Correlation of neuroactive steroid modulation of [35S]t-butylbicyclophosphorothionate and [3H]flunitrazepam binding and gamma-aminobutyric acidA receptor function.
Neuroactive steroids, including endogenously occurring metabolites of progesterone and deoxycorticosterone as well as their synthetic derivatives, are positive allosteric modulators of the gamma-aminobutyric acid (GABA)A receptor complex. They inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), enhance the binding of [3H]flunitrazepam, and potentiate GABA-evoked chloride currents and agonist-stimulated 36Cl- uptake. The structure-activity relationship for 31 neuroactive steroids and related compounds was explored by examining their relative ability to inhibit [35S]TBPS binding in rat brain cortical membranes. A free 3 alpha-hydroxy group is necessary for high potency inhibition. Whereas hydroxylation in the 21-position and subsequent esterification maintain activity, 11 alpha- or 12 alpha-hydroxylation greatly reduces activity. The rank order of potency for 17-position substitutions in the 5 alpha-reduced series is 17 beta-acetyl > 17 beta-cyano > 17 beta-methoxycarbonyl > 17 alpha-acetyl > 17-one > or = 17-oxime > or = 17 alpha-cyano. Introduction of a double bond between the 9- and 11-positions reduces potency, whereas a double bond in the 4-position reduces the maximal extent of inhibition. Comparing the activities of these neuroactive steroids and related compounds in the [35S]TBPS and [3H]flunitrazepam assays, there is a strong correlation between potency (r = 0.90, n = 17) and magnitude of modulation (r = 0.95, n = 31), indicating that the neuroactive steroid binding site is similarly coupled to the TBPS and benzodiazepine sites in rat cortex. However, there is a weaker correlation (r = 0.74-0.78, n = 31) between the degree of modulation in either binding assay and potentiation of muscimol-stimulated 36Cl- uptake in rat cortical synaptoneurosomes. Using an electrophysiological approach, stronger correlations (r = 0.89-0.94, n = 15) were observed between the magnitude of modulation in the binding assays and potentiation of GABA-evoked chloride currents in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2L receptor complexes. Thus, neuroactive steroid modulation of [35S]TBPS and [3H]flunitrazepam binding is predictive of functional activity at the GABAA receptor complex.


Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in Drosophila.
Peptidoglycan (PGN) detection by PGN recognition proteins (PGRP) is the main trigger of the antibacterial immune response in Drosophila. Depending on the type of immune cell, PGN can be sensed either at the cell membrane by PGRP-LC or inside the cell by PGRP-LE, which plays a role similar to that of Nod2 in mammals. Previous work, mainly in cell cultures, has shown that oligopeptide transporters of the SLC15 family are essential for the delivery of PGN for Nod2 detection inside of the cells, and that this function might be conserved in flies. By generating and analyzing the immune phenotypes of loss-of-function mutations in 3 SLC15 Drosophila family members, we tested their role in mediating PGRP-LE-dependent PGN activation. Our results show that Yin, CG2930, and CG9444 are required neither for PGRP-LE activation by PGN nor for PGN transport from the gut lumen to the insect blood. These data show that, while intracellular PGN detection is an essential step of the antibacterial response in both insects and mammals, the types of PGN transporters and sensors are different in these animals.


Mycobacterial spindle cell pseudotumour: epidemiology and clinical outcomes.
Mycobacterial spindle cell pseudotumour (MSP) is a rare disease characterised by tumour-like local proliferation of spindle-shaped histiocytes containing acid-fast positive mycobacteria. The aim of this literature review is to describe the clinical parameters and treatment outcomes of patients with MSP. A literature search was conducted using the search terms related to mycobacteria and spindle cell tumours. A previously unreported stem cell transplant recipient from our institution diagnosed with MSP was also included. Demographics, comorbidities, site of infection, treatment and clinical outcomes were analysed. Fifty-one patients were analysed. Twenty-six (51%) had HIV infection. Mycobacterium avium complex was the most frequent organism isolated in 24 (47.1%) followed by Mycobacterium tuberculosis complex in eight (16%) cases. Lymph nodes were the most common site of infection (45.1%). Twenty (39.2%) patients received antimycobacterial agents, 12 (23.5%) underwent surgical resection and six (11.8%) received antimycobacterial agents plus surgery. Treatment was successful in 24 (47.1%) patients and failed in 15 (29.4%); 13 of these 15 patients died. Antimycobacterial therapy was significantly associated with successful outcome compared with surgical resection or no treatment (P<0.001). MSP is a rare condition associated primarily with immunodeficiencies. Antimycobacterial therapy is significantly associated with successful outcome.


What's social about social learning?
Research on social learning in animals has revealed a rich variety of cases where animals--from caddis fly larvae to chimpanzees--acquire biologically important information by observing the actions of others. A great deal is known about the adaptive functions of social learning, but very little about the cognitive mechanisms that make it possible. Even in the case of imitation, a type of social learning studied in both comparative psychology and cognitive science, there has been minimal contact between the two disciplines. Social learning has been isolated from cognitive science by two longstanding assumptions: that it depends on a set of special-purpose modules--cognitive adaptations for social living; and that these learning mechanisms are largely distinct from the processes mediating human social cognition. Recent research challenges these assumptions by showing that social learning covaries with asocial learning; occurs in solitary animals; and exhibits the same features in diverse species, including humans. Drawing on this evidence, I argue that social and asocial learning depend on the same basic learning mechanisms; these are adapted for the detection of predictive relationships in all natural domains; and they are associative mechanisms--processes that encode information for long-term storage by forging excitatory and inhibitory links between event representations. Thus, human and nonhuman social learning are continuous, and social learning is adaptively specialized--it becomes distinctively "social"--only when input mechanisms (perceptual, attentional, and motivational processes) are phylogenetically or ontogenetically tuned to other agents.


Glutamate and neurotrophic factors in neuronal plasticity and disease.
Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.


The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study.
Fabry disease is a treatable cause of chronic kidney disease (CKD) characterized by a genetic deficiency of α-galactosidase A. European Renal Best Practice (ERBP) recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. This prospective study assessed α-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. Three (all males) of 313 CKD patients (0.95%) were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. The prevalence of Fabry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin.


Publication Rates and Inconsistencies of the Abstracts Presented at the National Anatomy Congresses in 2007 and 2008.
Despite significant efforts made for, most abstracts presented during a meeting do not proceed and publish as a manuscript in scientific journals. To investigate publication rates of national anatomy congresses. Descriptive study. All abstracts presented at two annual meetings in 2007 and 2008 were extracted. PubMed and Google Scholar database search used for publication history. Presentation and study types, publication rates and mean publishing times were evaluated. Inconsistency rates between meeting abstract and final published article were also considered. Among 342 abstracts, 195 (57%) were followed by a full-text article. Publication rates for oral and poster presentations were 75% and 52.2%, respectively. The mean publication time was 23.7±23 months. Overall, 89.2% of the articles were published within 5 years. There were no inconsistencies in 50 (25.6%) articles, while 145 (74.4%) had inconsistencies compared to the abstracts presented at the congress. Getting adequate information for 45 (23.1%) articles was not possible. There was no standard reporting format for the abstracts. Our study shows that, overall publication rates for abstracts presented at national anatomy meetings were higher than those presented at national meetings for clinical specialties.


Screening for psychological and mental health difficulties in young people who offend: a systematic review and decision model.
There is policy interest in the screening and treatment of mental health problems in young people who offend, but the value of such screening is not yet known. To assess the diagnostic test accuracy of screening measures for mental health problems in young people who offend; to evaluate the clinical effectiveness and cost-effectiveness of screening and treatment; to model estimates of cost; to assess the evidence base for screening against UK National Screening Committee criteria; and to identify future research priorities. In total, 25 electronic databases including MEDLINE, PsycINFO, EMBASE and The Cochrane Library were searched from inception until April 2011. Reverse citation searches of included studies were undertaken and reference list of included studies were examined. Two reviewers independently examined titles and abstracts and extracted data from included studies using a standardised form. The inclusion criteria for the review were (1) population - young offenders (aged 10-21 years); (2) intervention/instrument - screening instruments for mental health problems, implementation of a screening programme or a psychological or pharmacological intervention as part of a clinical trial; (3) comparator - for diagnostic test accuracy studies, any standardised diagnostic interview; for trials, any comparator; (4) outcomes - details of diagnostic test accuracy, mental health outcomes over the short or longer term or measurement of cost data; and (5) study design - for diagnostic test accuracy studies, any design; for screening programmes, randomised controlled trials or controlled trials; for clinical effectiveness studies, randomised controlled trials; for economic studies, economic evaluations of screening strategies or interventions. Of 13,580 studies identified, nine, including eight independent samples, met the inclusion criteria for the diagnostic test accuracy and validity of screening measures review. Screening accuracy was typically modest. No studies examined the clinical effectiveness of screening, although 10 studies were identified that examined the clinical effectiveness of interventions for mental health problems. There were too few studies to make firm conclusions about the clinical effectiveness of treatments in this population. No studies met the inclusion criteria for the assessment of the cost-effectiveness of screening or treatment. An exemplar decision model was developed for depression, which identified a number of the likely key drivers of uncertainty, including the prevalence of unidentified mental health problems, the severity of mental health problems and their relationship to generic measures of outcome and the impact of treatment on recidivism. The information evaluated as part of the review was relevant to five of the UK National Screening Committee criteria. On the basis of the above results, none of the five criteria was met. The conclusions of the review are based on limited evidence. Conclusions are tentative and the decision model should be treated as an exemplar. Evidence on the clinical effectiveness and cost-effectiveness of screening for mental health problems in young people who offend is currently lacking. Future research should consider feasibility trials of clinical interventions to establish important parameters ahead of conducting definitive trials. Future diagnostic studies should compare the diagnostic test accuracy of a range of screening instruments, including those recommended for use in the UK in this population. These studies should be designed to reduce the decision uncertainty identified by the exemplar decision model. This study is registered as PROSPERO CRD42011001466. The National Institute for Health Research Health Technology Assessment programme.


Inulin and oligofructose: effects on lipid metabolism from human studies.
Although convincing lipid-lowering effects of the fructo-oligosaccharide, inulin, have been demonstrated in animals, attempts to reproduce similar effects in man have produced conflicting findings. This may be because of the much lower doses which can be used due to the adverse gastrointestinal symptoms exhibited by most subjects consuming in excess of 15 g/d. There are nine studies reported in the literature which have investigated the response of blood lipids (usually total and LDL-cholesterol and triacylglycerol) to inulin or oligofructose supplementation in human volunteers. Three have observed no effects of inulin or oligofructose on blood levels of cholesterol or triacylglycerol, three have shown significant reductions in triacylglycerol, whilst four have shown modest reductions in total and LDL-cholesterol. Studies have been conducted in both normo- and moderately hyperlipidaemic subjects. Differences in study outcomes do not appear to be due to differences in the type or dose of oligosaccharides used nor the duration of the studies. Because animal studies have identified inhibition of hepatic fatty acid synthesis as the major site of action for the triacylglycerol lowering effects of inulin and oligofructose, and because this pathway is relatively inactive in man unless a high carbohydrate diet is fed, variability in response may be a reflection of differences in background diet or the experimental foods used.


Self-regulatory biofeedback training: an intervention to reduce school burnout and improve cardiac functioning in college students.
With the detrimental relationship between school burnout and physiological and cognitive functioning now well documented, interventions to ameliorate school burnout symptomology are needed. This study examined the effectiveness of a self-regulatory biofeedback intervention program (Heart Rate Variability Coherence Biofeedback Training [HRVCB]) in contrast to a protocol demonstrated to produce cognitive and physiological improvements (a high intensity interval training protocol [HIIT]) as well as a wait-list control condition at decreasing school burnout in an American collegiate sample (N = 90). Intervention training was conducted over a 4-week span (three sessions per week) with accompanying baseline and post-intervention assessments. In addition to measurements of school burnout and negative affect (depression and anxiety), intervention influences on cognition (via a serial subtraction task) and physiology (hemodynamics, electrocardiography, and a submaximal cardiorespiratory fitness test) were explored. Findings indicate HRVCB training significantly decreased school burnout and increased mathematical performance from pre- to post-intervention measurement. These changes did not occur for HIIT or waitlist participants. Brachial and aortic systolic blood pressure decreased pre to post-intervention for HRVCB but not HIIT or waitlist participants. Cardiovascular fitness (VO2max) improved pre to post-intervention for HIIT but not HRVCB or waitlist participants. Also, both HRVCB and HIIT training participants decreased heart rate from pre to post-intervention but not waitlist participants. Finally, all participants decreased cardiac sympathovagal tone from pre to post-intervention. These findings provide evidence that HRVCB training programs can decrease school burnout as well as improve components associated with cardiac health. Study limitations and directions for future research are discussed.


TGF-β-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC.
Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapeutic agents and remains an unmet medical need. Here, we demonstrate a mechanism of cell adhesion-mediated drug resistance using a variety of HCC spheroid models to overcome environment-mediated drug resistance in HCC. We classified spheroids into two groups, tightly compacted and loosely compacted aggregates, based on investigation of dynamics of spheroid formation. Our results show that compactness of HCC spheroids correlated with fibroblast-like characteristics, collagen 1A1 (COL1A1) content, and capacity for chemoresistance. We also showed that ablation of COL1A1 attenuated not only the capacity for compact-spheroid formation, but also chemoresistance. Generally, connective tissue growth factor (CTGF) acts downstream of transforming growth factor (TGF)-β and promotes collagen I fiber deposition in the tumor microenvironment. Importantly, we found that TGF-β-independent CTGF is upregulated and regulates cell adhesion-mediated drug resistance by inducing COL1A1 in tightly compacted HCC spheroids. Furthermore, losartan, which inhibits collagen I synthesis, impaired the compactness of spheroids via disruption of cell-cell contacts and increased the efficacy of anticancer therapeutics in HCC cell line- and HCC patient-derived tumor spheroids. These results strongly suggest functional roles for CTGF-induced collagen I expression in formation of compact spheroids and in evading anticancer therapies in HCC, and suggest that losartan, administered in combination with conventional chemotherapy, might be an effective treatment for liver cancer.


Plasmonic hot carrier-driven oxygen evolution reaction on Au nanoparticles/TiO2 nanotube arrays.
The use of hot carriers generated from the decay of localized surface plasmon resonance in noble metal nanoparticles is a promising concept for photocatalysis. Here, we report the enhancement of photocatalytic activity by the flow of hot electrons on TiO2 nanotube arrays decorated with 5-30 nm Au nanoparticles as photoanodes for photoelectrochemical water splitting. This enhanced photocatalytic activity is correlated to the size of the Au nanoparticles, where higher oxygen evolution was observed on the smaller nanoparticles. Conductive atomic force microscopy and ultraviolet photoelectron spectroscopy were used to characterize the Schottky barrier between Au and TiO2, which reveals a reduction in the Schottky barrier with the smaller Au nanoparticles and produces an enhanced transfer of photoinduced hot carriers. This study confirms that the higher photocatalytic activity was indeed driven by the hot electron flux generated from the decay of localized surface plasmon resonance.


A comparison of self and proxy quality of life ratings for people with dementia and their carers: a European prospective cohort study.
Objectives: To identify correlates of self-rated and proxy-rated quality of life (QoL) in people with dementia on (i) a dementia-specific and (ii) a capability-wellbeing QoL measure at baseline and 12-month follow-up, and to consider such factors in the context of QoL intervention development.Method: Prospective clinical and demographic data were collected from 451 community-dwelling dyads (mild-moderate dementia) across eight European countries. QoL was measured using the QOL-AD and the ICECAP-O. Multivariate modelling identified correlates of self- and proxy-rated QoL at baseline and at 12-month follow-up.Results: Carer's proxy-ratings of QoL were significantly lower than self-ratings at all time-points for both measures. Proxy-ratings declined over time, but self-ratings remained stable. Baseline predictors of greater self-rated QoL were education, and greater functional ability and relationship quality. Greater proxy-rated QoL was associated with education and greater functional ability, relationship quality, carer social support and carer QoL, lower carer anxiety/depression and less severe neuropsychiatric symptoms in people with dementia. At follow-up, greater self-rated QoL was predicted by greater functional ability, relationship quality, carer social support and having a spousal carer. Greater proxy-rated QoL at follow-up was associated with the same factors as at baseline; however, the dyad living together was an additional predictive factor.Conclusion: Both proxy-ratings and self-ratings of QoL should be interpreted with caution and in the context of each individual caregiving relationship. Different functional, psychosocial, relational and contextual factors influence self- and proxy-ratings, and both sets of factors should be considered in the context of QoL intervention development for the dyad.


Cardiaprotective effect of crocetin by attenuating apoptosis in isoproterenol induced myocardial infarction rat model.
Given study evaluates the cardioprotective effect of crocetin in myocardial infracted (MI) rats. MI was produced by administering isoproterenol (90mg/kg/day, i.p.) in rats for two consecutive days. all the animals were divided in to four groups such as control group receives only saline; MI group which receives only isoproterenol and crocetin treated group which receives crocetin (50, 100 and 200mg/kg/day, p.o.) for the duration of 15 days. At the end of dosing left ventricular functions was assessed to estimate its effect on cardiac functions. Catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), creatine kinase (CK-MB), lactate dehydrogenase (LDH) and inflammatory cytokines were determined in the cardiac tissue homogenate. Histopathology study was also carried out using hematoxylin and eosin staining. Immunohistochemistry was done for the estimation of Caspase-3, Bcl-2, Bax and Nrf-2 level in the myocardial tissues of MI rats. Result of the study suggested that GSH, CAT, CK-MB, and LDH were (p<0.01) increased in the tissue homogenate of crocetin treated group than MI group. However crocetin significantly (p<0.01) decreases the level of MDA and activity of SOD in the tissue homogenate than MI group. It was observed that treatment with crocetin attenuates the level of inflammatory cytokines in the myocardial tissues of MI rats. Moreover level of caspase-3, Bax and Nrf-2 significantly reduced and Bcl-2 enhanced in the myocardial tissues of MI rats than MI group. The altered cellular architecture of heart tissue sections in the myocardial infracted rats were reversed by administration of crocetin treatment. Taking all these data together, it may be suggested that the crocetin act as a possible protective agent in myocardial infarction by decreasing oxidative stress and inflammatory cytokines and thereby attenuates the apoptosis of myocardial cells.


In vitro phytotoxicity and antioxidant activity of selected flavonoids.
The knowledge of flavonoids involved in plant-plant interactions and their mechanisms of action are poor and, moreover, the structural characteristics required for these biological activities are scarcely known. The objective of this work was to study the possible in vitro phytotoxic effects of 27 flavonoids on the germination and early radical growth of Raphanus sativus L. and Lepidium sativum L., with the aim to evaluate the possible structure/activity relationship. Moreover, the antioxidant activity of the same compounds was also evaluated. Generally, in response to various tested flavonoids, germination was only slightly affected, whereas significant differences were observed in the activity of the various tested flavonoids against radical elongation. DPPH test confirms the antioxidant activity of luteolin, quercetin, catechol, morin, and catechin. The biological activity recorded is discussed in relation to the structure of compounds and their capability to interact with cell structures and physiology. No correlation was found between phytotoxic and antioxidant activities.


The effect of exhaustion exercise on thyroid hormones and testosterone levels of elite athletes receiving oral zinc.
The present study aims to investigate how exhaustion exercise affects thyroid hormones and testosterone levels in elite athletes who are supplemented with oral zinc sulfate for 4 weeks. The study included 10 male wrestlers, who had been licensed wrestlers for at least 6 years. Mean age of the wrestlers who volunteered in the study was 18.70 +/- 2.4 years. All subjects were supplemented with oral zinc sulfate (3 mg/kg/day) for 4 weeks in addition to their normal diet. Thyroid hormone and testosterone levels of all subjects were determined as resting and exhaustion before and after zinc supplementation. Resting TT3, TT4, FT3, FT4 and TSH levels of subjects were higher than the parameters measured after exhaustion exercise before zinc supplementation (p<0.05). Both resting and exhaustion TT3, TT4 and FT3 values after 4-week zinc supplementation were found significantly higher than both of the parameters (resting and exhaustion) measured before zinc supplementation (p<0.05). Resting total testosterone and free testosterone levels before zinc supplementation were significantly higher than exhaustion levels before zinc supplementation (p<0.05). Both resting and exhaustion total and free testosterone levels following 4-week zinc supplementation were found significantly higher than the levels (both resting and exhaustion) measured before zinc supplementation (p<0.05). Findings of our study demonstrate that exhaustion exercise led to a significant inhibition of both thyroid hormones and testosterone concentrations, but that 4-week zinc supplementation prevented this inhibition in wrestlers. In conclusion, physiological doses of zinc administration may benefit performance.


Tree mortality from drought, insects, and their interactions in a changing climate.
Climate change is expected to drive increased tree mortality through drought, heat stress, and insect attacks, with manifold impacts on forest ecosystems. Yet, climate-induced tree mortality and biotic disturbance agents are largely absent from process-based ecosystem models. Using data sets from the western USA and associated studies, we present a framework for determining the relative contribution of drought stress, insect attack, and their interactions, which is critical for modeling mortality in future climates. We outline a simple approach that identifies the mechanisms associated with two guilds of insects - bark beetles and defoliators - which are responsible for substantial tree mortality. We then discuss cross-biome patterns of insect-driven tree mortality and draw upon available evidence contrasting the prevalence of insect outbreaks in temperate and tropical regions. We conclude with an overview of tools and promising avenues to address major challenges. Ultimately, a multitrophic approach that captures tree physiology, insect populations, and tree-insect interactions will better inform projections of forest ecosystem responses to climate change.


Effects of changes in smoking status on blood pressure among adult males and females in Indonesia: a 15-year population-based cohort study.
The continuing rise of smoking behaviours will inevitably lead to a further increase in hypertension prevalence. However, limited research has examined the impacts of changes in smoking status on blood pressure (BP). We sought to assess correlations between increases or decreases of males' and females' cigarette consumption on systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP), and to investigate the relationship between smoking status changes and changes in BP through a 15-year examination period. Retrospective, cohort study. We used nationally representative secondary data collected in the years 2000, 2007 and 2015 by the Indonesia Family Life Survey. We measured the smoking habits, BP indices and other socioeconomic factors documented in the multiple follow-up surveys of a sample of 10 338 respondents. The primary outcome was the means of SBP, DBP and PP. The secondary outcome was the changes from baseline in SBP and DBP. Smoking caused different effects on male and female smokers. Female smokers who increased their daily cigarette consumption had significantly higher SBP and PP (p<0.001). During 15 years of follow-up, male and female smokers who decided to quit had the largest change of SBP (adjusted mean=16.64 mm Hg, SE=21.39 and adjusted mean=24.78 mm Hg, SE=23.25, respectively), whereas new male and female smokers exhibited the highest change of DBP (adjusted mean=2.86 mm Hg, SE=11.50 and adjusted mean=7.54 mm Hg, SE=14.39, respectively). Our study confirmed the adverse effects of smoking on BP, which can be used to inform efforts to tackle the growing cigarette epidemic and its negative effects on hypertension among former and new smokers and develop evidence-based tobacco control policies in Indonesia.


Coaxial nanotubes of stimuli responsive polymers with tunable release kinetics.
Stimuli responsive polymeric (SRP) nanotubes have great potential as nanocarriers of macromolecules due to their large surface areas and release mechanisms that can be activated externally. In this work, we demonstrate vapor phase synthesis of coaxial nanotubes with layers of different SRP polymers for improved release kinetics. Temperature responsive poly(N-isopropylacrylamide) (pNIPAAm), pH responsive poly(methacrylic acid) (pMAA) and poly(hydroxyethyl methacrylate) (pHEMA) are used to fabricate the responsive coaxial nanotubes and the phloroglucinol dye is used as the model molecule to study the release kinetics. Fastest release is observed with single layer pNIPAAm nanotubes with rates of 0.134 min(-1), whereas introducing pHEMA or pMAA as inner layers slows down the release, enabling tuning of the response. Furthermore, repeating the release studies multiple times shows that the release rates remain similar after each run, confirming the stability of the nanotubes.


Pharmacokinetically stabilized cystine knot peptides that bind alpha-v-beta-6 integrin with single-digit nanomolar affinities for detection of pancreatic cancer.
Detection of pancreatic cancer remains a high priority and effective diagnostic tools are needed for clinical applications. Many cancer cells overexpress integrin α(v)β(6), a cell surface receptor being evaluated as a novel clinical biomarker. To validate this molecular target, several highly stable cystine knot peptides were engineered by directed evolution to bind specifically and with high affinity (3-6 nmol/L) to integrin α(v)β(6). The binders do not cross-react with related integrin α(v)β(5), integrin α(5)β(1), or tumor-angiogenesis-associated integrin, α(v)β(3). Positron emission tomography showed that these disulfide-stabilized peptides rapidly accumulate at tumors expressing integrin α(v)β(6). Clinically relevant tumor-to-muscle ratios of 7.7 ± 2.4 to 11.3 ± 3.0 were achieved within 1 hour after radiotracer injection. Minimization of off-target dosing was achieved by reformatting α(v)β(6)-binding activities across various natural and pharmacokinetically stabilized cystine knot scaffolds with different amino acid content. We show that the primary sequence of a peptide scaffold directs its pharmacokinetics. Scaffolds with high arginine or glutamic acid content suffered high renal retention of more than 75% injected dose per gram (%ID/g). Substitution of these amino acids with renally cleared amino acids, notably serine, led to significant decreases in renal accumulation of less than 20%ID/g 1 hour postinjection (P < 0.05, n = 3). We have engineered highly stable cystine knot peptides with potent and specific integrin α(v)β(6)-binding activities for cancer detection. Pharmacokinetic engineering of scaffold primary sequence led to significant decreases in off-target radiotracer accumulation. Optimization of binding affinity, specificity, stability, and pharmacokinetics will facilitate translation of cystine knots for cancer molecular imaging.


A Multidimensional and Multilevel Extension of a Random-Effect Approach to Subjective Judgment in Rating Scales.
In responding to rating scale items, respondents may hold different perspectives on the given categories. The random-effect rating scale model (RERSM), developed to account for variations in the category thresholds across respondents, is unidimensional and unilevel. It becomes statistically inefficient when multiple unidimensional tests have to be analyzed and inapplicable when data have a multilevel structure (e.g., respondents nested within organizations, students nested within schools). To resolve these problems, this study develops a multidimensional and multilevel version of the RERSM. The parameters can be estimated with existing computer software. Thus, there is no need to develop estimation procedures or corresponding computer programs. Simulation studies were conducted to evaluate the parameter recovery of the multidimensional RERSM, the multilevel RERSM, and the multidimensional and multilevel RERSM using WinBUGS. The results showed that the parameter recovery was generally satisfactory. An empirical example of the application of the multidimensional and multilevel RERSM to 2006 Program for International Student Assessment inventories about attitudes toward learning sciences is provided.


Effect of surgical menopause on cognitive functions.
To investigate the effect of estrogen deficiency on cognitive function in surgically menopausal women, a prospective study was conducted at the University Hospital in Assiut, Egypt, during the period of July 1997 to August 1999. The study included 35 women subjected to total abdominal hysterectomy and bilateral salpingo-oophorectomy for nonmalignant causes. They were subjected to cognitive assessment by Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) subtests, and measurement of auditory Event-Related Potentials (ERPs) and serial serum estradiol levels determination. Eighteen age- and education-, body-weight- and parity-matched control women were recruited for comparison. A significant decline in MMSE, WMS subtests (digit span, visual memory, logical memory and mental control) and prolongation of P300 of ERP latency was observed in the patient group at 3 and 6 months postoperatively. These changes were not observed in the control group. A significant correlation was found between serum estradiol level and mental control subtest score and P300 latency in patients preoperatively. Patients who had a drop of estrogen level >50% had more cognitive function decline. Rapid decline in estrogen level following surgical menopause was associated with a deleterious effect on cognitive function. Such observations may contribute to more understanding of the age-related cognitive decline in females.


Interference of cranberry constituents in cell-cell signaling system of Vibrio harveyi.
Cranberry juice has long been recognized in folk medicine as a therapeutic agent, mainly in urinary track infections. It acts as an antibiofilm agent against various pathogens. Quorum sensing is process where bacteria communicate with each other via signal molecules known as autoinducers. This process is strongly involved in various bacterial pathological and physiological pathways. Various strains of Vibrio harveyi bacteria were incubated with different concentrations of nondialyzable material of cranberry (NDM) with or without addition of exogenous autoinducer. Bioluminescence regulated by the autoinducers was measured in GENios reader. Effect of NDM alone or NDM supplemented with autoinducer on quorum sensing was determined as change in bioluminescence in each treated sample compared to appropriate control in every strain. Using model of V. harveyi, we found an inhibitory effect of cranberry constituents on bacterial signaling system. This effect was reversible, since exogenous autoinducer was able to recover bioluminescence which was decreased by NDM. We hypothesized that cranberry NDM interacts with V. harveyi quorum sensing by competition with autoinducer for binding to autoinducer sensor.


Percent-predicted 6-minute walk distance in duchenne muscular dystrophy to account for maturational influences.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.


Mycoplasma pneumoniae in children: carriage, pathogenesis, and antibiotic resistance.
Both the diagnosis and treatment of Mycoplasma pneumoniae infections in children are currently facing two main challenges: a relatively high carriage in asymptomatic children, and a worldwide increase in macrolide-resistant M. pneumoniae (MRMP). This review focuses on the scientific and clinical implications of these crucial issues. Recent studies have indicated that the prevalence of M. pneumoniae in the upper respiratory tract is similar among asymptomatic, healthy children and children with a symptomatic respiratory tract infection, and that current diagnostic procedures for M. pneumoniae are unable to differentiate between bacterial carriage and infection. It is therefore possible that the burden of M. pneumoniae-associated disease is overestimated. Another phenomenon that has an important impact on the treatment of M. pneumoniae infections is the rapid worldwide emergence of MRMP isolates. The current diagnostic procedures for M. pneumoniae cannot discern between bacterial carriage and infection in a clinically relevant time frame. It is therefore imperative that these procedures be modified such as to unambiguously detect symptomatic M. pneumoniae infections. Moreover, the emergence of MRMP necessitates the application of methods to detect macrolide resistance as well as the implementation of restrictive policies regarding the use of macrolides.


Isolation of alkali-tolerant benzene-degrading bacteria from a contaminated aquifer.
To isolate benzene-degrading strains from neutral and alkaline groundwaters contaminated by benzene, toluene, ethylbenzene, xylenes (BTEX) from the SIReN aquifer, UK, and to test their effective pH range and ability to degrade TEX. The 14 isolates studied had an optimum pH for growth of 8, and could degrade benzene to below detection level (1 microg l(-1)). Five Rhodococcus erythropolis strains were able to metabolize benzene up to pH 9, two distinct R. erythropolis strains to pH 10, and one Arthrobacter strain to pH 8.5. These Actinobacteria also degraded benzene at least down to pH 5.5. Six other isolates, a Hydrogenophaga and five Pseudomonas strains, had a narrower pH tolerance for benzene degradation (pH 6 to 8.5), and could metabolize toluene; in addition, the Hydrogenophaga and two Pseudomonas strains utilized o-, m- or p-xylenes. None of these strains degraded ethylbenzene. Phylogenetically distinct isolates, able to degrade BTX compounds, were obtained, and some degraded benzene at high pH. High pH has previously been found to inhibit in situ degradation of benzene, a widespread, carcinogenic groundwater contaminant. These benzene-degrading organisms therefore have potential applications in the remediation or natural attenuation of alkaline waters.


Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection.
Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ vs. LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women. We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFNβ, CRP, AGP, I-FABP, IFNγ, IL-1β, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression. Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1β, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors. Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.


Efficacy and safety of decontamination for N95 respirator reuse: a systematic literature search and narrative synthesis.
Under times of supply chain stress, the availability of some medical equipment and supplies may become limited. The current pandemic involving severe acute respiratory syndrome coronavirus 2 has highlighted limitations to the ordinary provision of personal protective equipment (PPE). For perioperative healthcare workers, N95 masks provide a stark example of PPE in short supply necessitating the creation of scientifically valid protocols for their decontamination and reuse. We performed a systematic literature search of MEDLINE, Embase, Cochrane CENTRAL databases, and ClinicalTrials.gov to identify peer-reviewed articles related to N95 mask decontamination and subsequent testing for the integrity of mask filtration and facial seal. To expand this search, we additionally surveyed the official statements from key health agencies, organizations, and societies for relevant citations. Our initial database search resulted in five articles that met inclusion criteria, with 26 articles added from the expanded search. Our search did not reveal any relevant randomized clinical trials or cohort studies. We found that moist mask heating (65-80°C at 50-85% relative humidity for 20-30 min) and vaporous hydrogen peroxide treatment were supported by the literature to provide consistent viral decontamination without compromising mask seal and filtration efficiency. Other investigated decontamination methods lacked comprehensive scientific evidence for all three of these key criteria. N95 mask reprocessing using either moist heat or vaporous hydrogen peroxide is recommended to ensure healthcare worker safety.


Controlled Synthesis of Gold Nanoparticles in Copolymers Nanomolds by X-ray Radiolysis.
We show by X-ray and neutron small-angle scattering that gold nanoparticles with controlled sizes and morphologies can be obtained by the metallic reduction of AuCl4- ions trapped in 3D organic molds by X-ray radiolysis. The molds are spherical frozen micelles of polystyrene-b-poly(dimethylaminoethyl methacrylate) (PS-b-PDMAEMA) block copolymer in acidic aqueous solution with a PS spherical core surrounded by a corona of PDMAEMA chains in good solvent. The behavior of micelles is controlled by the [AuCl4-]/[DMAEMA] ratio RAuCl4-/DMAEMA. At low gold concentration, AuCl4- ions condense on the positively charged DMAEMA moieties without changing the behavior of the PDMAEMA chains. At intermediate gold concentration, the ions induce a progressive contraction of the corona's chains and dehydration of micelles. At large gold concentration, the corona becomes a fully dry phase loaded with gold ions, which induces micelle aggregation. Radiolysis of the solution by an intense X-ray beam produces different types of gold nanoparticles with respect to RAuCl4-/DMAEMA and irradiation time. At RAuCl4-/DMAEMA = 0.033, irradiation produces in the first step gold clusters in the micelle corona which in the second step merge to form nanoparticles of a similar size to that of the micelle. Conversely, at RAuCl4-/DMAEMA = 0.33, micelles do not operate as templates but only as nucleation zones and large nanoparticles grow outside the micelles.


Taking care of volunteers in a stroke trial: a new assisted-management strategy.
Providing participants with evidence-based care for secondary prevention is an ethical and scientific priority for trials in stroke therapy. The optimal strategy, however, is uncertain. We report the performance of a new approach for delivering preventive care to trial participants. Participants were enrolled in the Insulin Resistance Intervention after Stroke trial, which examined the insulin sensitiser, pioglitazone versus placebo for prevention of stroke and myocardial infarction after ischaemic stroke or transient ischaemic attack. Preventive care was the responsibility of the participants' personal healthcare providers, but investigators monitored care and provided feedback annually. We studied achievement of 8 prevention goals at baseline and 3 annual visits, with a focus on 3 priority goals: blood pressure <140/90 mm Hg, low-density lipoprotein (LDL) cholesterol <2.59 mmol/L and antithrombotic therapy. The proportion of participants achieving the priority goals was highest for antithrombotic use (96-99% in each year) and similar for blood pressure (66-72% in each year) and LDL (68-70% in each year). All 3 priority goals were achieved by 47-52% of participants in any given year. However, only 22% of participants achieved all 3 goals in each year. A strategy of monitoring care and providing feedback was associated with high average yearly achievement of 3 priority secondary prevention goals, but the majority of trial participants did not persist in being at goal over time. NCT00091949.


Vasoactive intestinal polypeptide-induced chloride secretion by a colonic epithelial cell line. Direct participation of a basolaterally localized Na+,K+,Cl- cotransport system.
We have used a well-differentiated human colonic cell line, the T84 cell line, as a model system to study the pathways of cellular ion transport involved in vasoactive intestinal polypeptide (VIP)-induced chloride secretion. A modified Ussing chamber was used to study transepithelial Na+ and Cl- fluxes across confluent monolayer cultures of the T84 cells grown on permeable supports. In a manner analogous to isolated intestine, the addition of VIP caused an increase of net Cl- secretion which accounted for the increase in short circuit current (Isc). The effect of VIP on Isc was dose dependent with a threshold stimulation at 10(-10) M VIP, and a maximal effect at 10(-8) M. Bumetanide prevented or reversed the response to VIP. Inhibition by bumetanide occurred promptly when it was added to the serosal, but not to the mucosal bathing media. Ion replacement studies demonstrated that the response to VIP required the simultaneous presence of Na+, K+, and Cl- in the serosal media. Utilizing cellular ion uptake techniques, we describe an interdependence of bumetanide-sensitive 22Na+, 86Rb+, and 36Cl- uptake, which is indicative of a Na+,K+,Cl- cotransport system in this cell line. This transport pathway was localized to the basolateral membrane. Extrapolated initial velocities of uptake for each of the three ions was consistent with the electroneutral cotransport of 1 Na+:1 K+ (Rb+):2 Cl-. Our findings indicate that VIP-induced Cl- secretion intimately involves a bumetanide-sensitive Na+,K+,Cl- cotransport system which is functionally localized to the basolateral membrane.


Mobile health and wellness application framework.
There is an increasing need for user-friendly and interoperable mobile applications in health and wellness domain. The objective of this work has been to provide support for rapid and cost-effective development of such applications. We have introduced an application framework which provides a generic tool for mobile application designers. We have demonstrated the usage of the application framework by providing an example implementation and demonstrating its usage in a Tele-ECG use case. In order to support interoperability we propose a solution compatible with clinical document standards such as the HL7 CDA. A new mobile platform applicable for a wide range of telemedicine and wellness applications is introduced. The platform provides connectivity between healthcare professionals, patients and measurement devices. It is based on an open application framework that provides interfaces for measurement, user interface, database and network connectivity implementations. Mobile application development based on the application framework was demonstrated successfully. The developed UPHIAC platform adopts a new technical approach using a local database solution for caching of information at the mobile terminal. The platform applies a document-based approach providing a versatile and reliable way of sharing and collaboratively complementing of health information including standard information model documents (HL7/CDA), and integration with health information systems and personal storages. The implemented mobile tele-ECG case demonstrates the overall function of the platform. The platform can be used as a basis for developing new applications for specific purposes.


The role of experience, specialty certification, and practice ownership in the gender wage gap for veterinarians in the United States.
To explore the role of various factors in the wage gap between male and female veterinarians in the United States in 2016 and 2017. 2,760 veterinarians across the United States. Data from the Census of Veterinarians Survey administered by the AVMA Economics Division in 2016 and 2017 were analyzed. The Kolmogorov-Smirnov 2-sample test was used to determine whether a difference existed between male and female income distributions at various levels of experience. Quantile regression was performed separately for male and female respondents to determine the direct effects of individual factors on incomes and compare the effects of practice ownership versus nonownership on income. Income distributions of men and women were unequal at lower experience ranges but equal at higher experience ranges. Income increased for men with each additional year of experience and with practice ownership. For women, practice owners in the lowest income quantile had a negative return to income; overall, their income benefited most from ownership in the form of partnerships. For certain groups, incomes of both genders were lower when they had absences from the workforce. Findings suggested that the largest source of gender income disparity for veterinarians was attributable to female practice owners earning less than their male counterparts. Indeed, women earned more from specialty certifications than from owning a clinic. To decrease income disparities between genders, ways should be identified to support women-owned practices and promote equal pay.


Treatment patterns among medicaid-eligible women with breast cancer in georgia: are patterns different under the breast and cervical cancer prevention and treatment act?
To investigate breast cancer treatment of patients enrolled under traditional Medicaid categories versus those in the Breast and Cervical Cancer Prevention and Treatment Act (BCCPTA) in Georgia. Georgia Comprehensive Cancer Registry linked to Medicaid enrollment files were used to identify 2,048 enrollees with a primary cancer of the breast, of whom 1,046 were enrolled in BCCPTA, 674 were disabled, and 328 were in other Medicaid eligibility groups. Logistic regressions were used to estimate factors associated with the odds of receiving lumpectomy, mastectomy, or other surgery in addition to any drug regimen (hormonal or chemotherapy) and radiation. Women in BCCPTA were more likely to receive any treatment (odds ratio [OR] = 4.71; 95% CI, 2.48 to 8.96), any drug regimen (OR = 3.58; 95% CI, 2.32 to 5.51), any radiation (OR = 1.61; 95% CI, 1.15to 2.24), and any definitive surgery (OR = 2.52; 95% CI, 1.74 to 3.66) than the "other" eligibility group after controlling for covariates. There were no significant differences by eligibility group in the receipt of a lumpectomy versus a mastectomy. However, women in BCCPTA were more likely to receive more adjuvant follow-up after a mastectomy. The BCCPTA program in Georgia appears to create a quicker pathway for low-income, previously uninsured women with breast cancer to access services and, in turn, receive more treatment than women enrolled in the other, more traditional Medicaid eligibility groups. Yet the overall rate of adjuvant therapy, whether radiation, hormonal, or chemotherapy, appears to fall short of national criteria. This deserves attention in Georgia and, most likely, Medicaid programs in other states as well.


Extracellular vesicles and their diagnostic potential in amyotrophic lateral sclerosis.
Extracellular vesicles, small reservoirs that carry various biomolecules, have gained significant interest from the clinical field in recent years based on the diagnostic, therapeutic and prognostic possibilities they offer. While information abound regarding the clinical potential of such vesicles in diverse conditions, the information demonstrating their likely importance in amyotrophic lateral sclerosis (ALS) is more limited. This review will thus provide a brief introduction to extracellular vesicles, highlight their diagnostic significance in various diseases with a focus on ALS and explore additional applications of extracellular vesicles in the medical field. Overall, this work sheds further light on the clinical importance of extracellular vesicles in diagnostic applications as well as supports the need to better characterize their roles and signatures in patients diagnosed with ALS.


Preventing critical failure. Can routinely collected data be repurposed to predict avoidable patient harm? A quantitative descriptive study.
To determine whether sharing of routinely collected health service performance data could have predicted a critical safety failure at an Australian maternity service. Observational quantitative descriptive study. A public hospital maternity service in Victoria, Australia. A public health service; the Victorian state health quality and safety office-Safer Care Victoria; the Health Complaints Commission; Victorian Managed Insurance Authority; Consultative Council on Obstetric and Paediatric Mortality and Morbidity; Paediatric Infant Perinatal Emergency Retrieval; Australian Health Practitioner Regulation Agency. Numbers and rates for events (activity, deaths, complaints, litigation, practitioner notifications). Correlation coefficients. Between 2000 and 2014 annual birth numbers at the index hospital more than doubled with no change in bed capacity, to be significantly busier than similar services as determined using an independent samples t-test (p<0.001). There were 36 newborn deaths, 11 of which were considered avoidable. Pearson correlations revealed a weak but significant relationship between number of births per birth suite room birth and perinatal mortality (r2 =0.18, p=0.003). Independent samples t-tests demonstrated that the rates of emergency neonatal and perinatal transfer were both significantly lower than similar services (both p<0.001). Direct-to-service patient complaints increased ahead of recognised excess perinatal mortality. While clinical activity data and direct-to-service patient complaints appear to offer promise as potential predictors of health service stress, complaints to regulators and medicolegal activity are less promising as predictors of system failure. Significant changes to how all data are handled would be required to progress such an approach to predicting health service failure.


Screening adherence in BRCA1/2 families is associated with primary physicians' behavior.
This study provides an assessment of long-term breast and ovarian cancer screening behaviors and the variables associated with adherence with screening among women with or at 50% for having a BRCA1/2 mutation. Participants in the study included 112 women (33 mutation carriers and 79 at 50% risk). Data was collected through a mailed questionnaire, which included items to assess screening behaviors in the last 2 years, risk perception, cancer specific distress, adherence determinants, specific barriers, and cancer history. Statistical analysis included descriptive statistics and non-parametric tests to describe bivariate associations and regression analysis. Adherence rates were 72% for annual mammography, 21% for semi-annual clinical breast exam (CBE), 29% for monthly breast self-exam (BSE), and 19% for annual transvaginal ultrasound (US). Only one participant was adherent with semi-annual CA125. Variables that had a significant association (P < 0.05) with at least one screening modality included: a lack of time, marital status, education, cancer history, provider concern, perceived screening utility, confidence in ability to overcome barriers, cancer specific distress, and risk perception. Primary physician behavior, either in terms of screening recommendations or screening performance in the case of CBE, had significant independent association with adherence to mammography, CBE, and US screening recommendations. The results of this study highlight the essential role that primary physicians play in supporting their very high-risk patients' adherence.


Ampullary carcinoma is often of mixed or hybrid histologic type: an analysis of reproducibility and clinical relevance of classification as pancreatobiliary versus intestinal in 232 cases.
Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was 'fair' (κ 0.39; P<0.001) with complete agreement in 23%. Using agreement by 3/5 observers as 'consensus' 40% of cases were classified as 'mixed' pancreatobiliary and intestinal. When observers were asked to provide a final diagnosis based on the predominant pattern in cases initially classified as mixed, there was 'moderate' agreement (κ 0.44; P<0.0001) with 5/5 agreeing in 35%. Cases classified as pancreatobiliary by consensus (including those with pure-pancreatobiliary or mixed-predominantly pancreatobiliary features) had shorter overall (median 41 months) and 5-year survival (38%) than those classified as pure-intestinal/mixed-predominantly intestinal (80 months and 57%, respectively; P=0.026); however, on multivariate analysis this was not independent of established prognostic parameters. Interestingly, when compared with 476 cases of pancreatic ductal adenocarcinomas, the pancreatobiliary-type ampullary carcinomas had better survival (16 versus 41 months, P<0.001), even when matched by size and node status. In conclusion, presumably because of the various cell types comprising the region, ampullary carcinomas frequently show mixed phenotypes and intratumoral heterogeneity, which should be considered when devising management protocols. Caution is especially warranted when applying this histologic classification to biopsies and tissue microarrays. While ampullary carcinomas with more pancreatobiliary morphology have a worse prognosis than intestinal ones this does not appear to be an independent prognostic factor. However, pancreatobiliary-type ampullary carcinomas have a much better prognosis than their pancreatic counterparts.


Playing with curricular milestones in the educational sandbox: Q-sort results from an internal medicine educational collaborative.
In competency-based medical education, the focus of assessment is on learner demonstration of predefined outcomes or competencies. One strategy being used in internal medicine (IM) is applying curricular milestones to assessment and reporting milestones to competence determination. The authors report a practical method for identifying sets of curricular milestones for assessment of a landmark, or a point where a resident can be entrusted with increased responsibility. Thirteen IM residency programs joined in an educational collaborative to apply curricular milestones to training. The authors developed a game using Q-sort methodology to identify high-priority milestones for the landmark "Ready for indirect supervision in essential ambulatory care" (EsAMB). During May to December 2010, the programs'ambulatory faculty participated in the Q-sort game to prioritize 22 milestones for EsAMB. The authors analyzed the data to identify the top 8 milestones. In total, 149 faculty units (1-4 faculty each) participated. There was strong agreement on the top eight milestones; six had more than 92% agreement across programs, and five had 75% agreement across all faculty units. During the Q-sort game, faculty engaged in dynamic discussion about milestones and expressed interest in applying the game to other milestones and educational settings. The Q-sort game enabled diverse programs to prioritize curricular milestones with interprogram and interparticipant consistency. A Q-sort exercise is an engaging and playful way to address milestones in medical education and may provide a practical first step toward using milestones in the real-world educational setting.


Early Patient Satisfaction with Different Treatment Pathways for Trigger Finger and Thumb.
Little is known about factors related to patient satisfaction with treatment for trigger digits. This study tested the null hypothesis that there are no factors associated with treatment satisfaction 2 months after completion of treatment (absence of triggering) or 4 months after the last visit for patients with a trigger thumb or finger. Secondary null hypotheses were: 1) There are no factors associated with a change in patients' preferred treatment before and after consultation with a hand surgeon; and 2) Initial treatment provided is not different from final received treatment. In an observational study, 63 English-speaking adult patients were enrolled after being diagnosed with one or more new idiopathic trigger digits by one of two hand surgeons, but before the hand surgeon discussed treatment options. Patients were asked to fill out questionnaires at enrollment. Final evaluation was by phone. Satisfaction with treatment was not related to the initial treatment or other patient or disease factors. Twenty-three patients (37 %) had a different preference for treatment after talking with a hand surgeon. Involvement of the long and ring fingers were the only factors associated with staying with pre-visit treatment preferences. There was a significant difference in proportions of the various treatments provided at enrollment and final treatment recorded at the final phone evaluation, 14 patients (22 %) had a subsequent alternative form of treatment. Patients' preferences for trigger finger treatment often change after consulting with a hand surgeon and during treatment, but these choices do not affect treatment satisfaction.


Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study.
To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.


STRT-seq-2i: dual-index 5' single cell and nucleus RNA-seq on an addressable microwell array.
Single-cell RNA-seq has become routine for discovering cell types and revealing cellular diversity, but archived human brain samples still pose a challenge to current high-throughput platforms. We present STRT-seq-2i, an addressable 9600-microwell array platform, combining sampling by limiting dilution or FACS, with imaging and high throughput at competitive cost. We applied the platform to fresh single mouse cortical cells and to frozen post-mortem human cortical nuclei, matching the performance of a previous lower-throughput platform while retaining a high degree of flexibility, potentially also for other high-throughput applications.


Regulation of iron metabolism by hepcidin.
Hepcidin, a peptide hormone made in the liver, is the principal regulator of systemic iron homeostasis. Hepcidin controls plasma iron concentration and tissue distribution of iron by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter. Synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia and hypoxia. Hepcidin is also elevated during infections and inflammation, causing a decrease in serum iron levels and contributing to the development of anemia of inflammation, probably as a host defense mechanism to limit the availability of iron to invading microorganisms. At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of hemochromatosis, either due to mutations in the hepcidin gene itself or due to mutations in the regulators of hepcidin synthesis. The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.


Collisional energy dependence of peptide ion fragmentation.
The energy dependence of fragmentation in a collision cell was measured for 2400 protonated peptide ions derived from the digestion of 24 proteins. The collision voltage at which the sum of the fragment ion abundances was equal to the remaining parent ion (V(1/2)) was the principal measure of fragmentation effectiveness. Each class of peptides was characterized by a linear relation between V(1/2) and m/z whose slope depended on the peptide class and, with little adjustment, intersected the origin. Peptide ions where the number of protons is no greater than the number of arginine residues show the greatest slope, V(1/2)/(m/z) = 0.0472 (all slopes in units of V Da(-1) e). For peptides where the number of protons is greater than the number of arginines, but not greater than the total number of basic residues, the slope decreases to 0.0414 for singly charged ions, 0.0382 for doubly charged, 0.0346 for triply charged, and 0.0308 for more highly charged ions. With one mobile proton, the slope is about 0.029 for singly and doubly charged ions and slightly lower for more highly charged ions. With two or more mobile protons the slope is 0.0207. By removing m/z dependence, the deviation of V(1/2) from a line provides a relative measure of the ease of fragmentation of an ion in each class. This information can guide the selection of optimal conditions for tandem mass spectrometry studies in collision cells for selected peptide ions as well as aid in comparing the reactivity of ions differing in m/z and charge state.


Role of metabolism in the biliary excretion of methadone metabolites.
The biliary excretion of the major methadone metabolites was studied after the administration of purified 14C-labeled metabolites of methadone. The three methadone metabolites administered to rats were the pyrrolidine and pyrroline metabolites and the glucuronide conjugate of the hydroxylated pyrroline metabolite. We found that the excretion of 14C into bile was greater after administration of the metabolites which underwent fewer metabolic steps prior to biliary excretion. Phenobarbital pretreatment of rats increased the biliary excretion of 14C after the administration of the 14C-labeled pyrrolidine and pyrroline metabolites, both of which undergo further metabolism. Phenobarbital pretreatment did not change the biliary excretion of 14C-labeled glucuronide of the pyrroline metabolite which does not undergo further metabolism in the liver. Analysis of bile samples showed that the increased biliary excretion of 14C in phenobarbital-pretreated rats after administration of the labeled pyrrolidine and pyrroline metabolites was due primarily to increases in the biliary excretion of methadone metabolites which resulted from further in vivo metabolism of the injected metabolites. These data confirm our earlier suggestion (Roerig et al., Biochem. Pharmacol. 24: 355-362, 1975) that phenobarbital pretreatment increases biliary excretion of methadone metabolites by increasing hepatic metabolism of methadone. Furthermore, it can be concluded from these studies that metabolism is a rate-limiting process in the excretion of methadone metabolites in bile.


A phylogenetic analysis identifies heterogeneity among hepatocellular carcinomas.
Primary hepatocellular carcinoma (HCC) is a significant cause of cancer morbidity and mortality on the global scale. Although epidemiologic studies have identified major risk factors for HCC, the sequence of oncogenic events at the molecular level remains poorly understood. While genetic allele loss appears to be a common event, the significance of the loss is not clear. In order to determine whether allele loss appears to be a random event among HCCs or whether patterns of loss cluster in groups of tumors, a phylogenetic approach was used to examine 32 tumors for genome-wide loss of heterozygosity employing 391 markers. Clusters identified by the phylogenetic analysis were then contrasted to compare candidate locus variation among individuals and to determine whether certain clusters exhibited higher loss rates than other clusters. The analysis found that 3 major and 1 minor cluster of loss could be identified and, further, these clusters were distinguished by variable rates of loss (cluster 1, 29%; cluster 2, 21%; cluster 3, 16%). The analyses also indicated that the allele loss rates in HCC were not insignificant and that the patterns of allele loss were complex. In addition, the results indicated that an individual's constitutional genotype at the EPHX1 locus may be a critical factor in determining the path of tumor evolution. In conclusion, it appears that in HCC, allele loss is not random, but clusters into definable groups that are characterized by distinctive rates of loss.


A Panel of Embryonic Stem Cell Lines Reveals the Variety and Dynamic of Pluripotent States in Rabbits.
Conventional rabbit embryonic stem cell (ESC) lines are derived from the inner cell mass (ICM) of pre-implantation embryos using methods and culture conditions that are established for primate ESCs. In this study, we explored the capacity of the rabbit ICM to give rise to ESC lines using conditions similar to those utilized to generate naive ESCs in mice. On single-cell dissociation and culture in fibroblast growth factor 2 (FGF2)-free, serum-supplemented medium, rabbit ICMs gave rise to ESC lines lacking the DNA-damage checkpoint in the G1 phase like mouse ESCs, and with a pluripotency gene expression profile closer to the rabbit ICM/epiblast profiles. These cell lines can be converted to FGF2-dependent ESCs after culture in conventional conditions. They can also colonize the rabbit pre-implantation embryo. These results indicate that rabbit epiblast cells can be coaxed toward different types of pluripotent stem cells and reveal the dynamics of pluripotent states in rabbit ESCs.


Multipotent Adult Progenitor Cells Suppress T Cell Activation in In Vivo Models of Homeostatic Proliferation in a Prostaglandin E2-Dependent Manner.
Lymphodepletion strategies are used in the setting of transplantation (including bone marrow, hematopoietic cell, and solid organ) to create space or to prevent allograft rejection and graft versus host disease. Following lymphodepletion, there is an excess of IL-7 available, and T cells that escape depletion respond to this cytokine undergoing accelerated proliferation. Moreover, this environment promotes the skew of T cells to a Th1 pro-inflammatory phenotype. Existing immunosuppressive regimens fail to control this homeostatic proliferative (HP) response, and thus the development of strategies to successfully control HP while sparing T cell reconstitution (providing a functioning immune system) represents a significant unmet need in patients requiring lymphodepletion. Multipotent adult progenitor cells (MAPC®) have the capacity to control T cell proliferation and Th1 cytokine production. Herein, this study shows that MAPC cells suppressed anti-thymocyte globulin-induced cytokine production but spared T cell reconstitution in a pre-clinical model of lymphodepletion. Importantly, MAPC cells administered intraperitoneally were efficacious in suppressing interferon-γ production and in promoting the expansion of regulatory T cells in the lymph nodes. MAPC cells administered intraperitoneally accumulated in the omentum but were not present in the spleen suggesting a role for soluble factors. MAPC cells suppressed lymphopenia-induced cytokine production in a prostaglandin E2-dependent manner. This study suggests that MAPC cell therapy may be useful as a novel strategy to target lymphopenia-induced pathogenic T cell responses in lymphodepleted patients.


Inhibitory Control Processes and the Strategies That Support Them during Hand and Eye Movements.
Background and Aims: Adaptive behavior depends on the ability to voluntarily suppress context-inappropriate behaviors, a process referred to as response inhibition. Stop Signal tests (SSTs) are the most frequently studied paradigm used to assess response inhibition. Previous studies of SSTs have indicated that inhibitory control behavior can be explained using a common model in which GO and STOP processes are initiated independent from one and another, and the process that is completed first determines whether the behavior is elicited (GO process) or terminated (STOP process). Consistent with this model, studies have indicated that individuals strategically delay their behaviors during SSTs in order to increase their stopping abilities. Despite being controlled by distinct neural systems, prior studies have largely documented similar inhibitory control performance across eye and hand movements. Though, no existing studies have compared the extent to which individuals strategically delay behavior across different effectors is not yet clear. Here, we compared the extent to which inhibitory control processes and the cognitive strategies that support them during oculomotor and manual motor behaviors. Methods: We examined 29 healthy individuals who performed parallel oculomotor and manual motor SSTs. Participants also completed a separate block of GO trials administered prior to the Stop Signal tests to assess baseline reaction times for each effector and reaction time increases during interleaved GO trials of the SST. Results: Our results showed that stopping errors increased for both effectors as the interval between GO and STOP cues was increased (i.e., stop signal delay), but performance deteriorated more rapidly for eye compared to hand movements with increases in stop signal delay. During GO trials, participants delayed the initiation of their responses for each effector, and greater slowing of reaction times on GO trials was associated with increased accuracy on STOP trials for both effectors. However, participants delayed their eye movements to a lesser degree than their hand movements, and strategic reaction time slowing was a stronger determinant of stopping accuracy for hand compared to eye movements. Overall, stopping accuracies for eye and hand movements were only modestly correlated, and the time it took individuals to cancel a response was not related for eye and hand movements. Discussion and Conclusion: Our findings that GO and STOP processes are independent and that individuals strategically delay their behavioral responses to increase stopping accuracy regardless of effector indicate that inhibitory control of oculomotor and manual motor behaviors both follow common guiding principles. Yet, our findings document that eye movements are more difficult to inhibit than hand movements, and the timing, magnitude, and impact of cognitive control strategies used to support voluntary response inhibition are less robust for eye compared to hand movements. This suggests that inhibitory control systems also show unique characteristics that are behavior-dependent. This conclusion is consistent with neurophysiological evidence showing important differences in the architecture and functional properties of the neural systems involved in inhibitory control of eye and hand movements. It also suggests that characterizing inhibitory control processes in health and disease requires effector-specific analysis.


5-Formylcytosine Could Be a Semipermanent Base in Specific Genome Sites.
5-Formyl-2'-deoxycytosine (fdC) is a recently discovered epigenetic base in the genome of stem cells, with yet unknown functions. Sequencing data show that the base is enriched in CpG islands of promoters and hence likely involved in the regulation of transcription during cellular differentiation. fdC is known to be recognized and excised by the enzyme thymine-DNA-glycosylase (Tdg). As such, fdC is believed to function as an intermediate during active demethylation. In order to understand the function of the new epigenetic base fdC, it is important to analyze its formation and removal at defined genomic sites. Here, we report a new method that combines sequence-specific chemical derivatization of fdC with droplet digital PCR that enables such analysis. We show initial data, indicating that the repair protein Tdg removes only 50 % of the fdCs at a given genomic site, arguing that fdC is a semipermanent base.


Changes in plasma osteocalcin concentration following treatment with stanozolol.
Treatment of healthy, adult, human volunteers with stanozolol, 5 mg twice daily, for six weeks caused a marked elevation in circulating levels of osteocalcin. Plasma osteocalcin concentrations did not fall to pretreatment values for a period in excess of four weeks after the cessation of treatment but remained similar to levels whilst on treatment. At the same time, as the rise in plasma osteocalcin was seen, plasma alkaline phosphatase activity fell; however, in this case, a return to pretreatment levels occurred within four weeks of treatment ending. These data demonstrate that stanozolol has a detectable effect on the plasma concentration of a protein thought to be a marker of osteoblast activity, and that this effect continues for a period after treatment has been discontinued.


Fred J. Frese III (1940-2018).
Fred J. Frese III, called a "national treasure" by Mike Hogan, Chair of the President's New Freedom Commission on Mental Health, died July 16, 2018, at his home in Hudson, Ohio, surrounded by his family. Fred was an extraordinary human being who was diagnosed with paranoid schizophrenia and rose to become an influential and accomplished psychologist who inspired all he met. Fred presented Congressional testimony to both Houses of Congress, appeared on several national TV and radio broadcasts, and spoke worldwide. Fred was a fellow of the APA and received the Association's Distinguished Service Award in 1987 and a Presidential Citation in 2005. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The complete nucleotide sequence of RNA 3 of citrus leaf rugose and citrus variegation ilarviruses.
Complete sequence data for the RNA 3 of both citrus leaf rugose (CiLRV) and citrus variegation (CVV) ilarviruses have been determined. The RNAs are 2289 nt (CiLRV) and 2309 nt (CVV) in length and both contain the typical Bromoviridae arrangement of two open reading frames (ORFs) which, when translated, code for proteins that correspond to the Mr 32,000 (32K) putative movement proteins (ORF 1) and the coat proteins (ORF 2) of the respective viruses. The 3' termini of both viruses can be folded to form a secondary structure similar to those reported for other ilarviruses. These are the first complete nucleotide sequences for RNA 3 of members of subgroup 2 of the ilarviruses. The two viruses share substantial homology in nucleic acid sequence, code for identically sized coat proteins and share high levels of identity in the translated products of both ORFs. Although related, these viruses differ sufficiently to be considered distinct. The RNA 3s of CiLRV and CVV appear to be distinct from those of other ilarviruses for which comparable sequence data are available and also from the closely related alfalfa mosaic virus.


The geographic spread of the CCR5 Delta32 HIV-resistance allele.
The Delta32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Delta32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles.


[Therapy of severe stenocardia with ultraviolet blood irradiation (UVB) and various action mechanisms of this therapy].
We observed 70 male patients with a seriously proceeding Chronic myocardial ischemia. They were hospitalised because of frequent, permanent and serious attacks of stenocardia at rest and in stress situations. More than 2/3 of these patients had suffered from a myocardial infarct. In the course of two weeks an intensive therapy with all modern preparations for vasodilatation was made. This therapy proved to be unsuccessful. Nearly all patients were administered more than 10 tables of nitroglycerin per day and, in addition, they were injected analgetics as a compensation of attack. The ultraviolet own blood irradiation (UVB) had a positive therapeutic effect in all patients. There was a good success in 46 patients, in all patients satisfactory results could be registered. The effect of therapy was evident by the decrease of administration of nitroglycerin required, by an increase in the degree of stress capacity, and by an easier treatment of stenocardia attacks. The observation time for patients amounted to 2-8 months. The success of therapy remained in 38 patients. After this time the success of therapy could partially be regained by a repeated number of irradiation series. Then, it remained positive in 9 of 22 patients who had been followed-up for 10 months. The half decay period of eliminating 131I from an intradermal depot could be normalised under the influence of ultraviolet own blood irradiation. This ultraviolet own blood irradiation had no significant influence on the fibrinogen level, fibrinolytic activity, and erythrocyte aggregation (examined in 11 patients). A 2 1/2-fold diminution of monomer fibrin complexes in the blood could be observed. The titre of antistreptolysin-O was increased in all patients who had got over the infarct. It had completely normalised a week after finishing the ultraviolet own blood irradiation. Spectroscopic examinations of the blood and plasma made after ultraviolet own blood irradiation revealed that this irradiation will not only affect the properties of Hb, but will also cause a photochemical transformation accompanied by a destruction of some plasma proteins, of the membrane of formed blood elements, and a photosynthesis of biochemically active compounds. The mechanism of action of ultraviolet own blood irradiation is complicated and requires further exact investigations. Even today, however, this method can be recommended as a complex therapy in patients with severe myocardial ischemia.


Temperature and magnetic field dependence of a Kondo system in the weak coupling regime.
The Kondo effect arises due to the interaction between a localized spin and the electrons of a surrounding host. Studies of individual magnetic impurities by scanning tunneling spectroscopy have renewed interest in Kondo physics; however, a quantitative comparison with theoretical predictions remained challenging. Here we show that the zero-bias anomaly detected on an organic radical weakly coupled to a Au (111) surface can be described with astonishing agreement by perturbation theory as originally developed by Kondo 60 years ago. Our results demonstrate that Kondo physics can only be fully conceived by studying both temperature and magnetic field dependence of the resonance. The identification of a spin 1/2 Kondo system is of relevance not only as a benchmark for predictions for Kondo physics but also for correlated electron materials in general.


3-Chloro-1-lithiopropene, a functional organolithium reagent, and its reactions with alkylboronates to give 3-alkylprop-1-en-3-ols.
The reagent 3-chloro-1-lithiopropene (4) can be generated by treating 1-bromo-3-chloropropene with t-BuLi. It is unstable but if generated at low temperature in the presence of alkylboronic esters, such as 3, is trapped in situ to give rearrangement products 2, which on oxidation give 3-alkylprop-1-en-3-ols in good yields. The reaction works for primary, secondary, benzylic, and even tertiary alkylboronic esters, providing allylic alcohols bearing almost any alkyl group available using organoborane chemistry and incorporating all features of such groups.


Postnatal systemic inflammation exacerbates impairment of hippocampal synaptic plasticity in an animal seizure model.
To investigate the effects of systemic inflammation in the critical postnatal stages on neurophysiological actions of immune processes and neural plasticity in adult rats after kainic acid (KA)-induced seizures. To determine changes in hippocampal synaptic plasticity after postnatal central nervous system inflammatory responses and seizure attacks, we performed intraperitoneal injections of lipopolysaccharide (LPS) in postnatal Sprague Dawley rats on day 14 (P14) to induce central nervous system inflammation. We then used a KA tail vein injection on P35 to induce seizure attacks. We compared the variability in synaptic plasticity in the hippocampal Schaffer collateral-CA1 region of seizure animals with or without LPS-induced inflammation preconditioning. P14 injection of LPS increased susceptibility to seizures, while treatment with KA on P35 induced seizures. Long-term potentiation (LTP) of the Schaffer collateral-CA1 region was impaired in seizure animals, and this effect was more pronounced in the P14 LPS injection group. Fluoro-Jade staining revealed an increase in degenerated hippocampal CA1 pyramidal cells in the P14 LPS injection group. Cytokine expression in the hippocampus in the pre-, peri- and postictus periods was greater in P14 LPS rats than in saline-treated rats. Intraperitoneal LPS injection on P14 induces higher cytokine secretion after KA-induced seizures, enhancing neuronal excitability, shortening seizure onset time and exacerbating neuronal degeneration and impairment of LTP formation in the hippocampal Schaffer collateral-CA1 region. Central nervous system inflammation during critical stages of childhood development could disrupt the balance needed for neurophysiological actions of immune processes, producing direct, pernicious effects on memory, neural plasticity and neurogenesis into adulthood.


Architecture and Evolution of Blade Assembly in β-propeller Lectins.
Lectins with a β-propeller fold bind glycans on the cell surface through multivalent binding sites and appropriate directionality. These proteins are formed by repeats of short domains, raising questions about evolutionary duplication. However, these repeats are difficult to detect in translated genomes and seldom correctly annotated in sequence databases. To address these issues, we defined the blade signature of the five types of β-propellers using 3D-structural data. With these templates, we predicted 3,887 β-propeller lectins in 1,889 species and organized this information in a searchable online database. The data reveal a widespread distribution of β-propeller lectins across species. Prediction also emphasizes multiple architectures and led to the discovery of a β-propeller assembly scenario. This was confirmed by producing and characterizing a predicted protein coded in the genome of Kordia zhangzhouensis. The crystal structure uncovers an intermediate in the evolution of β-propeller assembly and demonstrates the power of our tools.


Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease.
Glucose metabolism is depressed in the temporal and parietal regions of the cortex in patients with Alzheimer's disease. We measured the concentrations of two glucose transporters, GLUT1 and GLUT3, in six regions of brains from both control subjects and patients with Alzheimer's disease. The concentrations of both transporters were reduced in the cerebral cortex, with larger and highly significant reductions observed for GLUT3, the putative neuronal glucose transporter. The reductions in GLUT3 were greater than the loss of synapses, and should be considered as a potential cause of the deficits in glucose metabolism.


Regulation of Carotenoid Biosynthesis by Shade Relies on Specific Subsets of Antagonistic Transcription Factors and Cofactors.
Carotenoids are photosynthetic pigments essential for the protection against excess light. During deetiolation, their production is regulated by a dynamic repression-activation module formed by PHYTOCHROME-INTERACTING FACTOR1 (PIF1) and LONG HYPOCOTYL5 (HY5). These transcription factors directly and oppositely control the expression of the gene encoding PHYTOENE SYNTHASE (PSY), the first and main rate-determining enzyme of the carotenoid pathway. Antagonistic modules also regulate the responses of deetiolated plants to vegetation proximity and shade (i.e. to the perception of far-red light-enriched light filtered through or reflected from neighboring plants). These responses, aimed to adapt to eventual shading from plant competitors, include a reduced accumulation of carotenoids. Here, we show that PIF1 and related photolabile PIFs (but not photostable PIF7) promote the shade-triggered decrease in carotenoid accumulation. While HY5 does not appear to be required for this process, other known PIF antagonists were found to modulate the expression of the Arabidopsis (Arabidopsis thaliana) PSY gene and the biosynthesis of carotenoids early after exposure to shade. In particular, PHYTOCHROME-RAPIDLY REGULATED1, a transcriptional cofactor that prevents the binding of true transcription factors to their target promoters, was found to interact with PIF1 and hence directly induce PSY expression. By contrast, a change in the levels of the transcriptional cofactor LONG HYPOCOTYL IN FAR RED1, which also binds to PIF1 and other PIFs to regulate shade-related elongation responses, did not impact PSY expression or carotenoid accumulation. Our data suggest that the fine-regulation of carotenoid biosynthesis in response to shade relies on specific modules of antagonistic transcriptional factors and cofactors.