass Media in Organ Donation: Managing Conflicting Messages and Interests." We noted that Morgan and Feeley agree with the position that the primary aims of media campaigns are: "to educate the general public about organ donation process" and "help individuals make informed decisions" about organ donation. For those reasons, the educational messages in media campaigns should not be restricted to "information from pilot work or focus groups" but should include evidence-based facts resulting from a comprehensive literature research. We consider the controversial aspects about organ donation to be relevant, if not necessary, educational materials that must be disclosed in media campaigns to comply with the legal and moral requirements of informed consent. With that perspective in mind, we address the validity of Morgan and Feeley's claim that media campaigns have no need for informing the public about the controversial nature of death determination in organ donation. Scientific evidence has proven that the criteria for death determination are inconsistent with the Uniform Determination of Death Act and therefore potentially harmful to donors. The decision by campaign designers to use the statutory definition of death without disclosing the current controversies surrounding that definition does not contribute to improved informed decision making. We argue that if Morgan and Feeley accept the important role of media campaigns to enhance informed decision making, then critical controversies should be disclosed. In support of that premise, we will outline: (1) the wide-spread scientific challenges to brain death as a concept of death; (2) the influence of the donor registry and team-huddling on the medical care of potential donors; (3) the use of authorization rather than informed consent for donor registration; (4) the contemporary religious controversy; and (5) the effects of training desk clerks as organ requestors at the Department of Motor Vehicles offices. We conclude that organ donation is a medical procedure subject to all the ethical obligations that the medical profession must uphold including that of transparency and truthfulness.


The innate response to peanut extract in ovine afferent lymph and its correlation with allergen sensitisation.
The innate response generated after initial allergen exposure is crucial for polarising adaptive immunity, but little is known about how it drives an atopic or type-2 immune response. The present study characterises the response of skin-draining afferent lymph in sheep following injection with peanut (PN) extract in the presence or absence of aluminium hydroxide (AlOH) adjuvant. Lymph was collected and innate cell populations characterised over an 84 h time period. The innate response to PN extract in afferent lymph displayed an early increase in neutrophils and monocytes without any changes in the dendritic cell (DC) population. PN antigen was transported by neutrophils and monocytes for the first 36 h, after which time DCs were the major antigen trafficking cells. AlOH adjuvant gradually increased antigen uptake by DCs at the later time points. Following lymphatic characterisation, sheep were sensitised with PN extract by three subcutaneous injections of PN in AlOH, and the level of PN-specific immunoglobulin E (IgE) was determined. Sheep with higher levels of steady-state DCs in afferent lymph showed increased monocytic recruitment in afferent lymph and reduced PN-specific IgE following sensitisation. In addition, DCs from afferent lymph that had ingested PN antigen increased the expression of monocyte chemoattractant mRNA. The results of this study show that the innate response to PN extract involves a dynamic change in cell populations in the afferent lymph over time. In addition, DCs may determine the strength of the initial inflammatory cell response, which in turn may determine the nature of the antigen-specific adaptive response.


SLC gene-modified dendritic cells mediate T cell-dependent anti-gastric cancer immune responses in vitro.
Dendritic cells (DCs) are potent professional antigen-presenting cells (APCs) with the ability to prime naïve T cells, and play an important role in the initiation and regulation of immune responses. In this study, we constructed a recombinant adenovirus carrying the SLC gene (Ad-SLC), and detected the biological effects of Ad-SLC-modified DCs as an adjuvant for the initiation of gastric cancer immune responses. Human DCs were transfected with Ad-SLC and the recombinant adenovirus carrying the β-galactosidase gene, Ad-LacZ, respectively. Modified DCs were pulsed with the cell lysate antigen of SGC-7901 cells (a type of gastric cancer cell line) and co-cultured with autologous T cells. The T cells were harvested and incubated with SGC-7901 cells and the cytotoxic function of the T cells was detected. Based on the data, the expression of mature DC phenotypes CD83 and CCR7 was upregulated after transfection with Ad-SLC and the chemotaxis function of DCs was augmented after transfection with Ad-SLC. Moreover, the expression of RANTES in DCs was upregulated by Ad-SLC transfection, while expression levels of IL-12p70 and IL-10 were not significantly altered. When co-cultured with autologous T cells, DCs modified with the SLC gene and pulsed with SGC-7901 cell lysates significantly promoted the proliferation of autologous T cells and induced Th1 differentiation, and displayed a strong cytotoxicity to SGC-7901 cells. In conclusion, Ad-SLC promoted DC maturation, enhancing the ability of DCs for T-cell chemotaxis and T-cell stimulation, and induced specific anti-gastric cancer cellular immunity. Recombinant Ad-SLC-modified DCs may be used as an adjuvant to induce an effective anti-gastric cancer immune response.


The Protective Agents Used against Acrylamide Toxicity: An In Vitro Cell Culture Study-Based Review.
Acrylamide is a dangerous electrophile with the potency to react with many biological moieties including proteins, and nucleic acids as well as other macromolecules. Acrylamide was first only known a chemical exposed in working areas as a neurotoxicant, it was later discovered that beyond just being a neurotoxicant exposed in industrial areas, acrylamide is exposed via daily foods as well. As such, several strategies have been sought to be developed to relieve the toxic spectrum of this chemical. The utilization of a protective agent against acrylamide toxicity was one of those strategies. To date, many agents with protective potency have been investigated. Herein, we compiled these agents and their effects shown in in vitro studies. We used the search engines of Web of Knowledge and searched the keywords "acrylamide" and "protect" in the titles along with the keyword "cell" in the topics. Twenty-one directly related articles out of 35 articles were examined. Briefly, all agents used against acrylamide were reported to exhibit protective activity. In most of these reports, 5 mM concentration of acrylamide and 24-hour treatment were the employed dose and duration. Usually, the beneficial agents were pre-treated to the cells. PC12 cells were the most utilized cell line, and the mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways were the most studied pathways. This study, beside other importance, can be utilized as a guide for how the protective studies against acrylamide were done and which parameters were investigated in in vitro acrylamide studies. In conclusion, taking measures is of utmost importance to prevent or alleviate the toxicity of acrylamide, to which we are daily exposed even in our homes. Therefore, future studies should persist in focusing on mitigating acrylamide toxicity.


MicroRNA-200a promotes anoikis resistance and metastasis by targeting YAP1 in human breast cancer.
The process of metastases involves the dissociation of cells from the primary tumor, penetration into the basement membrane, invasion, and exiting from the vasculature to seed and colonize distant tissues. miR-200a is involved in this multistep metastatic cascade. This study aimed to test the hypothesis that miR-200a promotes metastasis through increased anoikis resistance in breast cancer. Breast cancer cells transfected with mimic or inhibitor for miR-200a were assayed for anoikis in vitro. miR-200a expression was assessed by quantitative real-time PCR (qRT-PCR). Luciferase assays, colony formation assays, and animal studies were conducted to identify the targets of miR-200a and the mechanism by which it promotes anoikis resistance. We found that overexpression of miR-200a promotes whereas inhibition of miR-200a suppresses anoikis resistance in breast cancer cells. We identified Yes-associated protein 1 (YAP1) as a novel target of miR-200a. Our data showed that targeting of YAP1 by miR-200a resulted in decreased expression of proapoptotic proteins, which leads to anoikis resistance. Overexpression of miR-200a protected tumor cells from anoikis and promoted metastases in vivo. Furthermore, knockdown of YAP1 phenocopied the effects of miR-200a overexpression, whereas restoration of YAP1 in miR-200a overexpressed breast cancer cells reversed the effects of miR-200a on anoikis and metastasis. Remarkably, we found that YAP1 expression was inversely correlated with miR-200a expression in breast cancer clinical specimens, and miR-200a expression was associated with distant metastasis in patients with breast cancer. Our data suggest that miR-200a functions as anoikis suppressor and contributes to metastasis in breast cancer.


Three-dimensional structure of the yeast ribosome.
The 80S ribosome from Saccharomyces cerevisiae has been reconstructed from cryo electron micrographs to a resolution of 35 A. It is strikingly similar to the 70S ribosome from Escherichia coli, while displaying the characteristic eukaryotic features familiar from reconstructions of ribosomes from higher eukaryotes. Aside from the elaboration of a number of peripherally located features on the two subunits and greater overall size, the largest difference between the yeast and E.coli ribosomes is in a mass increase on one side of the large (60S) subunit. It thus appears more elliptical than the characteristically globular 50S subunit from E.coli. The interior of the 60S subunit reveals a variable diameter tunnel spanning the subunit between the interface canyon and a site on the lower back of the subunit, presumably the exit site through which the nascent polypeptide chain emerges from the ribosome.


[Review of materials of the Fourth European Venous Forum (Stockholm, Sweden)].
The article provides a brief review of the opinions and experience of the leading phlebologists from various countries, reflecting the latest updates and current problems regarding state-of-the-art management of diseases of major veins of lower extremities. Special attention is focussed on deep vein thromboses and consequence thereof, as well as varicose disease. This is followed by description of novel approaches to treatment of the pathology concerned.


Impact of proximal colon retroflexion on adenoma miss rates.
Small adenomas are commonly missed during routine colonoscopy. The aim of this study was to determine whether routine retroflexion in the proximal colon would improve adenoma detection rates. One hundred patients underwent colonoscopy from the cecum to the splenic flexure by a gastroenterology fellow, with the removal of all visualized polyps. The cecum was then reintubated and patients were randomized to a second exam of the proximal colon by an experienced staff physician in either the forward view or a retroflexed view. Two patients were excluded due to a difficult initial cecal intubation. Forty-eight patients were randomized to forward view and 50 patients were randomized to a retroflexed view. Retroflexion was successful in the cecum in 60%, the ascending colon 100%, and the transverse colon 98%. The success in retroflexion was determined in part by the type of colonoscope used. If any portion of the retroflexed examination could not be performed, that reexamination was performed in the forward view. The calculated miss rates for all polyps and adenomas among patients randomized to second examination in the forward view was 36.8% and 33.3%, respectively. The calculated miss rate for all polyps and for adenomas among patients randomized to a second examination in the retroflexed view was 38.1% and 23.7%, respectively. There was no difference in miss rates for all polyps or for adenomas (p= 0.31) when the second examination was performed in the forward view versus retroflexed view. A second examination by retroflexion in the proximal colon did not increase the calculated miss rate relative to that performed by a forward view examination. These results do not support the addition of routine right colon retroflexion to colonoscopy.


Cannabinoid hyperemesis acute renal failure: a common sequela of cannabinoid hyperemesis syndrome.
We report the case of a 25-year-old man with an 8-year history of daily marijuana use diagnosed with acute renal failure secondary to cannabinoid hyperemesis syndrome. The patient presented with "constant" vomiting for over a day. His symptoms were completely relieved with compulsive hot showering and partially relieved by hot baths, by high ambient room temperature, and transiently after smoking marijuana. The patient was found to have a creatinine of 3.21 and admitted for acute renal failure secondary to cannabinoid hyperemesis syndrome. Cannabinoid hyperemesis syndrome (CHS) is a recently described condition affecting long-term marijuana users. We found 5 other case reports of acute renal failure secondary to CHS [1-5], and a total of 55 case reports of CHS. The unique combination of intractable vomiting and constant hot showers seems to put CHS patients at significant risk of severe dehydration and prerenal failure, a common and distinct entity we suggest be termed cannabinoid hyperemesis acute renal failure (CHARF). The characteristics of cannabinoid hyperemesis acute renal failure patients were similar to CHS patients, except a larger portion were over the age of 30 (4 of 6, vs 30%). Evaluating physicians should maintain a high degree of suspicion for this common sequela of CHS.


Substance P and immunoregulation.
Peptides released from peripheral nerve endings in mammals, including the tachykinin substance P (SP) and vasoactive intestinal polypeptide (VIP), are potent mediators of smooth muscle and vascular functions. Significant neurophysiological activities of SP and VIP include the transmission of nociceptive and interneuron excitatory signals, respectively. SP has been shown to modulate distinct immediate hypersensitivity responses by stimulating the generation of arachidonic acid-derived mediators from mucosal mast cells but not basophils. Functions of mononuclear and polymorphonuclear leukocytes that characterize the inflammatory response and that are altered by SP include chemotaxis, lysosomal enzyme release, and phagocytic activities. The effects of SP on cell-mediated immunity are largely stimulatory, in that synthesis of DNA, protein, and immunoglobulin by mature T and B lymphocytes, respectively, is significantly enhanced at nanomolar concentrations of the neuropeptide. Functionally relevant receptors for SP on T lymphocytes have been demonstrated by cell sorter and radioligand-binding techniques, and the lymphocyte membrane proteins that comprise the SP receptor are currently being isolated and purified to homogeneity. The characterization of the structure of the SP lymphocyte receptor and identification of the receptor gene will permit detailed analyses of the molecular interactions between the immune and nervous systems.


Phonological Knowledge Guides Two-year-olds' and Adults' Interpretation of Salient Pitch Contours in Word Learning.
Phonology provides a system by which a limited number of types of phonetic variation can signal communicative intentions at multiple levels of linguistic analysis. Because phonologies vary from language to language, acquiring the phonology of a language demands learning to attribute phonetic variation appropriately. Here, we studied the case of pitch-contour variation. In English, pitch contour does not differentiate words, but serves other functions, like marking yes/no questions and conveying emotions. We show that, in accordance with their phonology, English-speaking adults and two-year-olds do not interpret salient pitch contours as inherent to novel words. We taught participants a new word with consistent segmental and pitch characteristics, and then tested word recognition for trained and deviant pronunciations using an eyegaze-based procedure. Vowel-quality mispronunciations impaired recognition, but large changes in pitch contour did not. By age two, children already apply their knowledge of English phonology to interpret phonetic consistencies in their experience with words.


Impact of myocardial infarction symptom presentation on emergency response and survival.
We examined associations between symptom presentation and chance of receiving an emergency dispatch and 30-day mortality among patients with acute myocardial infarction (MI). Copenhagen, Denmark has a 24-h non-emergency medical helpline and an emergency number 1-1-2 (equivalent to 9-1-1). Both services register symptoms/purpose of calls. Among patients with MI as either hospital diagnosis or cause of death within 72 h after a call, the primary symptom was categorized as chest pain, atypical symptoms (breathing problems, unclear problem, central nervous system symptoms, abdominal/back/urinary, other cardiac symptoms, and other atypical symptoms), unconsciousness, non-informative symptoms, and no recorded symptoms. We identified 4880 emergency and 3456 non-emergency calls from patients with MI. The most common symptom was chest pain (N = 5219) followed by breathing problems (N = 556). Among patients with chest pain, 95% (3337/3508) of emergency calls and 76% (1306/1711) of non-emergency calls received emergency dispatch. Mortality was 5% (163/3508) and 3% (49/1711) for emergency/non-emergency calls, respectively. For atypical symptoms 62% (554/900) and 17% (137/813) of emergency/non-emergency calls received emergency dispatch and mortality was 23% (206/900) and 15% (125/813). Among unconscious, patients 99%/100% received emergency dispatch and mortality was 71%/75% for emergency/non-emergency calls. Standardized 30-day mortality was 4.3% for chest pain and 15.6% for atypical symptoms, and associations between symptoms and emergency dispatch remained in subgroups of age and sex. Myocardial infarction patients presenting with atypical symptoms when calling for help have a reduced chance of receiving an emergency dispatch and increased 30-day mortality compared to MI patients with chest pain.


Zhile Capsule Exerts Antidepressant-Like Effects through Upregulation of the BDNF Signaling Pathway and Neuroprotection.
Major depressive disorder is now becoming a common disease in daily life, and most patients do not have satisfactory treatment outcomes. We herein evaluated the therapeutic effects of Zhile capsule and clarified the molecular mechanism. A rat model of chronic unpredictable mild stress-induced depression was established to assess the antidepressant-like effects of Zhile by using the sucrose preference test, open field test, forced swim test, tail suspension test and HPLC. Systems pharmacology was then performed to unravel the underlying mechanism which was confirmed by western blot, enzyme-linked immunosorbent assay, and qPCR. Zhile alleviated depression-like behaviors by upregulating the cAMP-CREB-BDNF (brain-derived neurotrophic factor) axis to exert neuroprotective effects. It may be beneficial to depressive patients in clinical practice.


Clinical significance of BRAF (V600E) mutation and Ki-67 labeling index in papillary thyroid carcinomas.
Activating mutations of the BRAF gene have recently been reported in thyroid carcinomas. In particular, V600E mutation is highly prevalent in papillary thyroid carcinoma (PTC). In this study, the BRAF (V600E) mutation in 54 PTCs was investigated and the relationship between the BRAF mutation and clinicopathological features such as age, gender, tumor size, extrathyroid extension, lymph node metastasis, and distant metastasis was analyzed. Additionally, Ki-67 labeling index (LI) was determined to evaluate tumor cell proliferative activity. The BRAF mutation was detected in 26 (65%) of 40 primary and 12 (85.7%) of 14 recurrent PTCs. The BRAF mutation was significantly related to older age (57.4 vs. 43.1 years, p=0.012), extrathyroid extension (76.9% vs. 35.7%, p=0.026), and lymph node metastasis (88.5% vs. 57.1%, p=0.044). Moreover, the mean Ki-67 LI was significantly higher in BRAF-positive patients than in BRAF-negative patients (1.01% vs. 0.135%, p=0.014). The BRAF mutation was common in PTCs classified as advanced TNM stage. Eighteen of 20 (90%) patients in TNM stages III and IV were positive for this gene mutation. Similarly, the BRAF mutation was investigated in 14 recurrent PTCs and was detected in 85.7% (12 of 14). The BRAF mutation was also common in patients with regional lymph node recurrence. These results suggest that PTCs with BRAF (V600E) mutation are more aggressive than those with wildtype BRAF. This mutation may be important for predicting a worse prognosis in patients with PTC.


Autoimmunity to chaperonins in the pathogenesis of arthritis and diabetes.
The immunology of the 65 kd heat shock protein (hsp65) is paradoxical. Microbial and mammalian hsp65 molecules are 50% identical in amino acid sequence and immunologically cross-reactive, so microbial hsp65 looks like self; yet hsp65 is a dominant antigen in infection. Immunity to hsp65 can cause autoimmune diabetes in mice and may be related to autoimmune arthritis in rats and humans, so immunity to hsp65 should be forbidden; yet healthy persons manifest T-cell responses to self-hsp65. The aim of this chapter is to explore the immunological dominance of hsp65 and its role in autoimmunity--benign and pernicious.


Choice of Fluids in Severe Septic Patients - A Cost-effectiveness Analysis Informed by Recent Clinical Trials.
Fluid resuscitation with colloids is an established second line therapy for septic patients. Evidence of relative efficacy outcomes is tempered by considerations of the relative costs of the individual fluids. An assessment of recent large clinical trials was performed, resulting in a ranking in the efficacy of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) were derived and used to inform a decision analysis model comparing the effect of crystalloid, albumin and hydroxyethyl starch solutions in severe septic patients followed from hospital admission to 90 days in intensive care. The US payer perspective was used. Model inputs for costs and efficacy were derived from the peer-reviewed literature, assuming that that all fluid preparations are bio-equivalent within each class of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) data were synthesized using a Bayesian meta-analysis. Relative to crystalloid therapy, 0.21 life years were gained with albumin and 0.85 life years were lost with hydroxyethyl starch. One-way sensitivity analysis showed that the model's outcomes were sensitive to the cost of RRT but not to the costs of the actual fluids or any other costs. We conclude that albumin may be the most cost-effective treatment in these patients when the total medical costs and iatrogenic morbidities involved in treating sepsis with fluids are considered. These results should assist and inform decision making in the choice of these drugs.


Cytokines, Angiogenesis, and Extracellular Matrix Degradation are Augmented by Oxidative Stress in Endometriosis.
The effect of the interplay among inflammation, angiogenesis, extracellular matrix (ECM) degradation, and oxidative stress (OS) on the pathogenesis of endometriosis remains unclear. Previously, we demonstrated the role of OS in endometriosis. Here, we performed a comprehensive investigation of several molecules involved in inflammation, angiogenesis, and ECM degradation in women with endometriosis to study their interplay with OS. Blood samples were collected from women with endometriosis (N=80), as well as from women with tubal factor infertility as controls (N=80). Interleukin (IL)-1β, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta, IL-4, -10, -2, -6, -8, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, -9, tissue inhibitor of metalloproteinases (TIMP)-1, -2, and cyclooxygenase (COX)-2 levels in serum samples were measured using an ELISA. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in peripheral blood mononuclear cells was measured using flow cytometry. Cytokines, VEGF, MMPs, and COX-2 were significantly higher and TIMPs were significantly lower in patients with endometriosis. Multivariate statistical analysis indicated that IL-10 was the most significant variable capable of discriminating endometriosis samples from controls. Deregulation of NF-κB activation by OS affects the expression of various cytokines in endometriosis. Elevated cytokine levels further up-regulate IL-10, which subsequently activates the MMPs, leading to excessive ECM degradation and angiogenesis. Moreover, IL-10 emerged as the most important molecule involved in the pathogenesis of endometriosis. Measurement of these molecules may help in better management of the patients with endometriosis.


Genetic Features of Extended-Spectrum β-Lactamase-Producing Escherichia coli from Poultry in Mayabeque Province, Cuba.
A total of 434 poultry cloacal samples were collected from seven different farms in different years (2013-2015) in the Cuban province of Mayabeque and analyzed for the presence of third-generation cephalosporin-resistant Escherichia coli (3GC-R-Ec). Sixty-two 3GC-R-Ec isolates were recovered in total from the farms, with detection rates of 2.9% in 2013, 10.3% in 2014, and 28.7% in 2015. Characterization of 32 3GC-R-Ec isolates revealed the presence of the extended-spectrum β-lactamase (ESBL) genes blaCTX-M-1 (n = 27), blaCTX-M-15 (n = 4), and blaCTX-M-1 together with blaLAP-2 (n = 1). The isolates also contained different proportions of genes conferring decreased susceptibility to sulfonamides (sul1, sul2, sul3), trimethoprim (dfrA1, dfrA7, dfrA12, dfrA14, dfrA17), tetracyclines (tet(A), tet(B)), aminoglycosides (aac(6')-Ib-cr, strA, strB), chloramphenicol (cmlA1, floR), macrolides (mph(A), mph(D)), and quinolones (qnrS, qnrB, aac(6')-Ib-cr) as well as mutations in the fluoroquinolone-resistance determining regions of GyrA (S83L, D87N, D87Y) and ParC (S80I, E84G). The isolates belonged to 23 different sequence types and to phylogroups A (n = 25), B1 (n = 5), and D (n = 2), and they contained plasmid-associated incompatibility groups FII, X1, HI1, HI2, N, FIA, and FIB. These findings reveal a genetically diverse population of multiresistant ESBL-producing E. coli in poultry farms in Cuba, which suggests multiple sources of contamination and the acquisition of antibiotic resistance genes.


[Perioperative tobacco cessation: a crucial period to overcome clinical inertia and poor compliance].
Smoking concerns 30% of the patients scheduled to anesthesia. Tobacco is one of the most important risk factors for postoperative complications. There are two classes of complications: those induced by the smoking habits on the cardiovascular and the respiratory systems, and those that predispose to other complications by direct interference with processes required for the success of surgery: healing and immune responses. The preoperative period represents a crucial period to overcome clinical inertia and profit of a better compliance. Some strategies applicable by the general practitioner and the anesthesiologist during the preoperative consultation to establish smoking cessation and help the patient to comply with are proposed.


HLA antigens and seronegative rheumatoid arthritis.
HLA antigens and clinical features in a series of 46 Caucasian patients (40 females, 6 males) and definite repeatedly seronegative rheumatoid arthritis (RA) of more than two years' duration (mean 11.6 years) were compared with those in 77 seropositive RA patients and 110 controls of the same ethnic and geographic origin. Seronegative RA appeared to be less often erosive than seropositive RA, and seronegative patients had fewer extra-articular features. The frequency of the HLA antigen DR1 was raised in seronegative patients as compared with controls (p = 0.006, relative risk = 3) and with seropositive patients (p less than 0.05). HLA-DR4 was slightly increased in seronegative patients compared with controls (p less than 0.05) but was clearly less so than in seropositive patients (p less than 0.005). Early onset of disease was very significantly associated with HLA-DR1 in seronegative patients (p = 0.007), whereas HLA-DR4 was present more frequently in seropositive patients with onset prior to age 35 (p less than 0.05). No correlation between HLA antigens and intolerance to drugs was found in seronegative patients, whereas in seropositive patients side effects to gold salts were associated with DR3. These results suggest that seropositive and seronegative RA have distinct HLA-DR associations, especially in disease of early onset, in addition to well established clinical differences.


Efficient one-day sampling of mechanical job exposure data--a study based on upper trapezius activity in cleaners and office workers.
This ergonomics exposure assessment study compared the efficiency of eight 1-day-only strategies, that is, the relationship between the number of data collected per subject and the precision of the resulting mean exposure estimate. Whole-day electromyographic recordings from the right upper trapezius muscle in 24 cleaners and 23 office workers were processed to give minute-by-minute values of gap time and jerk time-parameters representing the level and frequency dimensions of muscle activation, respectively. On-site observations provided data on time spent in each of eight exhaustive task categories in the job, seven of which were associated with activities during work, and the last comprising breaks. On average, sampling at fixed intervals without regard to tasks doubled efficiency as compared with random sampling, which in turn was several times as efficient as consecutive sampling. Stratified sampling according to the two broad categories, work and breaks, increased efficiency for random and fixed-interval sampling, but the gain was distinct only among cleaners (about 20%). The commonly used strategy in ergonomic studies of sampling consecutively for short periods within tasks was highly inefficient. Further classification of work into the seven subcategories resulted in marginal additional increases in efficiency; on average less than 2%. A decision algorithm is given for determining appropriate sampling strategies in different types of jobs.


Continuous palliative sedation: not only a response to physical suffering.
Palliative sedation is a medical intervention aimed at relieving symptoms that can no longer be controlled by conventional treatment. Ample knowledge is available regarding the nature of such symptoms, but there is no in-depth information regarding how health care workers decide about palliative sedation. The study objective was to investigate considerations concerning the indications for continuous palliative sedation (CPS) and issues that influence these considerations. The study consisted of qualitative interviews regarding patients who had recently received CPS. The study involved physicians and nurses working in general practice, nursing homes, and hospitals. Analyses by a multidisciplinary research team used the constant comparative method. Together with physical symptoms, psychological and existential suffering may combine to produce a refractory state for which other treatment options than CPS were not available or considered inappropriate. A limited life expectancy was by many considered crucial (e.g., to avoid hastening death) and by some less important (e.g., because the patient's suffering was considered to be key). Issues influencing the decision to use CPS related to patient preferences (e.g., dignity, not wanting to experience further suffering) or family issues (impact of suffering on family, family requesting CPS). The indication for CPS typically originates from physical symptoms and nonphysical problems producing a refractory state in which a patient suffers unbearably. In such states, preferences of patients and families and the life expectancy criterion are weighed against the severity of refractory symptoms. Therefore the use of CPS is not only a response to the physical suffering of patients in the dying phase.


Reduction of the intake of food and water is responsible for reduction of litter growth when dams are treated with a progesterone antagonist.
Treatment of lactating rats with the anti-progestin Mifepristone or Onapristone adversely affects growth of their litters. The present studies aimed to elucidate the underlying mechanism. The treatment did not interfere with the behavioural interactions between mothers and pups, which are required for normal litter growth. Treatment with the antagonists had a stimulatory action on ovarian oestrogen production. However, ovarian hormones did not play a role in litter growth impairment, as this also occurred with lactating ovariectomized rats. Treatment with anti-progestins did not affect the concentrations of the macronutrients in milk (protein, lactose and lipid), nor did it change the fatty acid composition of lipid. Reduced litter growth was not related to a possible direct effect of exposure of the suckling young to the drugs via the milk. Direct injections into them unequivocally affected adrenal gland and testicular development, but did not affect their body-weight development. Milk secretion, as measured by the milk weight accumulating during 6 or 24 h following sudden removal of litters in advanced lactation, was not impaired by the treatments. However, the ingestion of food and water by dams treated with Mifepristone was significantly below that of control animals. It is concluded that litter growth impairment during treatment of lactating rats with anti-progestin results from the reduction of the intake of food and water by the mother.


Serotonin-storing secretory granules from thyroid parafollicular cells.
The subcellular storage of 5-HT was studied in sheep thyroid parafollicular cells. These cells are neural crest derivatives and were investigated as a serotonergic model system. Light and electron microscopic immunocytochemistry was used to examine the distributions of 5-HT, 45 and 56 kDa forms of 5-HT binding protein (SBP), and calcitonin. A single type of parafollicular cell was found that contained calcitonin, 5-HT, and 45 kDa SBP but not 56 kDa SBP. The secretory granules of parafollicular cells all displayed calcitonin immunoreactivity, and many were also immunoreactive for 5-HT and 45 kDa SBP. Granules were isolated, first by size and then by density, on successive metrizamide gradients. These provided a granular fraction that was enriched in calcitonin, endogenous 5-HT, and 45 kDa SBP. Immunoblots confirmed the presence of 45 kDa SBP in the isolated granules and in suspensions of parafollicular cells that were purified by an affinity chromatographic technique. Parafollicular cell granules did not appear to contain substantial stores of ATP. Granules isolated on Percoll gradients were morphologically homogeneous and took up 3H-5-HT. The specificity of this uptake was confirmed by quantitative electron microscopic radioautography. The granular uptake of 3H-5-HT was inhibited by reserpine (10 microM). It is concluded that parafollicular cell granules are different from other amine-storing vesicles that do contain ATP; nevertheless, since parafollicular cell granules store 5-HT and have the same 45 kDa SBP as is found in serotonergic axon terminals, parafollicular cell granules may be analogous to the synaptic vesicles of serotonergic neurons.


Relative abuse liability of triazolam: experimental assessment in animals and humans.
The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.


Cerebrospinal fluid vasopressin, oxytocin, somatostatin, and beta-endorphin in Alzheimer's disease.
As a first step toward assessing the status of brain neuropeptide systems that may be involved in Alzheimer's disease (AD), the cerebrospinal fluid (CSF) concentrations of the neuropeptides arginine vasopressin, somatostatin, oxytocin, and beta-endorphin were measured in patients with AD, normal elderly subjects, and normal young subjects. The plasma arginine vasopressin level was also measured in the three groups. The CSF arginine vasopressin level was significantly lower in patients with AD than in either elderly or young normal subjects, but oxytocin and beta-endorphin levels did not differ between groups. The CSF osmolarity also did not differ between groups. The plasma arginine vasopressin level did not significantly differ between groups, but high plasma arginine vasopressin values were absent in the patients with AD. The CSF somatostatin level was significantly lower in patients with AD than in normal elderly persons, but it did not differ in young normal subjects. These results suggest that central vasopressinergic activity may be decreased in AD and confirm reports of low CSF somatostatin levels in AD.


Interdisciplinary approach to balloon kyphoplasty in the treatment of osteoporotic vertebral compression fractures.
Osteoporotic vertebral compression fractures (VCFs) are associated with a series of clinical consequences leading to increased morbidity and even mortality. Early diagnosis and therapeutic intervention is desirable in order to remobilise patients and prevent further bone loss. Not all fractures are, however, sufficiently treatable by conservative measures. Here, vertebroplasty and kyphoplasty may provide immediate pain relief by minimally invasive fracture stabilisation. In cases of acute fractures, kyphoplasty has the potential to reduce kyphosis and restore the normal sagittal alignment of the spine. The complex nature of systemic osteoporosis, coupled with the intricate biomechanics of vertebral fractures, leads to a clinical setting which is ideally treated interdisciplinarily by the rheumatologist and spine surgeon.


[Bone mineral density and adequacy of dietary pattern of patients with chronic kidney disease in hemodialysis].
In chronic kidney disease (CKD) patients, malnutrition is common with loss of muscle mass and decreased bone mineral density (BMD), increasing the risk of morbidity. To compare body composition, bone mineral density (BMD) and bone mineral content (BMC) between CKD patients and healthy subjects, and relate these parameters with energy, macronutrients and micronutrients intake. Body composition was assessed 30 haemodialysis patients and compared with 28 healthy volunteers with DEXA. In patients, three 24 hours records of dietary intake were filled. A significantly lower BMD (p < 0.01) and BMC (p < 0.0) were found in CKD patients. There was a trend for patients to have lower fat free mass (FFM) than controls (p = 0.06). In men, differences in BMD and BMC lost significance when adjusting for fat mass FM (%) and FFM (kg). In CKD, 34.5% and 27.6% of patients had an adequate intake of energy and protein, respectively. However, it was observed a deficit of energy and protein intake in 31.0% and 44.8% of patients, respectively. No significant correlation was found in CKD patients between macronutrient and calcium intake and BMD or BMC. CKD have lower BMD and BMC than healthy volunteers. These differences lost significance in men, after adjusting for body composition parameters. A poor dietary adequacy was found in most patients with CKD, but no association was observed between these variables and body composition or bone mineral density.