Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.
After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.


Female pattern hair loss: current treatment concepts.
Fewer than 45% of women go through life with a full head of hair. Female pattern hair loss is the commonest cause of hair loss in women and prevalence increases with advancing age. Affected women may experience psychological distress and impaired social functioning. In most cases the diagnosis can be made clinically and the condition treated medically. While many women using oral antiandrogens and topical minoxidil will regrow some hair, early diagnosis and initiation of treatment is desirable as these treatments are more effective at arresting progression of hair loss than stimulating regrowth. Adjunctive nonpharmacological treatment modalities such as counseling, cosmetic camouflage and hair transplantation are important measures for some patients. The histology of female pattern hair loss is identical to that of male androgenetic alopecia. While the clinical pattern of the hair loss differs between men, the response to oral antiandrogens suggests that female pattern hair loss is an androgen dependant condition, at least in the majority of cases. Female pattern hair loss is a chronic progressive condition. All treatments need to be continued to maintain the effect. An initial therapeutic response often takes 12 or even 24 months. Given this delay, monitoring for treatment effect through clinical photography or standardized clinical severity scales is helpful.


Phthiocerol Dimycocerosates From Mycobacterium tuberculosis Increase the Membrane Activity of Bacterial Effectors and Host Receptors.
Mycobacterium tuberculosis (Mtb) synthesizes a variety of atypical lipids that are exposed at the cell surface and help the bacterium infect macrophages and escape elimination by the cell's immune responses. In the present study, we investigate the mechanism of action of one family of hydrophobic lipids, the phthiocerol dimycocerosates (DIM/PDIM), major lipid virulence factors. DIM are transferred from the envelope of Mtb to host membranes during infection. Using the polarity-sensitive fluorophore C-Laurdan, we visualized that DIM decrease the membrane polarity of a supported lipid bilayer put in contact with mycobacteria, even beyond the site of contact. We observed that DIM activate the complement receptor 3, a predominant receptor for phagocytosis of Mtb by macrophages. DIM also increased the activity of membrane-permeabilizing effectors of Mtb, among which the virulence factor EsxA. This is consistent with previous observations that DIM help Mtb disrupt host cell membranes. Taken together, our data show that transferred DIM spread within the target membrane, modify its physical properties and increase the activity of host cell receptors and bacterial effectors, diverting in a non-specific manner host cell functions. We therefore bring new insight into the molecular mechanisms by which DIM increase Mtb's capability to escape the cell's immune responses.


Possible paleohydrologic and paleoclimatic effects on hominin migration and occupation of the Levantine Middle Paleolithic.
This paper explores the impact of major glacial/interglacial paleohydrologic variations in the Middle-Paleolithic Levant on hominin migration and occupation. The climatic reconstruction is based primarily on the most straight-forward paleohydrologic records recently published. These terrestrial proxies convey direct paleoenvironmental signals of effective precipitation and aquifer recharge. The two main proxies are temporal changes of terminal lake levels in the Dead Sea basin and periods of deposition or non-deposition of speleothems. Other records, such as stable isotopes, if interpreted correctly, correspond well with these two direct proxies. All the records consistently indicate that the last two glacial periods in the central Levant were generally wet and cool, while the last two interglacials were dry and warm, so more water was available for the ecosystem and thus hominins during glacial periods than during interglacials. Some proxies indicate that the higher precipitation/evaporation ratio during glacial periods involved higher precipitation rather than only reduced evaporation. Beyond the general mean glacial/interglacial climate suggested here, variations occurred at all temporal scales throughout glacial or interglacial periods. In the Sahara-Negev arid barrier, moister conditions occurred during Marine Isotope Stage (MIS) 6a-5e, when Anatomically Modern Humans apparently migrated out of Africa. We suggest that this migration, as well as the later Neanderthal expansion from Southeast Europe or the Anatolian plateau into the Levant during early MIS 4, could be facilitated by the observed major climatic variations.


Relationship between expression of P-glycoprotein and efficacy of trifluoperazine in multidrug-resistant cells.
Tumor cell resistance due to enhanced efflux of drugs with diverse structures and/or mechanisms of action is termed multidrug resistance (MDR), and modulation of the MDR phenotype by calcium blockers or calmodulin inhibitors is suggested to involve P-glycoprotein. In drug-sensitive (S) and 5-fold doxorubicin (DOX)-resistant (R0) L1210 mouse leukemia cells, no obvious differences in mdr mRNA or P-glycoprotein expression or alterations in cellular uptake, retention, or cytotoxicity of vincristine (VCR) were observed. However, in the 10-fold (R1) and 40-fold (R2) DOX-resistant sublines, expression of P-glycoprotein was correlated with the level of resistance (R2 greater than R1). An RNase protection assay revealed that elevated levels of mdr1 and mdr2 mRNA were detected in R1 and R2 cells, with an additional increase in mdr3 mRNA in the R2 subline. Further, in the R1 and R2 sublines, no VCR dose-dependent cytotoxicity was apparent, and cell kill of greater than 40% was not achievable following a 3-hr drug exposure. Cellular uptake and retention of VCR were 2- to 4-fold lower in the R1 and R2 sublines, compared with similarly treated S or R0 cells. Potentiation of VCR cytotoxicity by a noncytotoxic concentration of 5 microM trifluoperazine (TFP) was greater than 2-fold in S and R0 cells and less than 1.3-fold in the R1 and R2 sublines. Modulation of VCR uptake by 5 microM TFP in the S and R0 cells was 2-fold and it was 4- to 7-fold in the R1 and R2 sublines. The presence of 5 microM TFP, by competing for efflux, enhanced VCR retention 1.5-fold in S and R0 cells and 2- to 4-fold in the R1 and R2 sublines. In contrast to these results with VCR, dose-dependent cytotoxicity of DOX was apparent in all the resistant sublines, and modulation of DOX cytotoxicity by 5 microM TFP was dependent on the level of resistance. Cellular accumulation of DOX was 20 and 50% lower in the R1 and R2 sublines, respectively, compared with similarly treated S or R0 cells. Marked increases (greater than 1.5-fold) in cellular accumulation of DOX by TFP were apparent only in the R2 subline. Results suggest that a relationship between overexpression of P-glycoprotein isoforms and their role in affecting cellular drug levels and consequent cytotoxicity in MDR L1210 cells determines resistance to VCR but not DOX.(ABSTRACT TRUNCATED AT 400 WORDS)


A mathematical model for simultaneous spatio-temporal dynamics of calcium and inositol 1,4,5-trisphosphate in Madin-Darby canine kidney epithelial cells.
The landmark paper by Hirose et al. (Hirose, K., Kadowaki, S., Tanabe, M., Takeshima, H., Iino, M., Science 284:1527-1530, 1999) presented experimental investigations to show that not only can calcium upregulate IP(3), but that it can also have an inhibitory effect on IP(3). In this paper, we present a preliminary model, which is consistent with these experiments. This model includes positive and negative feedback between calcium and IP(3) and is able to reproduce more precisely the data presented in Hirose et al. (Hirose, K., Kadowaki, S., Tanabe, M., Takeshima, H., Iino, M., Science 284:1527-1530, 1999). In the second part of the paper, the intracellular and intercellular calcium movement in Madin-Darby canine kidney epithelial cells is investigated. With the aid of the model we are able to identify the aspects of IP(3) and calcium signalling, which should be studied further experimentally before refining the model.


Care-related distress: a nationwide study of parents who lost their child to cancer.
Palliative care is an important part of cancer treatment. However, little is known about how care-related factors affect bereaved intimates in a long-term perspective. We conducted a population-based, nationwide study addressing this issue, focusing on potential care-related stressors in parents losing a child to cancer. In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer in 1992 to 1997. The parents were asked, through an anonymous postal questionnaire, about their experience of the care given and to what extent these experiences still affect them today. Information was supplied by 449 (80%) of 561 eligible parents. Among 196 parents of children whose pain could not be relieved, 111 (57%) were still affected by it 4 to 9 years after bereavement. Among 138 parents reporting that the child had a difficult moment of death, 78 (57%) were still affected by it at follow-up. The probability of parents reporting that their child had a difficult moment of death was increased (relative risk = 1.4; 95% CI, 1.0 to 1.8) if staff were not present at the moment of death. Ten percent of the parents (25 of 251 parents) were not satisfied with the care given during the last month at a pediatric hematology/oncology center; the corresponding figure for care at other hospitals was 20% (33 of 168 parents; P = .0163). Physical pain and the moment of death are two important issues to address in end-of-life care of children with cancer in trying to reduce long-term distress in bereaved parents.


Characteristics of student preparedness for clinical learning: clinical educator perspectives using the Delphi approach.
During clinical placements, clinical educators facilitate student learning. Previous research has defined the skills, attitudes and practices that pertain to an ideal clinical educator. However, less attention has been paid to the role of student readiness in terms of foundational knowledge and attitudes at the commencement of practice education. Therefore, the aim of this study was to ascertain clinical educators' views on the characteristics that they perceive demonstrate that a student is well prepared for clinical learning. A two round on-line Delphi study was conducted. The first questionnaire was emailed to a total of 636 expert clinical educators from the disciplines of occupational therapy, physiotherapy and speech pathology. Expert clinical educators were asked to describe the key characteristics that indicate a student is prepared for a clinical placement and ready to learn. Open-ended responses received from the first round were subject to a thematic analysis and resulted in six themes with 62 characteristics. In the second round, participants were asked to rate each characteristic on a 7 point Likert Scale. A total of 258 (40.56%) responded to the first round of the Delphi survey while 161 clinical educators completed the second (62.40% retention rate). Consensus was reached on 57 characteristics (six themes) using a cut off of greater than 70% positive respondents and an interquartile deviation IQD of equal or less than 1. This study identified 57 characteristics (six themes) perceived by clinical educators as indicators of a student who is prepared and ready for clinical learning. A list of characteristics relating to behaviours has been compiled and could be provided to students to aid their preparation for clinical learning and to universities to incorporate within curricula. In addition, the list provides a platform for discussions by professional bodies about the role of placement education.


Enhanced gamma-aminobutyric acid-B receptor agonist responses and mRNA within the nucleus of the solitary tract in hypertension.
Gamma-Aminobutyric acid-B (GABAB) receptor function and regulation in the nucleus of the solitary tract (NTS) was examined in Sprague-Dawley rats made chronically (4 to 5 weeks) hypertensive with the one-kidney, figure-8 renal wrap model of hypertension. NTS microinjection of the GABAB agonist baclofen produced a pressor response that was enhanced in hypertensive rats compared with the response observed in sham-operated normotensive rats (36+/-4 mm Hg increase in mean arterial pressure in 8 hypertensive rats compared with 21+/-2 mm Hg increase in 7 sham-operated normotensive rats, P=0. 03). Responses to microinjection of GABAB antagonists (CGP-55845A and SCH-90511), the GABAA agonist muscimol, the GABAA antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats. Renal sympathetic nerve responses to NTS microinjection of these drugs were not different in hypertensive compared with normotensive rats. Micropunches of the NTS were homogenized and reverse transcriptase-polymerase chain reaction was performed to examine mRNA levels for the GABAB receptor. There was a 3-fold increase in GABAB receptor mRNA levels in the caudal NTS of 7 chronically hypertensive rats compared with levels measured in 8 sham-operated normotensive rats (P=0.01). In conclusion, chronic hypertension is associated with an upregulation of GABAB receptor function; however, the tonic activity of the system does not appear to be different between normotensive and hypertensive rats. The upregulation of GABAB receptor function might be due to an increased number of receptors, as suggested by the elevated levels of GABAB receptor mRNA measured in the NTS of hypertensive rats. All of these alterations suggest that hypertension is associated with dynamic changes in receptor-mediated mechanisms within the NTS, and these alterations could modify baroreflex regulation of cardiovascular function in hypertension.


The Consequences of Glaucoma on Mobility and Balance Control in the Older Adults: A Cross-Sectional Study.
The aim of the study was to explore the functional impairments and related factors in older adults with moderate to advanced stages of glaucoma. Nineteen patients with glaucoma and 19 participants with no ocular disease performed step test and balance control tasks with analysis of overall stability index and fall risk index. Monocular and binocular Humphrey Visual Field tests were used to estimate visual field defect severity. The International Physical Activity Questionnaire was used to measure physical activity level. Patients with glaucoma showed poorer values for most of the mobility and balance control parameters with medium and large effect sizes (0.3-0.5). Mobility scores in patients were partly associated with their monocular visual field defect (rs = .507, p < .05). Low physical activity was identified as a risk factor for falls (rs = -.453, p < .05) and postural instability (rs = -.457, p < .05). Functional declines in dynamic tasks were not related to glaucoma severity. Older adults with glaucoma display impairment with mobility and balance control compared to controls, associated with the degree of monocular visual field loss and lower daily physical activity.


Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial.
Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. Trial registration number: NTR 4414 . Date of registration January 29th 2014.


AntBot: A six-legged walking robot able to home like desert ants in outdoor environments.
Autonomous outdoor navigation requires reliable multisensory fusion strategies. Desert ants travel widely every day, showing unrivaled navigation performance using only a few thousand neurons. In the desert, pheromones are instantly destroyed by the extreme heat. To navigate safely in this hostile environment, desert ants assess their heading from the polarized pattern of skylight and judge the distance traveled based on both a stride-counting method and the optic flow, i.e., the rate at which the ground moves across the eye. This process is called path integration (PI). Although many methods of endowing mobile robots with outdoor localization have been developed recently, most of them are still prone to considerable drift and uncertainty. We tested several ant-inspired solutions to outdoor homing navigation problems on a legged robot using two optical sensors equipped with just 14 pixels, two of which were dedicated to an insect-inspired compass sensitive to ultraviolet light. When combined with two rotating polarized filters, this compass was equivalent to two costly arrays composed of 374 photosensors, each of which was tuned to a specific polarization angle. The other 12 pixels were dedicated to optic flow measurements. Results show that our ant-inspired methods of navigation give precise performances. The mean homing error recorded during the overall trajectory was as small as 0.67% under lighting conditions similar to those encountered by ants. These findings show that ant-inspired PI strategies can be used to complement classical techniques with a high level of robustness and efficiency.


Phylogenetic resolution within the tribe Episcieae (Gesneriaceae): congruence of ITS and NDHF sequences from parsimony and maximum-likelihood analyses.
Generic relationships within Episcieae were assessed using ITS and ndhF sequences. Previous analyses of this tribe have focussed only on ndhF data and have excluded two genera, Rhoogeton and Oerstedina, which are included in this analysis. Data were analyzed using both parsimony and maximum-likelihood methods. Results from partition homogeneity tests imply that the two data sets are significantly incongruent, but when Rhoogeton is removed from the analysis, the data sets are not significantly different. The combined data sets reveal greater strength of relationships within the tribe with the exception of the position of Rhoogeton. Poorly or unresolved relationships based exclusively on ndhF data are more fully resolved with ITS data. These resolved clades include the monophyly of the genera Columnea and Paradrymonia and the sister-group relationship of Nematanthus and Codonanthe. A closer affinity between Neomortonia nummularia and N. rosea than has previously been seen is apparent from these data, although these two species are not monophyletic in any tree. Lastly, Capanea appears to be a member of Gloxinieae, although C. grandiflora remains within Episcieae. Evolution of fruit type, epiphytic habit, and presence of tubers is re-examined with the new data presented here.


Bone mechanobiology, gravity and tissue engineering: effects and insights.
Bone homeostasis strongly depends on fine tuned mechanosensitive regulation signals from environmental forces into biochemical responses. Similar to the ageing process, during spaceflights an altered mechanotransduction occurs as a result of the effects of bone unloading, eventually leading to loss of functional tissue. Although spaceflights represent the best environment to investigate near-zero gravity effects, there are major limitations for setting up experimental analysis. A more feasible approach to analyse the effects of reduced mechanostimulation on the bone is represented by the 'simulated microgravity' experiments based on: (1) in vitro studies, involving cell cultures studies and the use of bioreactors with tissue engineering approaches; (2) in vivo studies, based on animal models; and (3) direct analysis on human beings, as in the case of the bed rest tests. At present, advanced tissue engineering methods allow investigators to recreate bone microenvironment in vitro for mechanobiology studies. This group and others have generated tissue 'organoids' to mimic in vitro the in vivo bone environment and to study the alteration cells can go through when subjected to unloading. Understanding the molecular mechanisms underlying the bone tissue response to mechanostimuli will help developing new strategies to prevent loss of tissue caused by altered mechanotransduction, as well as identifying new approaches for the treatment of diseases via drug testing. This review focuses on the effects of reduced gravity on bone mechanobiology by providing the up-to-date and state of the art on the available data by drawing a parallel with the suitable tissue engineering systems.


Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis. A randomized trial.
Impedance plethysmography is an accurate noninvasive method to test for proximal vein thrombosis, but it is insensitive to calf-vein thrombi. We randomly assigned patients on referral with clinically suspected deep-vein thrombosis and normal impedance plethysmographic findings to either serial impedance plethysmography alone or combined impedance plethysmography and leg scanning (which has been shown to be essentially as sensitive as venography) and compared the long-term outcomes. During the initial surveillance, deep-vein thrombosis was detected in 6 of 311 patients (1.9%) tested by serial impedance plethysmography alone and in 30 of 323 patients (9.3%) (most with calf-vein thrombi) tested by the combined approach (p less than 0.001). During long-term follow-up, no patient died from pulmonary embolism; but 6 patients (1.9%; 95% confidence limits, 0.7% to 4.2%) tested by serial impedance plethysmography developed deep-vein thrombosis compared with 7 patients (2.2%; 95% confidence limits, 0.9% to 4.4%) tested by the combined approach. Serial impedance plethysmography used alone is an effective strategy to evaluate such symptomatic patients.


High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma.
Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients. By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%). Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.


A green strategy for federated and heterogeneous clouds with communicating workloads.
Providers of cloud environments must tackle the challenge of configuring their system to provide maximal performance while minimizing the cost of resources used. However, at the same time, they must guarantee an SLA (service-level agreement) to the users. The SLA is usually associated with a certain level of QoS (quality of service). As response time is perhaps the most widely used QoS metric, it was also the one chosen in this work. This paper presents a green strategy (GS) model for heterogeneous cloud systems. We provide a solution for heterogeneous job-communicating tasks and heterogeneous VMs that make up the nodes of the cloud. In addition to guaranteeing the SLA, the main goal is to optimize energy savings. The solution results in an equation that must be solved by a solver with nonlinear capabilities. The results obtained from modelling the policies to be executed by a solver demonstrate the applicability of our proposal for saving energy and guaranteeing the SLA.


Is depression associated with increased oxidative stress? A systematic review and meta-analysis.
It has been suggested that depressed persons have increased oxidative stress and decreased anti-oxidant defences. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and F2-isoprostanes, measures of oxidative DNA and lipid damage respectively, are among the most reliable oxidative stress markers, but studies on their association with depression show conflicting results. This meta-analysis quantifies the association between depression and these markers and explores factors that may explain inconsistencies in the results. A systematic literature search was conducted in PubMed, EMBASE and PsycINFO. Studies assessing the association of 8-OHdG or F2-isoprostanes with elevated depressive symptoms, major depressive disorder (MDD) or bipolar disorder (BD) were pooled in two random-effect models. The pooled effect size (Hedges' g) for the association of depression with oxidative stress was 0.31 (p=0.01, I(2)=75%) for 8-OHdG (10 studies, 1308 subjects) and 0.48 (p=0.001, I(2)=73%) for F2-isoprostanes (8 studies, 2471 subjects), indicating that both markers are increased in depression. There was no indication of publication bias for either marker. The F2-isoprostane results did not differ by type of depression, biological specimen, laboratory method or quality, however subgroup analyses in the 8-OHdG studies showed significantly stronger associations in plasma/serum vs. urine samples (p<0.01), in measurements performed with immuno-assay vs. chromatography-mass spectrometry (p<0.01) and weaker associations in high quality studies vs. low (p=0.02). This meta-analysis finds that oxidative stress, as measured by 8-OHdG and F2-isoprostanes, is increased in depression. Larger-scale studies are needed to extend the evidence on oxidative stress in depression, and examine the potential impact of treatment.


Corticosteroid injection therapy for trigger finger or thumb: a retrospective review of 577 digits.
Stenosing flexor tenosynovitis of the digital flexor tendon (trigger digit) is a common condition encountered by hand surgeons. Our purpose was to determine the efficacy of corticosteroid injections and review the demographic profile of patients with trigger digits. We reviewed the records of 362 patients (577 trigger digits) treated with steroid injections (8 mg of triamcinolone acetonide in 1 % lidocaine) from 1998 through 2011. Follow-up (intervention to last visit) averaged 66.4 months. We assessed patient demographics (e.g., gender, age, diabetes mellitus, hand dominance, trigger digit distribution) and determined recurrence rate and injection duration of efficacy. If one injection failed, additional injections or surgical A1 pulley release were offered. Results were analyzed with Student's t test or Fisher's exact test (significance, p < 0.05). Women (258, 71.3 %) were affected significantly (p < 0.001) more frequently than men (104, 28.7 %) and at a significantly (p < 0.001) younger age (average, 58.3 versus 62.1 years, respectively). Eighty patients (22.1 %) were diabetic. We observed no correlation between trigger digit and hand dominance. The two most commonly affected digits were the right long finger (17.8 %) and right thumb (17.7 %). For 721 injections, the recurrence rate was 20.3 %; there were no major complications. For recurrences, the injection efficacy averaged 315 days. Surgery was required for 117 patients. Injection therapy is safe and highly effective (79.7 %). Women were affected by trigger digits more often than men and at a younger age. Surgical release provides a definitive therapeutic option if corticosteroid injection fails.


Regulation of Golgi structure and function by ARF-like protein 1 (Arl1).
Arl1 is a member of the ARF-like protein (Arl) subfamily of small GTPases. Nothing is known about the function of Arl1 except for the fact that it is essential for normal development in Drosophila and that it is associated with the Golgi apparatus. In this study, we first demonstrate that Arl1 is enriched at the trans side of the Golgi, marked by AP-1. Association of Arl1 with the Golgi is saturable in intact cells and depends on N-terminal myristoylation. Over-expression of Arl1(T31N), which is expected to be restricted to the GDP-bound form and thus function as a dominant-negative mutant, causes the disappearance of the Golgi apparatus (marked by Golgi SNARE GS28), suggesting that Arl1 is necessary for maintaining normal Golgi structure. Overexpression of Arl1(Q71L), a mutant restricted primarily to the activated GTP-bound form, causes an expansion of the Golgi apparatus with massive and stable Golgi association of COPI and AP-1 coats. Interestingly, Golgi ARFs also become stably associated with the expanded Golgi. Transport of the envelope protein of vesicular stomatitis virus (VSV-G) along the secretory pathway is arrested at the expanded Golgi upon expression of Arl1(Q71L). The structure of stacked cisternae of the Golgi is disrupted in cells expressing Arl1(Q71L), resulting in the transformation of the Golgi into an extensive vesicule-tubule network. In addition, the GTP form of Arl1 interacts with arfaptin-2/POR1 but not GGA1, both of which interact with GTP-restricted ARF1, suggesting that Arl1 and ARF1 share some common effectors in regulating cellular events. On the basis of these observations, we propose that one of the mechanisms for the cell to regulate the structure and function of the Golgi apparatus is through the action of Arl1.


Pupil Diameter May Reflect Motor Control and Learning.
Non-luminance-mediated changes in pupil diameter have been used since the first studies by Darwin in 1872 as indicators of clinical, cognitive, and arousal states. However, the relation between processes involved in motor control and changes in pupil diameter remains largely unknown. Twenty participants attempted to compensate random walks of a cursor with a computer mouse to restrain its trajectory within a target circle while the authors recorded their pupil diameters. Two conditions allowed the authors to experimentally manipulate the motor and cognitive components of the task. First, the step size of the cursor's random walk was either large or small leading to 2 task difficulties (difficult or easy). Second, they instructed participants to imagine controlling the cursor by moving the mouse, but without actually moving it (task modality: imagined movement or real movement condition). Task difficulty and modality allowed the authors to show that pupil diameters reflect processes involved in motor control and in the processing of feedback, respectively. Furthermore, the authors also demonstrate that motor learning can be quantified by pupil size. This noninvasive approach provides a promising method for investigating not only motor control, but also motor imagery, a research field of growing importance in sports and rehabilitation.


Electrolytes and glucose in cerebrospinal fluid of premature infants with intraventricular haemorrhage: role of potassium in cerebral infarction.
Potassium, sodium, and glucose concentrations in cerebrospinal fluid and plasma were determined in 73 infants whose gestational ages ranged from 25 to 40 weeks. Six of 29 (21%) neonates with intraventricular haemorrhages had raised potassium concentrations in the cerebrospinal fluid (3.7-30 mmol/l); five developed cerebral infarctions. There was a significant correlation between sodium and glucose concentrations in plasma and cerebrospinal fluid with prolonged hypoglycorrhachia accompanying posthaemorrhagic hydrocephalus. Raised concentrations of potassium in cerebrospinal fluid occur with intraventricular haemorrhage and may contribute to the development of cerebral infarction.


Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.
Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions. F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1α-/- mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production. Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity. Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity. Microarray data of ATMs isolated from obese or lean mice have been submitted to the Gene Expression Omnibus (accession no. GSE84000).


Maternal placental abnormality and the risk of sudden infant death syndrome.
To determine whether placental abnormality (placental abruption or placental previa) during pregnancy predisposes an infant to a high risk of sudden infant death syndrome (SIDS), the authors conducted a population-based case-control study using 1989-1991 California linked birth and death certificate data. They identified 2,107 SIDS cases, 96% of whom were diagnosed through autopsy. Ten controls were randomly selected for each case from the same linked birth-death certificate data, matched to the case on year of birth. About 1.4% of mothers of cases and 0.7% of mothers of controls had either placental abruption or placenta previa during the index pregnancy. After adjustment for potential confounders, placental abnormality during pregnancy was associated with a twofold increase in the risk of SIDS in offspring (odds ratio = 2.1, 95% confidence interval 1.3-3.1). The individual effects of placental abruption and placenta previa on the risk of SIDS did not differ significantly. An impaired fetal development due to placental abnormality may predispose an infant to a high risk of SIDS.


Risk of developing a mitochondrial DNA deletion disorder.
Pathogenic mitochondrial DNA (mtDNA) mutations are found in at least one in 8000 individuals. No effective treatment for mtDNA disorders is available, making disease prevention important. Many patients with mtDNA disease harbour a single pathogenic mtDNA deletion, but the risk factors for new cases and disease recurrence are not known. We did a multicentre study of 226 families in which a single mtDNA deletion had been identified in the proband, including patients with chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome. We studied the relation between maternal age and the risk of unaffected mothers having an affected child, and determined the recurrence risks among the siblings and offspring of affected individuals. We noted no relation between maternal age and the risk of unaffected mothers having children with an mtDNA deletion disorder. None of the 251 siblings of the index cases developed clinical features of mtDNA disease. Risk of recurrence among the offspring of affected women was 4.11% (95% CI 0.86-11.54, or one in 117 to one in nine births). Only one of the mothers who had an affected child had a duplication of mtDNA in skeletal muscle. Unlike nuclear chromosomal rearrangements, incidence of mtDNA deletion disorders does not increase with maternal age, and unaffected mothers are unlikely to have more than one affected child. Affected women were previously thought to have a negligible chance of having clinically affected offspring, but the actual risk is, on average, about one in 24 births.


Validation of the flexible electrogoniometer for measuring thoracic kyphosis.
Three experiments to validate the use of the flexible electrogoniometer (FEG) as a tool to measure thoracic kyphosis. To investigate the accuracy, test-retest reliability, and concurrent validity of the FEG as applied to the thoracic spine. Thoracic kyphosis is commonly measured by the Cobb angle from lateral radiograph. Other less-invasive tools have been developed, but all yield only static measurements or are restricted to the laboratory. The FEG, which can record joint angles over time outside the laboratory, has been used to measure other joints but has not yet been validated for measurement of the thoracic spine. First, the FEG was bench-tested against a plurimeter for accuracy. Second, 12 subjects performed 7 functional activities 1 week apart to assess the test-retest reliability. Finally, to examine concurrent validity, 12 subjects underwent radiography in "upright" and "slumped" standing with the FEG attached to the skin over their thoracic spine. Three Cobb angles, which corresponded with the inner, mid, and outer margins, respectively, of the overlying FEG end blocks were compared with the FEG angles. The correlation between the FEG and the plurimeter was excellent (r > 0.99, P < 0.0001), although some accuracy was lost at extremes of range. The mean correlation between the first and second measurements was very strong (intraclass correlation coefficient(2,1) 0.92, P < 0.0001; range, 0.89-0.95). The mid-Cobb angle showed the least absolute angular difference from, and was highly correlated with, the FEG angle (r = 0.81, P < 0.01). The FEG demonstrated excellent accuracy and test-retest reliability and correlated very well with the Cobb angle. The FEG measurement seemed to correspond most closely with the Cobb angle measured between the middle of the FEG end blocks.


Written consent to use the drug in children: the problem of off-label drugs.
Cardiac arrhythmias in pediatric patients have different mechanisms and frequencies compared to adult patients. There are many physiological differences between children and adults that may affect the pharmacodynamic and pharmacokinetic of the antiarrhythmic drugs in pediatric population. Children, and specially breast feeding children, cannot be considered low weighted adults to select antiarrhythmic drug doses. Although radiofrequency ablation has experienced great technological advances, it is performed in selected pediatric patients. Therefore, the main therapeutic strategy is the use of antiarrhythmic drugs in children. The medical management of arrhythmias in pediatric patients is challenging and complex. There are few clinical guidelines. There is scarce and incomplete information about the efficacy and safety of antiarrhythmic drugs in pediatric population. Most of the doses and drug administration intervals are extrapolated from adult population and applied to children. Antiarrhythmic drug doses have been extensively studied in adult population. However, in pediatric population, there are very few clinical trials and the safety of these drugs is not well known. In general, dose regimens are based on small uncontrolled studies, extrapolation of drug doses from studies performed in the adult population or physician experience. As a consequence, there is a need for further studies to assess the most effective antiarrhythmic drug regimens in children reducing the risk of side effects. Evidence suggests that medical research in pediatric population is necessary and morally valuable. But investigators involved must take care of moral and ethical values, including the respect for the child-subject and his parents or legal representatives, and this respect compels them to consider the patient and family in the decision making process. The participation request and the informed consent must be obtained according to the competitions the patient exhibits, trying to anticipate information about benefits and possible damages derived from the investigation in an understandable language for him. In our opinion the pharmacologic clinical investigation of antiarrhythmic treatments in pediatrics is necessary. More clinical studies must be carried out under rigorous scientific rules that contemplate the particular ethical dilemmas this population faces.


Boquila trifoliolata mimics leaves of an artificial plastic host plant.
Upon discovery that the Boquila trifoliolata is capable of flexible leaf mimicry, the question of the mechanism behind this ability has been unanswered. Here, we demonstrate that plant vision possibly via plant-specific ocelli is a plausible hypothesis. A simple experiment by placing an artificial vine model above the living plants has shown that these will attempt to mimic the artificial leaves. The experiment has been carried out with multiple plants, and each plant has shown attempts at mimicry. It was observed that mimic leaves showed altered leaf areas, perimeters, lengths, and widths compared to non-mimic leaves. We have calculated four morphometrical features and observed that mimic leaves showed higher aspect ratio and lower rectangularity and form factor compared to non-mimic leaves. In addition, we have observed differences in the leaf venation patterns, with the mimic leaves having less dense vascular networks, thinner vascular strands, and lower numbers of free-ending veinlets.


"Yummy" versus "Yucky"! Explicit and implicit approach-avoidance motivations towards appealing and disgusting foods.
Wanting and rejecting food are natural reactions that we humans all experience, often unconsciously, on a daily basis. However, in the food domain, the focus to date has primarily been on the approach tendency, and researchers have tended not to study the two opposing tendencies in a balanced manner. Here, we develop a methodology with which to understand people's implicit and explicit reactions to both positive (appealing) and negative (disgusting) foods. It consists of a combination of direct and indirect computer-based tasks, as well as a validated food image stimulus set, specifically designed to investigate motivational approach and avoidance responses towards foods. Fifty non-dieting participants varying in terms of their hunger state (hungry vs. not hungry) reported their explicit evaluations of pleasantness, wanting, and disgust towards the idea of tasting each of the food images that were shown. Their motivational tendencies towards those food items were assessed indirectly using a joystick-based approach-avoidance procedure. For each of the food images that were presented, the participants had to move the joystick either towards or away from themselves (approach and avoidance movements, respectively) according to some unrelated instructions, while their reaction times were recorded. Our findings demonstrated the hypothesised approach-avoidance compatibility effect: a significant interaction of food valence and direction of movement. Furthermore, differences between the experimental groups were observed. The participants in the no-hunger group performed avoidance (vs. approach) movements significantly faster; and their approach movements towards positive (vs. negative) foods were significantly faster. As expected, the self-report measures revealed a strong effect of the food category on the three dependent variables and a strong main effect of the hunger state on wanting and to a lesser extent on pleasantness.


Comparative evaluation of bovine porous bone mineral.
The aim of the present clinical study was to compare the efficacy of bovine porous bone mineral (BPBM) with and without platelet-rich plasma (PRP) for the treatment of periodontal intrabony defects. Twenty eight identical bilateral periodontal intrabony defects were selected from 14 chronic periodontitis patients. The subjects were randomly assigned to test group (BPBM+PRP) or the control group (BPBM). The clinical, radiographic, and intrasurgical (re-entry) measurements were made at baseline and at 9 months postoperatively. Both treatment modalities resulted in significant reduction in probing depth and gain in clinical attachment level as compared to baseline values. The probing depth reduction was 6.20±1.40 mm in BPBM and 6.60±1.43 mm for the BPBM/PRP-treated sites. The gain in clinical attachment level observed was 4.16±1.05 mm for BPBM and 4.70±0.76 mm for the BPBM/PRP group. Radiographically, there was a significant defect fill (3.83±1.01 mm) for the BPBM group and (4.04±1.77 mm) in the BPBM/PRP group. Similar trend was observed between the two groups in relation to intrasurgical parameters. The combination therapy (BPBM+PRP) showed more favorable clinical outcome in the treatment of intrabony defects than the BPBM alone group, although the mean difference between the two groups was statistically nonsignificant.


The improved phytoextraction of lead (Pb) and the growth of maize (Zeamays L.): the role of plant growth regulators (GA3 and IAA) and EDTA alone and in combinations.
This investigation was made to examine the role of gibberellic acid (GA(3)), indole-3-acetic acid (IAA) and EDTA in improving phytoextraction of the Pb and plant growth on Pb added soil. GA(3), IAA and EDTA were applied separately and in combinations. GA(3) and IAA were applied as foliar spray and seed soaking. EDTA was applied in single and split doses. Analysis of the Pb in different parts of plant was carried out using atomic absorption/flame spectrophotometer. EDTA significantly reduced the plant growth and dry biomass, whereas GA(3) and IAA foliar spray increased it significantly when compared with control (only Pb added soil). In combined treatments of EDTA+GA(3) and EDTA+IAA, the growth and biomass was restored, which shows that GA(3) and IAA did compensate the negative effect of EDTA on plant growth. The separate treatments of EDTA, GA(3) and IAA increased the Pb uptake and translocation significantly moreover in combine treatments, synergistic effect was found and remarkable increase in Pb uptake and translocation into shoot was observed. EDTA increased the Pb uptake but declined the biomass; subsequently the total Pb accumulation was decreased in plant. The maximum total Pb was found in combined treatment of EDTA+GA(3). These findings suggest more investigation to find a combination of GA(3) with a very low concentration of EDTA, as in high concentration it causes soil and ground water pollution.


The facial massage reduced anxiety and negative mood status, and increased sympathetic nervous activity.
The aim of this study was to clarify the effects of 45 min of facial massage on the activity of autonomic nervous system, anxiety and mood in 32 healthy women. Autonomic nervous activity was assessed by heart rate variability (HRV) with spectral analysis. In the spectral analysis of HRV, we evaluated the high-frequency components (HF) and the low- to high-frequency ratio (LF/HF ratio), reflecting parasympathetic nervous activity and sympathetic nervous activity, respectively. The State Trait Anxiety Inventory (STAI) and the Profile of Mood Status (POMS) were administered to evaluate psychological status. The score of STAI and negative scale of POMS were significantly reduced following the massage, and only the LF/HF ratio was significantly enhanced after the massage. It was concluded that the facial massage might refresh the subjects by reducing their psychological distress and activating the sympathetic nervous system.


Evidence for distinct vascular and tubular urea transporters in the rat kidney.
Facilitated urea transport has been demonstrated in several mammalian tissues, including those of the collecting ducts and red blood cells. Two urea transporters have been recently cloned: UT2, expressed in rabbit inner medullary collecting ducts, and HUT11, expressed in human erythrocytes. Because of significant identity (63%) between these two transporters, and because HUT11 is also expressed in the human kidney, they could represent the same transporter with species-related differences in their-sequences. In the study presented here, two different cDNA fragments, corresponding to the rat equivalents (rUT2 and rUT11) of the two previously cloned urea transporters, were isolated by reverse transcription-polymerase chain reaction. These rat probes were used for Northern analysis of RNA extracted from rat tissues. From the following findings, the results show that rUT2 and rUT11 are two distinct urea transporters: (1) The two cDNA fragments isolated in the rat exhibit different sequences; (2) The mRNA for rUT2 is found exclusively in the kidney, with two transcripts (3.2- and 4.4-kilobase (kb)), whereas rUT11 (only one transcript, 4.2 kb) is present in the brain, spleen, kidney, and testis; (3) in the kidney, the inner stripe of the outer medulla expresses rUT11 mRNA and the short transcript of rUT2, whereas the inner medulla expresses rUT11 and the two rUT2 transcripts; (4) In hydronephrotic kidneys that have completely lost their tubular epithelium but have intact vasculature, rUT2 transcripts are no longer expressed, whereas expression of rUT11 is intensified; (5) Experimental chronic alterations in urine concentrating activity induced different changes in the expression of rUT2 and rUT11.


Kudzu (Pueraria montana) invasion doubles emissions of nitric oxide and increases ozone pollution.
The nitrogen-fixing legume kudzu (Pueraria montana) is a widespread invasive plant in the southeastern United States with physiological traits that may lead to important impacts on ecosystems and the atmosphere. Its spread has the potential to raise ozone levels in the region by increasing nitric oxide (NO) emissions from soils as a consequence of increasing nitrogen (N) inputs and cycling in soils. We studied the effects of kudzu invasions on soils and trace N gas emissions at three sites in Madison County, Georgia in 2007 and used the results to model the effects of kudzu invasion on regional air quality. We found that rates of net N mineralization increased by up to 1,000%, and net nitrification increased by up to 500% in invaded soils in Georgia. Nitric oxide emissions from invaded soils were more than 100% higher (2.81 vs. 1.24 ng NO-N cm(-2) h(-1)). We used the GEOS-Chem chemical transport model to evaluate the potential impact of kudzu invasion on regional atmospheric chemistry and air quality. In an extreme scenario, extensive kudzu invasion leads directly to an increase in the number of high ozone events (above 70 ppb) of up to 7 days each summer in some areas, up from 10 to 20 days in a control scenario with no kudzu invasion. These results establish a quantitative link between a biological invasion and ozone formation and suggest that in this extreme scenario, kudzu invasion can overcome some of the air quality benefits of legislative control.


Genetic interference: don't stand so close to me.
Meiosis is a dynamic process during which chromosomes undergo condensation, pairing, crossing-over and disjunction. Stringent regulation of the distribution and quantity of meiotic crossovers is critical for proper chromosome segregation in many organisms. In humans, aberrant crossover placement and the failure to faithfully segregate meiotic chromosomes often results in severe genetic disorders such as Down syndrome and Edwards syndrome. In most sexually reproducing organisms, crossovers are more evenly spaced than would be expected from a random distribution. This phenomenon, termed interference, was first reported in the early 20(th) century by Drosophila geneticists and has been subsequently observed in a vast range of organisms from yeasts to humans. Yet, many questions regarding the behavior and mechanism of interference remain poorly understood. In this review, we examine results new and old, from a wide range of organisms, to begin to understand the progress and remaining challenges to understanding the fundamental unanswered questions regarding genetic interference.


Transmission dynamics for Methicilin-resistant Staphalococous areus with injection drug user.
Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen resistance to antibiotics including methicillin. The resistance first emerged in 1960 in a healthcare setting only after two years of using methicillin as a viable treatment for methicillin-susceptible Staphylococcus aureus. MRSA leads to infections in different parts of the body including the skin, bloodstream, lungs, or the urinary tract. A deterministic model for methicillin-resistant Staphylococcus aureus (MRSA) with injection drug users is designed. The model incorporates transmission of MRSA among non-injection drug users and injection drug users (IDUs) who are both low-and high-risk users. A reduced MRSA transmission model with only non-IDUs is fitted to a 2008-2013 MRSA data from the Agency for Healthcare and Research and Quality (AHRQ). The parameter estimates obtained are projected onto the parameters for the low-and high-risk IDUs subgroups using risk factors obtained by constructing a risk assessment ethogram. Sensitivity analysis is carried out to determine parameters with the greatest impact on the reproduction number using the reduced non-IDUs model. Change in risk associated behaviors was studied using the full MRSA transmission model via the increase in risky behaviors and enrollment into rehabilitation programs or clean needle exchange programs. Three control effectiveness levels determined from the sensitivity analysis were used to study control of disease translation within the subgroups. The sensitivity analysis indicates that the transmission probability and recovery rates within the subgroup have the highest impact on the reproduction number of the reduced non-IDU model. Change in risk associated behaviors from non-IDUs to low-and high-risk IDUs lead to more MRSA cases among the subgroups. However, when more IDUs enroll into rehabilitation programs or clean needle exchange programs, there was a reduction in the number of MRSA cases in the community. Furthermore, MRSA burden within the subgroups can effectively be curtailed in the community by implementing moderate- and high-effectiveness control strategies. MRSA burden can be curtailed among and within non-injection drug users and both low-and high-risk injection drug users by encouraging positive change in behaviors and by moderate- and high-effectiveness control strategies that effectively targets the transmission probability and recovery rates within the subgroups in the community.


Modeling excitation-dependent bandstructure effects on InGaN light-emitting diode efficiency.
Bandstructure properties in wurtzite quantum wells can change appreciably with changing carrier density because of screening of quantum-confined Stark effect. An approach for incorporating these changes in an InGaN light-emitting-diode model is described. Bandstructure is computed for different carrier densities by solving Poisson and k·p equations in the envelop approximation. The information is used as input in a dynamical model for populations in momentum-resolved electron and hole states. Application of the approach is illustrated by modeling device internal quantum efficiency as a function of excitation.


alpha-Helical nascent polypeptide chains visualized within distinct regions of the ribosomal exit tunnel.
As translation proceeds, the nascent polypeptide chain passes through a tunnel in the large ribosomal subunit. Although this ribosomal exit tunnel was once thought only to be a passive conduit for the growing nascent chain, accumulating evidence suggests that it may in fact play a more active role in regulating translation and initial protein folding events. Here we have determined single-particle cryo-electron microscopy reconstructions of eukaryotic 80S ribosomes containing nascent chains with high alpha-helical propensity located within the exit tunnel. The maps enable direct visualization of density for helices as well as allowing the sites of interaction with the tunnel wall components to be elucidated. In particular regions of the tunnel, the nascent chain adopts distinct conformations and establishes specific contacts with tunnel components, both ribosomal RNA and proteins, that have been previously implicated in nascent chain-ribosome interaction.


Does change in cognitive function predict change in costs of care for people with a schizophrenia diagnosis following cognitive remediation therapy?
Schizophrenia leads to significant personal costs matched by high economic costs. Cognitive function is a strong predictor of disabilities in schizophrenia, which underpin these costs. This study of cognitive remediation therapy (CRT), which has been shown to improve cognition and reduce disability in schizophrenia, aims to investigate associations between improvements in cognition and cost changes. Eighty-five participants with schizophrenia were randomized to receive CRT or treatment as usual and were assessed at baseline, posttherapy, and 6 month follow-up. Four structural equation models investigated associations between changes in cognitive function and costs of care. All 4 models provided a good fit. Improvement in 3 individual cognitive variables did not predict total cost changes (model 1). But improvement in a single latent cognition factor was associated with a reduction in depression, which in turn was associated with reduced subsequent total costs (model 2). No significant associations with constituent daycare and special accommodation cost changes were apparent with 3 individual cognitive change variables (model 3). But improvement in a single latent cognitive change variable was associated with subsequent reductions in both daycare and special accommodation costs (model 4). This study exemplifies a method of using cost changes to investigate the effects and mechanisms of CRT and suggests that executive function change may be an important target if we are to reduce disability and resultant health and social care costs.


School-Located Vaccination Clinics for Adolescents: Correlates of Acceptance Among Parents.
Four vaccines are recommended by The Advisory Committee for Immunization Practices for adolescents: tetanus, diphtheria, acellular pertussis vaccine (Tdap), meningococcal conjugate vaccine (MCV4), human papillomavirus vaccine (HPV), and annual seasonal influenza vaccine. However, coverage among adolescents is suboptimal. School-located vaccination clinics (SLVCs) offer vaccines to students at school, increasing access. This study seeks to determine the relationship between attitudes of parents of middle- and high-school students and acceptance of SLVCs for all four adolescent recommended vaccines. We conducted a telephone and web-based survey among parents of students enrolled in six middle and five high schools in Georgia. Analyses were conducted to examine associations between parental attitudes and willingness to allow their child to be vaccinated at school. Tdap and influenza vaccine had the highest rates of parental SLVC acceptance while HPV vaccine had the lowest. Parents who accepted SLVCs had higher perceived severity of influenza, meningococcal, and HPV illnesses compared to parents who did not accept SLVC. Intention to vaccinate was associated with SLVC acceptance for Tdap [Adjusted OR (AOR) 7.38; 95% confidence interval (CI) 2.44-22.31], MCV4 (AOR 2.97; 95% CI 1.67-5.28), and HPV vaccines (AOR 7.61; 95% CI 3.43-16.89). Social norms were associated with acceptance of SLVCs for influenza vaccine (AOR 1.44; 95% CI 1.12-1.84). These findings suggest parents of adolescents are generally supportive of SLVCs for recommended adolescent vaccines. Perceived severity of illness and intention to get their adolescent vaccinated were the most consistent correlates of parental SLVC acceptance for all vaccines. Future SLVC planning should focus on perceptions of disease severity and benefits of vaccination.


Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus.
Serum antibodies to the Yo antigen are usually associated with paraneoplastic cerebellar degeneration arising in female patients with gynecological or breast malignancy and are rarely associated with other tumors. We report a male patient who presented with paraneoplastic cerebellar degeneration and anti-Yo antibodies following removal of an esophageal adenocarcinoma. This is only the third report of anti-Yo antibodies occurring in a male patient. The Yo antigen was expressed by the esophageal tumor but not in a frontal lobe cerebral metastasis identified at postmortem. Interestingly, CD8+ T-cell infiltration was also found in the tumor, but not in the metastasis, consistent with down-regulation of Yo expression by the tumor cells leading to evasion from immune-mediated tumor surveillance.


Mathematical model of the morphogenesis checkpoint in budding yeast.
The morphogenesis checkpoint in budding yeast delays progression through the cell cycle in response to stimuli that prevent bud formation. Central to the checkpoint mechanism is Swe1 kinase: normally inactive, its activation halts cell cycle progression in G2. We propose a molecular network for Swe1 control, based on published observations of budding yeast and analogous control signals in fission yeast. The proposed Swe1 network is merged with a model of cyclin-dependent kinase regulation, converted into a set of differential equations and studied by numerical simulation. The simulations accurately reproduce the phenotypes of a dozen checkpoint mutants. Among other predictions, the model attributes a new role to Hsl1, a kinase known to play a role in Swe1 degradation: Hsl1 must also be indirectly responsible for potent inhibition of Swe1 activity. The model supports the idea that the morphogenesis checkpoint, like other checkpoints, raises the cell size threshold for progression from one phase of the cell cycle to the next.


Keratin 8 overexpression promotes mouse Mallory body formation.
Keratins 8 and 18 (K8/18) are major constituents of Mallory bodies (MBs), which are hepatocyte cytoplasmic inclusions seen in several liver diseases. K18-null but not K8-null or heterozygous mice form MBs, which indicates that K8 is important for MB formation. Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression. We used transgenic mice that overexpress K8, K18, or K8/18 to test the importance of K8 and/or K18 in MB formation. MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Livers of young K8 or K8/K18 overexpressors had no histological abnormalities despite increased keratin protein and phosphorylation. In aging mice, only K8-overexpressing livers spontaneously developed small "pre-MB" aggregates. Only K8-overexpressing young mice are highly susceptible to MB formation after short-term DDC feeding. Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation. K8 overexpression is sufficient to form pre-MB and primes animals to accumulate MBs upon DDC challenge, which may help explain MB formation in human liver diseases.


Difference in outcomes following allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia and myelodysplastic syndromes.
To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) (n = 3318), AML evolving from myelodysplastic syndromes (MDS) (n = 208), and MDS with excess blasts (MDS-EB) (n = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% (p < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM (p = 0.030) and MDS-EB with a higher risk of relapse (p < 0.001), both leading to lower OS (p = 0.010 and p < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB.


Implementation strategies in pediatric neurocritical care.
Brain-directed critical care for children is a relatively new area of subspecialization in pediatric critical care. Pediatric neurocritical care teams combine the expertise of neurology, neurosurgery, and critical care medicine. The positive impact of delivering specialized care to pediatric patients with acute neurological illness is becoming more apparent, but the optimum way to implement and sustain the delivery of this is complicated and poorly understood. We aim to provide emerging evidence supporting that effective implementation of pediatric neurocritical care pathways can improve patient survival and outcomes. We also provide an overview of the most effective strategies across the field of implementation science that can facilitate deployment of neurocritical care pathways in the pediatric ICU. Implementation strategies can broadly be grouped according to six categories: planning, educating, restructuring, financing, managing quality, and attending to the policy context. Using a combination of these strategies in the last decade, several institutions have improved patient morbidity and mortality. Although much work remains to be done, emerging evidence supports that implementation of evidence-based care pathways for critically ill children with two common neurological diagnoses - status epilepticus and traumatic brain injury - improves outcomes. Pediatric and neonatal neurocritical care programs that support evidence-based care can be effectively structured using appropriately sequenced implementation strategies to improve outcomes across a variety of patient populations and in a variety of healthcare settings.


Safety and efficacy of l-tryptophan produced by fermentation using Escherichia coli CGMCC 7.267 for all animal species.
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on l-tryptophan produced by fermentation with a genetically modified strain of Escherichia coli CGMCC 7.267 when used as a nutritional additive in feed and water for drinking for all animal species and categories. The production strain E. coli CGMCC 7.267 is safe for the production of l-tryptophan. No viable cells or DNA of the production strain were detected in the additive under assessment. The use of l-tryptophan produced using E. coli CGMCC 7.267 in supplementing feed to compensate for tryptophan deficiency in feedingstuffs is safe for non-ruminant target species. However, excess doses would create amino acid imbalances with negative consequences on animal performance. The use of unprotected l-tryptophan in feed poses safety concerns for ruminants. The use of l-tryptophan produced by fermentation with E. coli CGMCC 7.267 in animal nutrition is considered safe for the consumers and for the environment. The endotoxin activity in the product and its dusting potential indicate an inhalation risk for the user. In the absence of data, the FEEDAP Panel cannot conclude on the potential of the additive to be irritant to skin and eyes or to be a skin sensitiser. The additive l-tryptophan produced using E. coli CGMCC 7.267 is regarded as an effective source of the amino acid l-tryptophan. In order to be as efficacious in ruminants as in non-ruminants, it should be protected from ruminal degradation.


The gut microbiota and inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut. Although the precise cause of IBD remains unknown, the most accepted hypothesis of IBD pathogenesis to date is that an aberrant immune response against the gut microbiota is triggered by environmental factors in a genetically susceptible host. The advancement of next-generation sequencing technology has enabled identification of various alterations of the gut microbiota composition in IBD. While some results related to dysbiosis in IBD are different between studies owing to variations of sample type, method of investigation, patient profiles, and medication, the most consistent observation in IBD is reduced bacterial diversity, a decrease of Firmicutes, and an increase of Proteobacteria. It has not yet been established how dysbiosis contributes to intestinal inflammation. Many of the known IBD susceptibility genes are associated with recognition and processing of bacteria, which is consistent with a role of the gut microbiota in the pathogenesis of IBD. A number of trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in IBD.


Cannabis use in patients 3 months after ceasing nabiximols for the treatment of cannabis dependence: Results from a placebo-controlled randomised trial.
Previous studies suggest cannabinoid agonist treatment is effective in reducing cannabis use in dependent treatment seekers, however few studies have reported on post-treatment outcomes. We examine cannabis use outcomes 12 weeks after cessation of treatment from a randomised placebo-controlled trial of nabiximols for the treatment of cannabis dependence. 128 participants received either nabiximols (n = 61) or placebo (n = 67) for 12 weeks, in combination with psychosocial interventions. Self-reported number of days of cannabis use in the previous 28 days was measured at baseline, 4, 8, and 12 weeks (end of treatment) and again at 24 weeks (3 months after treatment ceased). Urinalysis was used to confirm self-report data at Week 24 interview. A factorial mixed-effects model for repeated measures regression revealed that the nabiximols group used cannabis on 6.8 fewer days in the previous 28 days at week 12 (end of treatment) than the placebo group (p = 0.002, CI: 2.1,11.4), and 6.7 fewer days in the previous 28 days at the week-24 follow-up than the placebo group (p = 0.006, CI: 1.4,12.1). A significantly higher proportion of the nabiximols group (14/61; 23 %) than the placebo group (6/67; 9%) reported abstinence from cannabis in the previous 28 days at the week-24 research interview OR=3.0, CI: 1.1, 9.1; p=0.035, NNT=8, CI: 4, 71). The benefits of treatment incorporating nabiximols with psychosocial interventions in reducing cannabis use appears to persist for up to 3 months after the cessation of treatment. A stepped care model of treatment is proposed. Australian New Zealand Clinical Trials Registry (ACTRN12616000103460) https://www.anzctr.org.au.


Older immigrants' experiences of their life situation in the context of receiving public care in Sweden.
Objectives. The aim of this study was to illuminate older immigrants' experience of their life situation in the context of receiving public care in Sweden. Background. To meet the varying needs from the growing number of older immigrants, more knowledge about the experience of their life situation, health, illness and family ties is needed, especially in the context of receiving public health care and service. Methods. Data were collected through interviews with sixteen immigrants aged 65 years and older, originally from nine different countries, living in Southern Sweden and receiving continuous care and service. The texts were analysed using qualitative content analysis. Results. The overall impression from the texts was that the informants expressed a debt of gratitude to Swedish society. Their experience could be understood as - being burdened with health complaints; experiencing painful losses; wanting to manage by oneself and feeling exposed and deserted. Conclusions. The results show that older immigrants are vulnerable when receiving public care. This was related to previous life events, cultural differences as well as communication difficulties. When planning for and providing care for older immigrants, it is important to be aware of their exposed situation and to acknowledge their life history and family context.


Cachexia and Sarcopenia in Older Adults with Cancer: A Comprehensive Review.
Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic muscle wasting and weakness, also known as sarcopenia, can compound deficits associated with cancer cachexia in older adults and makes studying this condition more complex in this population. Multiple measurement options are available to assess the older patient with cancer and cachexia and/or sarcopenia including anthropometric measures, imaging modalities such as Dual X-ray absorptiometry (DEXA) and Computed Tomography (CT), muscular strength and physical performance testing, and patient-reported outcomes (PROs). A geriatric assessment (GA) is a useful tool when studying the older patient with cachexia given its comprehensive ability to capture aging-sensitive PROs. Interventions focused on nutrition and increasing physical activity may improve outcomes in older adults with cachexia. Efforts to develop targeted pharmacologic therapies with cachexia have not been successful thus far. Formal treatment guidelines, an updated consensus definition for cancer cachexia and the development of a widely adapted assessment tool, much like the GA utilized in geriatric oncology, could help advance the field of cancer cachexia over the next decade.


Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice.
Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1-null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10(-9) mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1-null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1-null mice. CT-1-null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1-null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process.


Age specific differences in efficacy and safety for the CYD-tetravalent dengue vaccine.
CYD-TDV is the first dengue vaccine to have completed Phase 3 efficacy trials. Efficacy was consistently higher in those aged 9 and above for all variables studied: efficacy against virologically confirmed dengue of any severity and serotype, serotype specific efficacy, efficacy dependent on baseline seropositivity, efficacy against hospitalizations and efficacy against severe disease. Because of the higher efficacy and the absence of a safety signal, the age group with the best benefit of the use of CYD-TDV is individuals aged 9 and above - the age group for which licensure is now being sought.


Plant community responses to long-term fertilization: changes in functional group abundance drive changes in species richness.
Declines in species richness due to fertilization are typically rapid and associated with increases in aboveground production. However, in a long-term experiment examining the impacts of fertilization in an early successional community, we found it took 14 years for plant species richness to significantly decline in fertilized plots, despite fertilization causing a rapid increase in aboveground production. To determine what accounted for this lag in the species richness response, we examined several potential mechanisms. We found evidence suggesting the abundance of one functional group-tall species with long-distance (runner) clonality-drove changes in species richness, and we found little support for other mechanisms. Tall runner species initially increased in abundance due to fertilization, then declined dramatically and were not abundant again until later in the experiment, when species richness and the combined biomass of all other functional groups (non-tall runner) declined. Over 86 % of the species found throughout the course of our study are non-tall runner, and there is a strong negative relationship between non-tall runner and tall runner biomass. We therefore suggest that declines in species richness in the fertilized treatment are due to high tall runner abundance that decreases the abundance and richness of non-tall runner species. By identifying the functional group that drives declines in richness due to fertilization, our results help to elucidate how fertilization decreases plant richness and also suggest that declines in richness due to fertilization can be lessened by controlling the abundance of species with a tall runner growth form.


The effect of hypertension in pregnant women on fetal adrenal function and fetal plasma lipoprotein-cholesterol metabolism.
In the present investigation, we evaluated the effect(s) of long-term hypertension and pregnancy-induced hypertension in women on the activity of the adrenals of their fetuses. We measured dehydroisoandrosterone sulfate, cortisol, and lipoprotein-cholesterol in umbilical cord plasma of newborn infants delivered (30 to 41 weeks' gestation) of 120 women whose pregnancies were uncomplicated and of 98 women with pregnancy-induced or long-term hypertension. Umbilical cord plasma levels of cortisol were similar in both groups of newborn infants at each gestational period. Fetal plasma levels of dehydroisoandrosterone sulfate also were similar in both groups at 30 to 33 weeks of gestation but were significantly reduced in newborn infants of hypertension women who were delivered between 34 and 41 weeks of gestation compared with those of newborn infants of normal women who were delivered at a similar gestational age. At term, umbilical cord plasma levels of total cholesterol and low-density lipoprotein-cholesterol were significantly higher in the newborn infants of hypertensive women compared with those levels in newborn infants of normotensive women; fetal plasma levels of high-density lipoprotein-cholesterol and very low-density lipoprotein-cholesterol were similar in both groups of newborn infants. The lowest plasma levels of dehydroisoandrosterone sulfate and the highest plasma levels of total cholesterol and low-density lipoprotein-cholesterol were found in newborn infants of women with the most severe pregnancy-induced hypertension. Based on these findings, we conclude that maternal hypertension effects a decrease in the rate of steroidogenesis of the fetal zone of the fetal adrenal cortex but does not act in a similar manner to effect steroidogenesis of the neocortical zone and leads to hypercholesterolemia in the fetus as a consequence of reduced adrenal utilization of low-density lipoprotein-cholesterol. In addition, the effects of pregnancy-induced hypertension appear to be manifest in the fetus late in pregnancy at a time when the fetal adrenal normally undergoes an accelerated rate of growth and steroid biosynthesis.


High mortality in Bufo gargarizans eggs associated with an undescribed Saprolegnia ferax strain in the Republic of Korea.
Pathogenic water molds have a significant impact on many species, especially amphibians. The genus Saprolegnia is a pathogenic oomycete restricted to aquatic and moist habitats, and its presence is strongly linked to the abundance of amphibians and fishes. We investigated the influence of Saprolegnia presence on egg mortality and egg occurrence under varying environmental conditions in the Asiatic toad Bufo gargarizans at 27 breeding sites in the Republic of Korea. We then assessed the impact of Saprolegnia on the presence of B. gargarizans at the 27 sites surveyed weekly during the B. gargarizans breeding season for 3 consecutive years. We used molecular tools to identify the water molds as belonging to an undescribed S. ferax strain. We demonstrated that the presence of S. ferax was positively associated with higher water conductivity and ponds. In addition, while S. ferax prevalence was associated with a reduction in B. gargarizans breeding activity and breeding success, we could not determine its impact on the subsequent breeding seasons. Our study highlights the potential negative effects of Saprolegnia on amphibian reproduction, although additional research is necessary to determine the relationship between Saprolegnia, its hosts and the impacts of habitat loss on amphibians.


Regulatory proteins and cis-acting elements involved in the transcriptional control of Rhizobium etli reiterated nifH genes.
In Rhizobium etli the nitrogenase reductase genes are reiterated. Strain CE3 has three copies; nifHa and nifHb form part of nifHDK operons with the nitrogenase structural genes, while nifHc is linked to a truncated nifD homolog. Their sequences are identical up to 6 residues upstream from a sigma54-dependent promoter. A remarkable difference among them is the absence of canonical NifA binding sites upstream of nifHc while a canonical binding site is located 200 bp upstream of nifHa and nifHb. To evaluate the transcriptional regulation of the reiterated nifH genes, we constructed fusions of nifHa and nifHc with the lacZ gene of Escherichia coli. Both genes were expressed at maximum levels under 1% oxygen in free-living cultures, and their expression declined as the oxygen concentration was increased. This expression was dependent on the integrity of nifA, and nifHc was expressed at higher levels than nifHa. The same pattern was observed with root nodule bacteroids. Expression of both genes in E. coli required sigma54 in addition to NifA bound to the upstream activator sequence. In vivo dimethyl sulfate footprinting analyses showed that NifA binds to the canonical site upstream of nifHa and to a TGT half-site 6 nucleotides further upstream. NifA protected an imperfect binding site upstream of nijHc at position 85 from the promoter. The integration host factor stimulated each gene differently, nifHa being more dependent on this protein. The above results correlate the asymmetric arrangement of cis-acting elements with a differential expression of the reiterated nifH genes, both in culture and during symbiosis with bean plants.


Blue-green laser-induced fluorescence from intact leaves: actinic light sensitivity and subcellular origins.
Remote sensing of the health status of vegetation should be possible by using UV laser-induced fluorescence; nevertheless, the molecular origin of the leaf blue-green fluorescence emission is still unknown. In order to investigate possible relations of this fluorescence to the photosynthetic apparatus, we looked for its intensity changes after the addition of actinic light. The lack of any changes outside the chlorophyll fluorescence bands (Kautsky effect) was further investigated by collecting spectra from cell, protoplast, and chloroplast suspensions. These spectra led us to ascribe most of the blue-green laser-induced fluorescence that is detectable on a leaf by UV laser excitation to extrachloroplastic compartments. In active chloroplast suspensions blue fluorescence from photosynthetically reduced nicotinamide adenine dinucleotide phosphate (NADPH) has been detected and should be characterized by time-resolved fluorescence techniques.


Ion/molecule reactions performed in a miniature cylindrical ion trap mass spectrometer.
A recently constructed miniature mass spectrometer, based on a cylindrical ion trap (CIT) mass analyzer, is used to perform ion/molecule reactions in order to improve selectivity for in situ analysis of explosives and chemical warfare agent simulants. Six different reactions are explored, including several of the Eberlin reaction type (M. N. Eberlin and R. G. Cooks, Org. Mass Spectrom., 1993, 28, 679-687) as well as novel gas-phase Meerwein reactions. The reactions include (1) Eberlin transacetalization of the benzoyl, 2,2-dimethyloximinium, and 2,2-dimethylthiooximinium cations with 2,2-dimethyl-1,3-dioxolane to form 2-phenyl-1,3-dioxolanylium cations, 2,2-dimethylamine-1,3-dioxolanylium cations and the 2,2-dimethylamin-1,3-oxathiolanylium cations, respectively; (2) Eberlin reaction of the phosphonium ion CH3P(O)OCH3+, formed from the chemical warfare agent simulant dimethyl methylphosphonate (DMMP), with 1,4-dioxane to yield the 1,3,2-dioxaphospholanium ion, a new characteristic reaction for phosphate ester detection; (3) the novel Meerwein reaction of the ion CH3P(O)OCH3+ with propylene sulfide forming 1,3,2-oxathionylphospholanium ion; (4) the Meerwein reaction of the benzoyl cation with propylene oxide and propylene sulfide to form 4-methyl-2-phenyl-1,3-dioxolane and its thio analog, respectively; (5) ketalization of the benzoyl cation with ethylene glycol to form the 2-phenyl-1,3-dioxolanylium cation; (6) addition/NO2 elimination involving benzonitrile radical cation in reaction with nitrobenzene to form an arylated nitrile, a diagnostic reaction for explosives detection and (7) simple methanol addition to the C7H7+ ion, formed by NO2 loss from the molecular ion of p-nitrotoluene to form an intact adduct. Evidence is provided that these reactions occur to give the products described and their potential analytical utility is discussed.


Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.
Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)). We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice). One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1β and IL-1RA mRNA. AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.


Transfemoral TAVR in Nonagenarians: From the CENTER Collaboration.
This study aimed to compare differences in patient characteristics and clinical outcomes of nonagenarians undergoing transcatheter aortic valve replacement (TAVR) versus patients younger than 90 years of age and to test the predictive accuracy of the logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation), the EuroSCORE II, and the STS-PROM (Society of Thoracic Surgeons Predicted Risk of Mortality) for mortality after TAVR in nonagenarians. The prevalence of severe aortic valve stenosis is increasing due to the rising life expectancy. However, there are limited data evaluating outcomes in patients older than 90 years of age. Moreover, the predictive accuracy of risk scores for mortality has not been evaluated in nonagenarian patients undergoing transfemoral TAVR. The CENTER (Cerebrovascular EveNts in Patients Undergoing TranscathetER Aortic Valve Implantation) collaboration (N = 12,381) is an international collaboration consisting of 3 national registries, 6 local or multicenter registries, and 1 prospective clinical study, selected through a systematic online search. The primary endpoint of this study was the difference in 30-day all-cause mortality and stroke after TAVR in nonagenarians versus patients younger than 90 years of age. Secondary endpoints included differences in baseline characteristics, in-hospital outcomes, and the differences in predictive accuracy of the logistic EuroSCORE, the EuroSCORE II, and STS-PROM. A total of 882 nonagenarians and 11,499 patients younger than 90 years of age undergoing transfemoral TAVR between 2007 and 2018 were included. Nonagenarians had considerably fewer comorbidities than their counterparts. Nevertheless, rates of 30-day mortality (9.9% vs. 5.4%; relative risk [RR]: 1.8; 95% confidence interval [CI]: 1.4 to 2.3; p = 0.001), in-hospital stroke (3.0% vs. 1.9%; RR: 1.5; 95% CI: 1.0 to 2.3; p = 0.04), major or life-threatening bleeding (8.1% vs. 5.5%; RR: 1.6; 95% CI: 1.1 to 2.2; p = 0.004), and new-onset atrial fibrillation (7.9% vs. 5.2%; RR: 1.6; 95% CI: 1.1 to 2.2; p = 0.01) were higher in nonagenarians. The STS-PROM adequately estimated mortality in nonagenarians, with an observed-expected mortality ratio of 1.0. In this large, global, patient-level analysis, mortality after transfemoral TAVR was 2-fold higher in nonagenarians compared with patients younger than 90 years of age, despite the lower prevalence of baseline comorbidities. Moreover, nonagenarians had a higher risk of in-hospital stroke, major or life-threatening bleeding, and new-onset atrial fibrillation. The STS-PROM was the only surgical risk score that accurately predicted the risk of mortality in nonagenarians.


Crystal structure of a catalytic antibody with a serine protease active site.
The three-dimensional structure of an unusually active hydrolytic antibody with a phosphonate transition state analog (hapten) bound to the active site has been solved to 2.5 A resolution. The antibody (17E8) catalyzes the hydrolysis of norleucine and methionine phenyl esters and is selective for amino acid esters that have the natural alpha-carbon L configuration. A plot of the pH-dependence of the antibody-catalyzed reaction is bell-shaped with an activity maximum at pH 9.5; experiments on mechanism lend support to the formation of a covalent acyl-antibody intermediate. The structural and kinetic data are complementary and support a hydrolytic mechanism for the antibody that is remarkably similar to that of the serine proteases. The antibody active site contains a Ser-His dyad structure proximal to the phosphorous atom of the bound hapten that resembles two of the three components of the Ser-His-Asp catalytic triad of serine proteases. The antibody active site also contains a Lys residue to stabilize oxyanion formation, and a hydrophobic binding pocket for specific substrate recognition of norleucine and methionine side chains. The structure identifies active site residues that mediate catalysis and suggests specific mutations that may improve the catalytic efficiency of the antibody. This high resolution structure of a catalytic antibody-hapten complex shows that antibodies can converge on active site structures that have arisen through natural enzyme evolution.