Erythema multiforme.
An active duty male Soldier presents to your clinic with concerns of blister-like lesions on both hands and feet several weeks after receiving immunizations. He is diagnosed with erythema multiforme (EM), a hypersensitivity reaction that is typically self-resolving. This article reviews the etiologies, pathophysiology, course, diagnosis, and treatment of erythema multiforme.


Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation.
In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.


Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer.
We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-l-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05-1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15-1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01-1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC.


Outcomes of care in birth centers. The National Birth Center Study.
We studied 11,814 women admitted for labor and delivery to 84 free-standing birth centers in the United States and followed their course and that of their infants through delivery or transfer to a hospital and for at least four weeks thereafter. The women were at lower-than-average risk of a poor outcome of pregnancy, according to many but not all of the recognized demographic and behavioral risk factors. Among the women, 70.7 percent had only minor complications or none; 7.9 percent had serious emergency complications during labor and delivery or soon thereafter, such as thick meconium or severe shoulder dystocia. One woman in six (15.8 percent) was transferred to a hospital; 2.4 percent had emergency transfers. Twenty-nine percent of nulliparous women and only 7 percent of parous women were transferred, but the frequency of emergency transfers was the same. The rate of cesarean section was 4.4 percent. There were no maternal deaths. The overall intrapartum and neonatal mortality rate was 1.3 per 1000 births. The rates of infant mortality and low Apgar scores were similar to those reported in large studies of low-risk hospital births. We conclude that birth centers offer a safe and acceptable alternative to hospital confinement for selected pregnant women, particularly those who have previously had children, and that such care leads to relatively few cesarean sections.


Exercise capacity and body composition as predictors of mortality among men with diabetes.
To quantify the relation of fitness to mortality among men with diabetes, adjusted for BMI and within levels of BMI. In this observational cohort study, we calculated all-cause death rates in men with diabetes across quartiles of fitness and BMI categories. Study participants were 2,196 men with diabetes (average age 49.3 years, SD 9.5) who underwent a medical examination, including a maximal exercise test, during 1970 to 1995, with mortality follow-up to 31 December 1996. We identified 275 deaths during 32,161 person-years of observation. Risk of all-cause mortality was inversely related to fitness. For example, in the fully adjusted model, the risk of mortality was 4.5 (2.6-7.6), 2.8 (1.6-4.7), and 1.6 (0.93-2.76) for the first, second, and third fitness quartiles, respectively, with the fourth quartile (highest fitness level) as the referent (P for trend <0.0001). There was no significant trend across BMI categories for mortality after adjustment for fitness. Similar results were found when the fitness-mortality relation was examined within levels of body composition. In normal-weight men with diabetes, the relative risks of mortality were 6.6 (2.8-15.0), 3.2 (1.4-7.0), and 2.2 (1.1-4.6) for the first, second, and third quartiles of fitness, respectively, as compared with the fourth quartile (P for trend <0.0001). We found similar results in the overweight and obese weight categories. There was a steep inverse gradient between fitness and mortality in this cohort of men with documented diabetes, and this association was independent of BMI.


Fed-Batch Cultivations of Rhodospirillum rubrum Under Multiple Nutrient-Limited Growth Conditions on Syngas as a Novel Option to Produce Poly(3-Hydroxybutyrate) (PHB).
Syngas from gasified organic waste materials is a promising feedstock for the biotechnological synthesis of the bioplastic poly([R]-3-hydroxybutyrate) (PHB) with Rhodospirillum rubrum. In a first approach, growth studies were carried out with this strain in gas-tight serum vials. When syngas (40% CO, 40% H2, 10% CO2, and 10% N2 v/v) was diluted with N2 to 60%, a 4-fold higher biomass production was detected compared to samples grown on 100% syngas, thus indicating a growth inhibitory effect. The best performing syngas-mixture was then used for C-, C,N-, and C,P-limited fed-batch fermentations in a bioreactor with continuous syngas and acetate supply. It was found that C,P-limited PHB productivity was 5 times higher than for only C-limited growth and reached a maximal PHB content of 30% w/w. Surprisingly, growth and PHB production stopped when N, as a second nutrient, became growth-limiting. Finally, it was concluded that a minimal supply of 0.2 g CO g-1 biomass h-1 has to be guaranteed in order to cover the cellular maintenance energy.


Dual role of the carboxyl-terminal region of pig liver L-kynurenine 3-monooxygenase: mitochondrial-targeting signal and enzymatic activity.
l-kynurenine 3-monooxygenase (KMO) is an NAD(P)H-dependent flavin monooxygenase that catalyses the hydroxylation of l-kynurenine to 3-hydroxykynurenine, and is localized as an oligomer in the mitochondrial outer membrane. In the human brain, KMO may play an important role in the formation of two neurotoxins, 3-hydroxykynurenine and quinolinic acid, both of which provoke severe neurodegenerative diseases. In mosquitos, it plays a role in the formation both of eye pigment and of an exflagellation-inducing factor (xanthurenic acid). Here, we present evidence that the C-terminal region of pig liver KMO plays a dual role. First, it is required for the enzymatic activity. Second, it functions as a mitochondrial targeting signal as seen in monoamine oxidase B (MAO B) or outer membrane cytochrome b(5). The first role was shown by the comparison of the enzymatic activity of two mutants (C-terminally FLAG-tagged KMO and carboxyl-terminal truncation form, KMOΔC50) with that of the wild-type enzyme expressed in COS-7 cells. The second role was demonstrated with fluorescence microscopy by the comparison of the intracellular localization of the wild-type, three carboxyl-terminal truncated forms (ΔC20, ΔC30 and ΔC50), C-terminally FLAG-tagged wild-type and a mutant KMO, where two arginine residues, Arg461-Arg462, were replaced with Ser residues.


clubber: removing the bioinformatics bottleneck in big data analyses.
With the advent of modern day high-throughput technologies, the bottleneck in biological discovery has shifted from the cost of doing experiments to that of analyzing results. clubber is our automated cluster-load balancing system developed for optimizing these "big data" analyses. Its plug-and-play framework encourages re-use of existing solutions for bioinformatics problems. clubber's goals are to reduce computation times and to facilitate use of cluster computing. The first goal is achieved by automating the balance of parallel submissions across available high performance computing (HPC) resources. Notably, the latter can be added on demand, including cloud-based resources, and/or featuring heterogeneous environments. The second goal of making HPCs user-friendly is facilitated by an interactive web interface and a RESTful API, allowing for job monitoring and result retrieval. We used clubber to speed up our pipeline for annotating molecular functionality of metagenomes. Here, we analyzed the Deepwater Horizon oil-spill study data to quantitatively show that the beach sands have not yet entirely recovered. Further, our analysis of the CAMI-challenge data revealed that microbiome taxonomic shifts do not necessarily correlate with functional shifts. These examples (21 metagenomes processed in 172 min) clearly illustrate the importance of clubber in the everyday computational biology environment.


Detection of mitral valve abnormalities by carotid Doppler flow study: implications for the management of patients with cerebrovascular disease.
Patients with symptoms of cerebral ischemia are often evaluated with non-invasive carotid artery testing. An abnormal carotid Doppler ultrasound frequency shift pattern of early systolic flutter (ESF) was demonstrated by auscultation and velocity wave form analysis in patients with normal carotid bifurcations. Ten of these patients were studied with echocardiography (echo) and eight had mitral valve prolapse (MVP). To evaluate the association between ESF and MVP, a prospective blinded study was performed, recording carotid Doppler frequency shift in 50 patients referred for routine echocardiography. A total of 18 patients had ESF: 9/12 patients with MVP by echocardiography had ESF. Nine additional patients without MVP had ESF (two with mitral regurgitation and two with redundant mitral valves). The association of ESF with MVP was significant (p less than 0.001). The findings of ESF with a normal carotid artery by non-invasive testing suggests a possible mitral valve origin for symptoms of cerebrovascular disease.


Investigation of surface-modified solid lipid nanocontainers formulated with a heterolipid-templated homolipid.
There is increasing interest in the search for improved drug delivery systems with greater versatility. Consequently, many drug delivery systems have been studied. In this study, surface-modified lipid nanocontainers were formulated with a homolipid from Capra hircus (goat fat) templated with a heterolipid (Phospholipon 90G) which was also the surface modifier. The solid lipid nanocontainers (SLN) were formulated by hot high pressure homogenisation using increasing concentrations of polysorbate 80 as the mobile surfactant. Prior to SLN preparation, the templated homolipid was formulated by fusion to obtain a homogeneous lipid matrix, which was characterized using differential scanning calorimetry (DSC), polarized light microscopy (PLM) and wide angle X-ray diffraction (WAXD) to obtain its thermal and crystal characteristics. Isothermal heat conduction microcalorimetry (IMC) and freeze-fracture transmission electron microscopy (FFTEM) studies were carried out on the templated homolipid and SLN containing 1.0% (w/w) of polysorbate 80 to study their in situ crystallization kinetics and morphology, respectively. The formulated SLN were also subjected to time-resolved DSC, WAXD and particle size analyses for one month. The thermal and crystal characteristics were compared with those of the bulk lipid matrix (templated homolipid). Result of the particle size analysis indicated that the particles size remained roughly within the lower nanometer range after one month. FFTEM micrograph of the lipid matrices revealed lamellar sheets for Phospholipon 90G and layered triglyceride structures for the homolipid and Phospholipon 90G-templated homolipid. FFTEM micrograph of SLN revealed anisometric structures. PLM of the templated homolipid did not show, but goat fat (homolipid) alone showed slight growth in crystals with time. WAXD and DSC studies revealed minor increase in crystallinity of the new lipid matrix after one month and DSC also detected templation of homolipid by the heterolipid noted by the disappearance of the lower melting peak of the homolipid. However, for the SLN, WAXD results showed low crystalline particles while DSC only showed a very little endothermic process after one month of storage at 20 degrees C. The implication of this finding is that progression of the SLN to highly ordered particles over time would not occur. This will be favourable for any incorporated drug as drug expulsion, due to increase in crystallinity, will not occur. Result obtained from analysis of the isothermal crystallization exotherms indicated that the templated homolipid and SLN1 containing 1.0% polysorbate 80 possess similar nucleation mechanisms and growth dimensions different from the pure homolipid. The SLN containing 0.5 and 1.0% polysorbate 80 possessed good properties and could prove to be good delivery systems for drugs for parenteral or ocular administration. The result of this study also shows a method of improving natural lipids for use in particulate drug delivery systems.


YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction.
Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.


Spin-wave-beam driven synchronization of nanocontact spin-torque oscillators.
The synchronization of multiple nanocontact spin-torque oscillators (NC-STOs) is mediated by propagating spin waves (SWs). Although it has been shown that the Oersted field generated in the vicinity of the NC can dramatically alter the emission pattern of SWs, its role in the synchronization behaviour of multiple NCs has not been considered so far. Here we investigate the synchronization behaviour in multiple NC-STOs oriented either vertically or horizontally, with respect to the in-plane component of the external field. Synchronization is promoted (impeded) by the Oersted field landscape when the NCs are oriented vertically (horizontally) due to the highly anisotropic SW propagation. Not only is robust synchronization between two oscillators observed for separations larger than 1,000 nm, but synchronization of up to five oscillators, a new record, has been observed in the vertical array geometry. Furthermore, the synchronization can no longer be considered mutual in nature.


A hypnotherapy intervention for the treatment of anxiety in patients with cancer receiving palliative care.
This pilot study aimed to assess the benefits of hypnotherapy in the management of anxiety and other symptoms, including depression and sleep disturbance, in palliative care patients with cancer. Eleven hospice patients received four sessions of hypnotherapy and completed the Hospital Anxiety and Depression Scale, the Edmonton Symptom Assessment System, and the Verran and Snyder-Halpern Scale at set time points. Wrist actigraphy also provided an objective assessment of sleep quality. After the second hypnotherapy session there was a statistically significant reduction in mean anxiety and symptom severity, but not in depression or sleep disturbance. After the fourth session there was a statistically significant reduction in all four patient-reported measures but not in actigraphy. These results offer evidence that hypnotherapy can reduce anxiety in palliative care patients, as well as improving sleep and the severity of psychological and physical symptoms. Further studies are needed to explore whether the observed benefits were a direct result of the hypnotherapy and how the intervention could most benefit this patient population.


The Mechanism of Procedural Stroke Following Carotid Endarterectomy within the Asymptomatic Carotid Surgery Trial 1.
Understanding the pathophysiological mechanism of procedural stroke during carotid intervention may help reduce the risk of stroke in those undergoing surgery. We therefore studied the features of procedural strokes within the first Asymptomatic Carotid Surgery Trial-1 (ACST-1) to identify the underlying pathophysiological mechanism. In ACST-1, 3,120 patients with severe asymptomatic carotid stenosis thought suitable for surgery were randomized to CEA or indefinite deferral of surgery. Information on procedural (within 30 days) stroke type, laterality, severity and timing was collected. Eight possible mechanisms were defined: embolism from the carotid artery, haemodynamic, thrombosis or occlusion of the carotid artery, hyperperfusion syndrome, cardioembolic, either carotid embolic or haemodynamic, either carotid embolic or thrombotic occlusion, or undetermined. Procedural strokes occurred in 53 patients (2.7%). Strokes were predominantly ischaemic (n = 43; 81%), ipsilateral to the treated artery (n = 42; 79%), often occurred on the day of the operation (n = 32; 60%) and in over half the patients, were disabling or fatal (n = 27; 51%). The identified stroke mechanism was carotid embolic (n = 7), haemodynamic (n = 5), thrombosis or occlusion of the carotid artery (n = 9), hyperperfusion (n = 7), cardioembolic (n = 3), 'probably carotid embolic or haemodynamic' (n = 7), 'probably carotid embolic or thrombotic occlusion' (n = 3) and undetermined in 12 cases. In ACST-1, the risk of procedural stroke was low. Most strokes (60%) occurred on the day of the procedure and were caused by thrombosis or thrombotic occlusion of the ipsilateral carotid artery. These findings emphasize the importance of immediate assessment of the treated carotid artery when a stroke occurs after CEA.


Analgosedation: The Use of Fentanyl Compared to Hydromorphone.
The 2018 Society of Critical Care Medicine guidelines on the "Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU" advocate for protocol-based analgosedation practices. There are limited data available to guide which analgesic to use. This study compares outcomes in patients who received continuous infusions of fentanyl or hydromorphone as sedative agents in the intensive care setting. This retrospective cohort study evaluated patients admitted into the medical intensive care unit, the surgical intensive care unit, and the cardiac intensive care unit from April 1, 2017, to August 1, 2018, who were placed on continuous analgesics. Patients were divided according to receipt of fentanyl or hydromorphone as a continuous infusion as a sedative agent. The primary endpoints were ICU length of stay and time on mechanical ventilation. A total of 177 patients were included in the study; 103 received fentanyl as a continuous infusion, and 74 received hydromorphone as a continuous infusion. Baseline characteristics were similar between groups. Patients in the hydromorphone group had deeper sedation targets. Median ICU length of stay was eight days in the fentanyl group compared to seven days in the hydromorphone group (p = 0.11) and median time on mechanical ventilation was 146.47 hours in the fentanyl group and 122.33 hours in the hydromorphone group (p = 0.31). There were no statistically significant differences in the primary endpoints of ICU length of stay and time on mechanical ventilation between fentanyl and hydromorphone for analgosedation purposes. No statistically significant differences were found in the primary endpoints studied. Patients in the hydromorphone group required more tracheostomies, restraints, and were more likely to have a higher proportion of Critical Care Pain Observation Tool (CPOT) scores > 2.


Cognitive emotional consequences of male infertility in their female partners: a qualitative content analysis.
Infertility, as a global phenomenon and one of the most important issues of reproductive health, affects women more often than men, even when the infertility is due to a male factor. The purpose of this study was to explore the cognitive emotional experiences of women faced with male infertility. This qualitative study was conducted in 2014-2015 in Mashhad, Iran. The perceptions and experiences of healthy women whose husbands were diagnosed with primary male factor infertility were investigated using a qualitative content analysis approach. Participants were selected through purposeful sampling, and data collection was conducted using in-depth semistructured interviews. Data were analyzed using conventional content analysis with MAXqda software. Study rigor was verified via criteria proposed by Lincoln and Guba. One main theme emerged through analysis entitled "cognitive emotional reactions confronting infertility diagnosis" with sub-themes of cognitive emotional reactions when confronted with male infertility diagnosis with subthemes of disbelief and denial, fear and apprehension, suffering and emotional distress, disappointment, frustration, confusion, and joy. The diagnosis of male infertility was associated with important emotional cognitive consequences for their female partners. Emotional support, providing new insights into how to treat the issue, and trying to shorten the process of diagnosis are necessary for these women. This kind of support could reduce the psychological effects of confrontation with the diagnosis of male infertility, including social insecurity for women.


CK1δ restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1α/ARNT complex formation.
Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1δ phosphorylates HIF-1α in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIF-1α interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1δ-dependent modification of HIF-1α impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1δ increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1α- and lipin-1-dependent manner. These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.


Transcriptome analysis of Solanum melongena L. (eggplant) fruit to identify putative allergens and their epitopes.
Eggplant is the third most important Solanaceae crop after tomato and potato, particularly in India and China. A transcriptome analysis of eggplant's fruit was performed to study genes involved in medicinal importance and allergies. Illumina HiSeq 2000 system generated 89,763,638 raw reads (~18 Gb) from eggplant. High quality reads (59,039,694) obtained after trimming process, were assembled into a total of 149,224 non redundant set of transcripts. Out of 80,482 annotated sequences of eggplant fruit (BLASTx results against nr-green plant database), 40,752 transcripts showed significant similarity with predicted proteins of Solanum tuberosum (51%) followed by Solanum lycopersicum (34%) and other sequenced plant genomes. With BLASTx top hit analysis against existing allergens, a total of 1986 homologous allergen sequences were found, which had >37% similarity with 48 different allergens existing in the database. From the 48 putative allergens, 526 B-cell linear epitopes were identified using BepiPred linear epitope prediction tool. Transcript sequences generated from this study can be used to map epitopes of monoclonal antibodies and polyclonal sera from patients. With the support of this whole transcriptome catalogue of eggplant fruit, complete list of genes can be predicted based on which secondary structures of proteins may be modeled.


A faster Rubisco with potential to increase photosynthesis in crops.
In photosynthetic organisms, D-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the major enzyme assimilating atmospheric CO2 into the biosphere. Owing to the wasteful oxygenase activity and slow turnover of Rubisco, the enzyme is among the most important targets for improving the photosynthetic efficiency of vascular plants. It has been anticipated that introducing the CO2-concentrating mechanism (CCM) from cyanobacteria into plants could enhance crop yield. However, the complex nature of Rubisco's assembly has made manipulation of the enzyme extremely challenging, and attempts to replace it in plants with the enzymes from cyanobacteria and red algae have not been successful. Here we report two transplastomic tobacco lines with functional Rubisco from the cyanobacterium Synechococcus elongatus PCC7942 (Se7942). We knocked out the native tobacco gene encoding the large subunit of Rubisco by inserting the large and small subunit genes of the Se7942 enzyme, in combination with either the corresponding Se7942 assembly chaperone, RbcX, or an internal carboxysomal protein, CcmM35, which incorporates three small subunit-like domains. Se7942 Rubisco and CcmM35 formed macromolecular complexes within the chloroplast stroma, mirroring an early step in the biogenesis of cyanobacterial β-carboxysomes. Both transformed lines were photosynthetically competent, supporting autotrophic growth, and their respective forms of Rubisco had higher rates of CO2 fixation per unit of enzyme than the tobacco control. These transplastomic tobacco lines represent an important step towards improved photosynthesis in plants and will be valuable hosts for future addition of the remaining components of the cyanobacterial CCM, such as inorganic carbon transporters and the β-carboxysome shell proteins.


Short-term impact of a university based smoke free campaign.
The aim of this study was to evaluate the impact of a smoke free programme implemented at the University of Geneva, Switzerland, in 1996. This programme included a prohibition to smoke in university buildings everywhere except in limited areas, and a smoking cessation counselling service. Surveys were conducted before and four months after the programme was implemented, in representative samples of programme participants (n = 833) and university members not exposed to the programme (n = 1023). In retrospective assessments, participants reported being less bothered by environmental tobacco smoke after programme implementation, but no between group difference was detected in prospective assessments. Relationships between smokers and non-smokers improved moderately in the intervention group and remained unchanged in the comparison group (between group p = 0.001). Proportions of smokers who attempted to quit smoking in the past four months increased from 2.0% to 3.8% in the intervention group and remained unchanged at 3.5% in the comparison group (between group difference: p = 0.048). No impact on smoking prevalence (25%) was detected. The programme was appreciated by university members, although some of its modalities were criticised. A regulation prohibiting smoking everywhere but in limited areas of university buildings was acceptable and reduced the perception of bother by environmental tobacco smoke. It did not, however, influence smoking habits or attitudes toward smoking.


Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta.
Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IkappaBzeta.


Serine-Rich Repeat Adhesins Mediate Shear-Enhanced Streptococcal Binding to Platelets.
The binding of bacteria to platelets is thought to be a central event in the pathogenesis of infective endocarditis. The serine-rich repeat (SRR) glycoproteins of viridans group streptococci have been shown to mediate platelet binding in vitro and to contribute to virulence in animal models. However, it is not known whether SRR adhesins can mediate streptococcal binding under the high fluidic shear stress conditions present on the endocardial surface. We found that three streptococcal SRR adhesins (GspB, Hsa, and SrpA) with differing structures and sialoglycan binding specificities nevertheless exhibited similar biomechanical properties. All three adhesins mediated shear-enhanced streptococcal binding to immobilized platelets through the platelet receptor GPIbα. Shear-enhanced adhesion was manifested in three ways. First, the number of circulating streptococci binding via SRR adhesins to immobilized platelet receptors peaked at 1 dyn/cm2 Second, bound streptococci switched from weak rolling to strong stationary adhesion as shear stress increased to 10 dyn/cm2 Third, while a few streptococci detached each time the flow was increased, the majority of streptococci bound to platelets remained firmly attached through 20 to 80 dyn/cm2 (shear levels typical of arteries and the endocardium). Thus, all three adhesins mediated shear-enhanced streptococcal binding to platelets under the flow conditions found in heart valves. The ability of the SRR adhesins to mediate shear-enhanced binding strongly suggests that they form catch bonds that are activated by tensile force and provides a mechanism for the selective targeting of bacteria to platelet receptors immobilized on the endocardial surface.


Weak Lips? A Possible Merger of /i:/ and /y:/ in Gothenburg.
This study investigates a possible merger in the early stages between /i:/ and /y:/ among young speakers in Gothenburg, Sweden. (1) A large-scale online perception experiment testing listeners' abilities to identify the two vowels and (2) acoustic analysis of 705 vowels from 19 speakers. The perception study shows that listeners classify the horizontally centralized /y:/ as /i:/, both in isolated vowel items and in items containing the full word. This indicates that /y:/ is moving into the perceptual space of /i:/. Listeners also classify the unmerged /y:/ as /i:/ when listening to [y:] in isolation, indicating that lip rounding is a perceptually weak feature, for this centralized vowel, in this variety. The acoustic analysis shows that /i:/ tends to be produced as [ɨ:], and that there is no acoustic difference between /i:/ and /y:/ in measurements correlated with the first two formants, i.e. lip rounding is the most important distinctive feature. Results point in the direction of an incipient vowel merger, following a merger-by-approximation model. These results indicate a lack of perceptual strength of an articulatory feature in the disappearing phoneme, namely lip rounding, and the consequent perceptual similarities between the horizontally centralized [ɨ:] and /y:/.


First fossil evidence for the advance of replacement teeth coupled with life history evolution along an anagenetic mammalian lineage.
In mammals that grow up more slowly and live longer, replacement teeth tend to appear earlier in sequence than in fast growing mammals. This trend, known as 'Schultz's Rule', is a useful tool for inferring life histories of fossil taxa. Deviations from this rule, however, suggest that in addition to the pace of life history, ecological factors may also drive dental ontogeny. Myotragus balearicus is an extinct insular caprine that has been proved to be an excellent test case to correlate morphological traits with life history. Here we show that Myotragus balearicus exhibits a slow signature of dental eruption sequence that is in agreement with the exceptionally slow life history of this species, thus conforming to 'Schultz's Rule'. However, our results also show an acceleration of the absolute pace of development of the permanent incisors in relation to that of the posterior teeth. The rodent-like incisors of Myotragus balearicus erupted early not only in relative but also in absolute terms (chronological age), suggesting that feeding characteristics also plays an important role in dental ontogeny. This is in agreement with ecological hypotheses based on primates. Our study documents a decoupling of the pace of development of teeth in mammals that is triggered by different selection pressures on dental ontogeny. Moreover, we show that Myotragus kopperi from the early Pleistocene (a direct ancestor of the late Pleistocene-Holocene M. balearicus) follows the pattern of first incisor replacement known in living bovids. Hence, the advance in the eruption sequence of the first incisors occurs along the Myotragus evolutionary lineage over a period of about 2.5 Myr. To our knowledge, this is the first fossil evidence of an advance of the emergence of the permanent first incisor along an anagenetic mammalian lineage.


Exploration of the factor structure of the Kirton Adaption-Innovation Inventory using bootstrapping estimation.
Exploratory factor analyses of the Kirton Adaption-Innovation Inventory (KAI), which serves to measure individual cognitive styles, generally indicate three factors: sufficiency of originality, efficiency, and rule/group conformity. In contrast, a 2005 study by Im and Hu using confirmatory factor analysis supported a four-factor structure, dividing the sufficiency of originality dimension into two subdimensions, idea generation and preference for change. This study extends Im and Hu's (2005) study of a derived version of the KAI by providing additional evidence of the four-factor structure. Specifically, the authors test the robustness of the parameter estimates to the violation of normality assumptions in the sample using bootstrap methods. A bias-corrected confidence interval bootstrapping procedure conducted among a sample of 356 participants--members of the Arkansas Household Research Panel, with middle SES and average age of 55.6 yr. (SD = 13.9)--showed that the four-factor model with two subdimensions of sufficiency of originality fits the data significantly better than the three-factor model in non-normality conditions.


Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes.
Ischemic heart disease still remains the most common cause of cardiac death. During ischemia-reperfusion (I/R), reactive oxygen species (ROS) are produced in excess in cardiac tissue, where they induce cell death. Our previous study showed that 9-phenanthrol (9-Phe), a specific inhibitor of the TRPM4 channel, preserves cardiac contractile function and protects the heart from I/R injury-related infarction in the excised rat heart. Accordingly, we hypothesized that TRPM4 channels are involved in the 9-Phe-mediated cardioprotection against ROS-induced injury. In rats, intravenous 9-Phe mitigated the development of myocardial infarction caused by the occlusion of the left anterior descending artery. Immunohistochemical analysis indicated that TRPM4 proteins are expressed in ventricular myocytes susceptible to I/R injury. Hydrogen peroxide (H2O2) is among the main ROS overproduced during I/R. In the cardiomyocyte cell line H9c2, pretreatment with 9-Phe prevented cell death induced by conditions mimicking I/R, namely 200 μM H2O2 and hypoxia-reoxygenation. Gene silencing of TRPM4 preserved the viability of H9c2 cardiomyocytes exposed to 200 μM H2O2. These results suggest that the cardioprotective effects of 9-Phe are mediated through the inhibition of the TRPM4 channels.


Immunophenotypic differentiation between neoplastic plasma cells in mature B-cell lymphoma vs plasma cell myeloma.
Some non-Hodgkin lymphomas show marked plasmacytic differentiation. In such cases, it may be difficult to differentiate these lymphoma from plasmacytoma or myeloma, especially with limited diagnostic material. However, there may be immunophenotypic differences in the plasma cells in these disorders that distinguish them. This study characterizes the immunophenotypes of neoplastic plasma cells in 41 cases of B-lineage non-Hodgkin lymphoma and compares them with those in plasma cell myeloma. We found that plasma cells in lymphoma were significantly more likely to express CD19, CD45, and surface immunoglobulin and less likely to express CD56 than those in myeloma. We further show that CD 19 and CD56 expression can be used reliably to distinguish these entities. Myeloma-associated osseous lesions and solitary plasmacytoma of bone showed myeloma-like immunophenotypes. However, some extramedullary plasmacytomas showed lymphoma-like phenotypes, suggesting that, in reality, they may represent non-Hodgkin lymphomas with extensive plasmacytic differentiation.


Mechanisms of progesterone receptor inhibition of inflammatory responses in cellular models of breast cancer.
Both pro- and antimitogenic activities have been ascribed to progesterone receptor (PR) agonists and antagonists in breast cancer cells; however, the transcriptional responses that underlie these paradoxical functions are not apparent. Using nontransformed, normal human mammary epithelial cells engineered to express PR and standard microarray technology, we defined 2370 genes that were significantly regulated by the PR agonist R5020. Gene ontology (GO) analysis revealed that GO terms involved in inflammation and nuclear factor-κB (NF-κB) signaling were among the most significantly regulated. Interestingly, on those NF-κB responsive genes that were inhibited by agonist-activated PR, antagonists either 1) mimicked the actions of agonists or 2) reversed the inhibitory actions of agonists. This difference in pharmacological response could be attributed to the fact that although agonist- and antagonist-activated PR is recruited to NF-κB-responsive promoters, the physical presence of PR tethered to the promoter of some genes is sufficient for transcriptional inhibition, whereas on others, an agonist-activated PR conformation is required for inhibition of NF-κB signaling. Importantly, the actions of PR on the latter class of genes were reversed by an activation function-2-inhibiting, LXXLL-containing peptide. Consideration of the relative activities of these distinct antiinflammatory pathways in breast cancer may be instructive with respect to the likely therapeutic activity of PR agonists or antagonists in the treatment of breast cancer.


Serum apolipoprotein E is associated with long-term risk of Alzheimer's disease: The Rotterdam Study.
Serum levels of apolipoprotein E (apoE) have been suggested as potential biomarker for dementia, but the long-term association between apoE and risk of dementia is uncertain. Between 1990 and 1993, we measured serum apoE by immunoassay in 1042 non-demented individuals (mean ± SD age 68.4 ± 7.3 years; 59.3% women) from the population-based Rotterdam Study. Follow-up for dementia was complete until 2014. We used Cox models to determine the risk of dementia and Alzheimer's disease in relation to apoE, adjusting for age, sex, educational level, cardiovascular risk factors, and additionally APOE genotype. Serum apoE was associated to APOE genotype (p-trend=1.0E-51, r(2)=0.21). In men, apoE tended to be lower with age, whereas in women the opposite was observed (p-trend=0.07 and 0.08, respectively). During a median follow-up of 15.7 years (IQR 9.7-21.7), 220 participants developed dementia, of whom 180 had Alzheimer's disease. Lower serum apoE was associated with an increased risk of dementia (HR, 95%CI, per SD decrease: 1.25, 1.05-1.48) and in particular Alzheimer's disease (1.51, 1.23-1.86), which remained statistically significant for Alzheimer's disease after additionally adjusting for APOE genotype (1.28, 1.01-1.62). When stratifying analyses in 5-year time frames, risk estimates were similar throughout the study period. Serum apoE tended to marginally improve 20-year prediction of Alzheimer's disease (IDI 0.008, 95%CI -0.001-0.026, p=0.086), but not all dementia. Serum apoE is associated with long-term risk of Alzheimer's disease in the general population, independent of APOE genotype. Additional predictive value of serum apoE was limited.


Prospective association between handgrip strength and cardiac structure and function in UK adults.
Handgrip strength, a measure of muscular fitness, is associated with cardiovascular (CV) events and CV mortality but its association with cardiac structure and function is unknown. The goal of this study was to determine if handgrip strength is associated with changes in cardiac structure and function in UK adults. Left ventricular (LV) ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), mass (M), and mass-to-volume ratio (MVR) were measured in a sample of 4,654 participants of the UK Biobank Study 6.3 ± 1 years after baseline using cardiovascular magnetic resonance (CMR). Handgrip strength was measured at baseline and at the imaging follow-up examination. We determined the association between handgrip strength at baseline as well as its change over time and each of the cardiac outcome parameters. After adjustment, higher level of handgrip strength at baseline was associated with higher LVEDV (difference per SD increase in handgrip strength: 1.3ml, 95% CI 0.1-2.4; p = 0.034), higher LVSV (1.0ml, 0.3-1.8; p = 0.006), lower LVM (-1.0g, -1.8 --0.3; p = 0.007), and lower LVMVR (-0.013g/ml, -0.018 --0.007; p<0.001). The association between handgrip strength and LVEDV and LVSV was strongest among younger individuals, while the association with LVM and LVMVR was strongest among older individuals. Better handgrip strength was associated with cardiac structure and function in a pattern indicative of less cardiac hypertrophy and remodeling. These characteristics are known to be associated with a lower risk of cardiovascular events.


Governing obesity policies from England, France, Germany and Scotland.
Defining a phenomenon as a political problem could be considered a crucial part of any political process. Body weight, when categorised as obesity, has been defined as a political problem since the beginning of the 21st century and has entered the political agenda in many countries. In this article, I present a study of four plans from four Western European countries: England, France, Germany and Scotland, identifying how obesity is defined as a political issue. The questions addressed are: How is the development in the obesity prevalence explained and who is considered responsible for the development? What are the suggested remedies and who is considered responsible for acting? All plans state that obesity is a political issue because it causes health problems; in fact, weight is almost equated to health. The English and Scottish plans present a bio-political argument, characterising obesity as a serious threat to the countries' economies. So does the German plan, but not with the same emphasis. The plans portray people with obesity as being economically harmful to their fellow citizens. The French plan expresses another concern by focussing on the discrimination and stigmatization of obese people. All plans define the physical and food environment as a crucial factor in the obesity development, but only the Scottish Government is prepared to use statutory means towards industry and other actors to achieve change. The policies convey an unresolved dilemma: To govern or not to govern? The Governments want individuals to choose for themselves, yet they try to govern the populations to choose as the Governments find appropriate. The plans have a legitimising function, showing that the Governments take the issue seriously. Accordingly, in this case, the actual problematisations seem to be less crucial.


Steroids for migraine headaches: a randomized double-blind, two-armed, placebo-controlled trial.
Recurrence of migraine headache after treatment in the emergency department (ED) is common. Conflicting evidence exists regarding the utility of steroids in preventing migraine headache recurrence at 24-48 h. To determine if steroids decrease the headache recurrence in patients treated for migraine headaches in the ED. Double-blind placebo-controlled, two-tailed randomized trial. Patients aged >17 years with a moderately severe migraine headache diagnosed by treating Emergency Physician were approached for participation. Enrollees received either dexamethasone (10 mg i.v.) if intravenous access was utilized or prednisone (40 mg by mouth × 2 days) if no intravenous access was obtained. Each medication was matched with an identical-appearing placebo. Patients were contacted 24-72 h after the ED visit to assess headache recurrence. A total of 181 patients were enrolled. Eight were lost to follow-up, 6 in the dexamethasone group and 2 in the prednisone arm. Participants had a mean age of 37 years (±10 years), with 86% female. Eighty-six percent met the International Headache Society Criteria for migraine headache. Of the 173 patients with completed follow-up, 20/91 (22%) (95% confidence interval [CI] 13.5-30.5) in the steroid arm and 26/82 (32%) (95% CI 21.9-42.1) in the placebo arm had recurrent headaches (p = 0.21). We did not find a statistically significant decrease in headache recurrence in patients treated with steroids for migraine headaches.


The creatine kinase energy transport system in the failing mouse heart.
Characteristic alterations of the creatine kinase (CK) system occur in heart failure and may contribute to contractile dysfunction. We examined two mouse models of chronic cardiac stress, transverse aortic constriction (TAC) and coronary artery ligation (CAL), and examined the relationship of CK system changes with hypertrophy and heart failure development. C57Bl/6 mice were subjected to TAC or sham surgery and sacrificed after 2-10 weeks according to echocardiographic criteria of myocardial hypertrophy and function to create four groups representing progressive dysfunction from normal, through compensated hypertrophy, to heart failure. Only mice with congestive heart failure had LV total creatine concentration and total CK activity significantly lower than sham values (11% and 30% lower, respectively). However for all aortic banded mice, a linear relationship was observed between ejection fraction and estimated maximal CK reaction velocity. Mice with heart failure also had corresponding decreases in the activities of the Mito-, MM-, and MB-CK isoenzymes, while the BB isoform remained unchanged. To determine whether these changes were model specific, mice were subjected to CAL or sham operation and followed for 7 weeks. Quantitative changes in total creatine, total CK activity, Mito-CK and MM-CK activities were similar for CAL and TAC mice. We conclude that alterations in the creatine kinase system occur during heart failure in mice qualitatively similar to those occurring in larger animals and humans, suggesting that mice are a suitable model for studying the role of such changes in the pathogenesis of heart failure.


Clinical and Serological Features of Eosinophilic and Vasculitic Phases of Eosinophilic Granulomatosis with Poliangiitis: a Case Series of 15 Patients.
Eosinophilic granulomatosis with poliangiitis (EGPA) which was previously called Churg-Strauss Syndrome, is classified into eosinophilic and vasculitic phases. To characterize the eosinophilic and vasculitic phases of the disease in terms of clinical findings, serology, and treatment. We included 15 EGPA patients in the study. The clinical, serological, and therapeutic characteristics and the treatment responses of the patients were recorded. Thirteen patients were classified as being in the eosinophilic phase and two were classified as being in the vasculitic phase of EGPA. Initial symptoms were worsening asthma in all patients (n=15; 100%). All patients had rhinosinusitis, and 66.6% had hypersensitivity to nonsteroidal anti-inflammatory drugs. The two patients in the vasculitic phase did not have nasal polyposis. Pulmonary and nervous system involvement were the most common symptoms. The erythrocyte sedimentation rates (ESRs) of the two patients in the vasculitic phase were 65 mm/h and 55 mm/h, while ESR was normal in eosinophilic-phase patients. Antineutrophil cytoplasmic antibodies (ANCA) was detected in one patient (6.6%) who was in the vasculitic phase (Case 15). The disease was under control with higher doses of methylprednisolone in the vasculitic phase (Case 14: 12 mg/day, Case 15: 10 mg/day) than in the eosinophilic phase. Relapse was detected in the two patients in the vasculitic phase. Oral corticosteroid was not discontinued in any case, and no mortality was reported. Patients with eosinophilic phase or vasculitic phase EGPA had similar clinical onset. However, higher ESR, ANCA positivity, and extrapulmonary organ involvement were only found in patients in the vasculitic phase. Corticosteroid responsiveness was very good in all patients in the eosinophilic phase, and the disease could be controlled with a very low maintenance dose of a corticosteroid.


Levels and trends of poly- and perfluorinated compounds in the arctic environment.
Poly- and perfluorinated organic compounds (PFCs) are ubiquitous in the Arctic environment. Several modeling studies have been conducted in attempt to resolve the dominant transport pathway of PFCs to the arctic-atmospheric transport of precursors versus direct transport via ocean currents. These studies are generally limited by their focus on perfluorooctanoate (PFOA) fluxes to arctic seawater and thus far have only used fluorotelomer alcohols (FTOHs) and sulfonamide alcohols as inputs for volatile precursors. There have been many monitoring studies from the North American and European Arctic, however, almost nothing is known about PFC levels from the Russian Arctic. In general, there are very few measurements of PFCs from the abiotic environment. Atmospheric measurements show the widespread occurrence of PFC precursors, FTOHs and perfluorinated sulfonamide alcohols. Further, PFCAs and PFSAs have been detected on atmospheric particles. The detection of PFCAs and PFSAs in snow deposition is consistent with the volatile precursor transport hypothesis. There are very limited measurements of PFCs in seawater. PFOA is generally detected in the greatest concentrations. Additional seawater measurements are needed to validate existing model predications. The bulk of the monitoring efforts in biological samples have focused on the perfluorinated carboxylates (PFCAs) and sulfonates (PFSAs), although there are very few measurements of PFC precursors. The marine food web has been well studied, particularly the top predators. In contrast, freshwater and terrestrial ecosystems have been poorly studied. Studies show that in wildlife perfluorooctane sulfonate (PFOS) is generally measured in the highest concentration, followed by either perfluorononanoate (PFNA) or perfluoroundecanoate (PFUnA). However, some whale species show relatively high levels of perfluorooctane sulfonamide (PFOSA) and seabirds are typically characterized by high proportions of the C(11)-C(15) PFCAs. PFOA is generally infrequently detected and is present in low concentrations in arctic biota. Food web studies show high bioaccumulation in the upper trophic-level animals, although the mechanism of PFC biomagnification is not understood. Spatial trend studies show some differences between populations, although there are inconsistencies between PFC trends. The majority of temporal trend studies are from the Northern American Arctic and Greenland. Studies show generally increasing levels of PFCs from the 1970s, although some studies from the Canadian Arctic show recent declines in PFOS levels. In contrast, ringed seals and polar bears from Greenland continue to show increasing PFOS concentrations. The inconsistent temporal trends between regions may be representative of differences in emissions from source regions.


Evolution of human immunodeficiency virus type 1 in relation to disease progression in children.
To compare patterns of nonsynonymous and synonymous substitutions over time in the V1V2 and C2V3 regions of human immunodeficiency virus type 1 (HIV-1) env and in a conserved segment of pol in HIV-1-infected children with varying rates of CD4+ T-cell decline. Longitudinal study of HIV-1 genetic variants sampled from peripheral blood of 3 children affected with acquired immunodeficiency syndrome (AIDS) and 4 children with slow disease progression. Nested polymerase chain reaction (PCR) was used to detect HIV-1 genetic material in plasma-derived virions and cellular DNA. Sequence variants were enumerated by screening cloned PCR products using heteroduplex mobility assay (HMA) or single-strand conformation polymorphism analysis (SSCP) and nucleotide sequencing. Frequencies of nonsynonymous and synonymous substitutions within sampling points and the accumulation rate of nucleotide substitutions over the period of observation were calculated. In the C2V3 region, higher rates of accumulation of nonsynonymous substitutions were associated with more precipitous declines in CD4+ cell numbers. In the V1V2 region, rates of accumulation of nonsynonymous substitutions were comparable with those in the C2V3 region, but similar rates were observed in AIDS-affected children and children with slow disease progression. The rate of accumulation of nonsynonymous substitutions in the pol region was lower than that in the C2V3 and V1V2 regions. Rates of accumulation of nucleotide substitutions vary across the HIV-1 genome and differ in relation to disease progression in children. The finding of greater rates of nonsynonymous substitution in the immunodominant C2V3 region in children whose disease progressed rapidly is consistent with a vigorous but inadequate immune response in children who are unable to control HIV-1 infection.


Fear of recurrence among head and neck cancer survivors: longitudinal trends.
Fear of recurrence (FoR) following head and neck cancer (HNC) treatment is a major patient concern but is infrequently discussed in outpatient settings and may cause significant detrimental effect on patient psychological well-being. The aim of this paper is to determine longitudinal trends and predictors of significant FoR. Prospective data collection was obtained in 189 post-treatment HNC patients with 456 clinic attendances from October 2008 to January 2011. All patients completed Patient Concerns Inventory (PCI), University of Washington Quality of Life Questionnaire version 4 and the FoR questionnaires using a combination of paper and touch-screen technology. The prevalence of significant FoR was 35%, which was stable longitudinally. Logistic regression-delineated predictors of significant FoR were young age (<65 years), anxiety/mood and patient-reported FoR. Conventional prognostic factors including standard clinicopathological factors, treatment modality and length of follow-up did not predict significant FoR. Over time, 20% of patients reported significant FoR intermittently, whereas 30% experienced it consistently. The remaining 50% did not experience significant FoR. Patient-related characteristics were more important than clinicopathological prognostic factors in predicting significant FoR, potentially creating a mismatch between the doctors' perception of patient's experience of FoR with what patients may experience. In the long term, FoR is expressed across a spectrum extending from 'normal' FoR to persistent significant FoR with an intermediate category of intermittent significant FoR. Those patients experiencing intermittent and consistent levels of significant FoR may benefit from psychological support. This study confirmed that self-reported screening FoR using the PCI is a valuable tool in identifying significant FoR.


Sociodemographic and delivery risk factors for developing postpartum depression in a sample of 3233 mothers from the Czech ELSPAC study.
In the postpartum period, certain groups of women are at a higher risk for developing depressive episodes. Several studies have described risk factors for developing postpartum depression (PPD). However, these studies have used limited numbers of participants, and therefore the estimated prevalence of PPD varies greatly. The objective of this study is to identify the main risk factors for developing PPD by using data collected via the Czech version of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC). This database provides a representative sample (n = 7589) observed prospectively and a large amount of data on depressive symptoms and on biological, socioeconomic, and environmental factors. The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for incidence of PPD. The affective pathology was examined at three time points: before delivery, 6 weeks after delivery, and 6 months after delivery. The prevalence of depressive symptoms before delivery was 12.8%, 6 weeks after delivery 11.8%, and 6 months after delivery 10.1%. The prevalence rates are based on women who completed questionnaires at all three time-points (N = 3233). At all three time points, the main risk factors for developing PPD identified as significant by both univariate and multivariate analysis were personal history of depressive episodes and mothers experiencing psychosocial stressors. Other risk factors occurring in both types of analysis were: family history of depression from expectant mother's paternal side (prenatal), mothers living without partners (6 weeks postpartum) and feelings of unhappiness about being pregnant (6 months postpartum). Several protective factors were also observed: male child gender (prenatal), primiparous mothers (6 months postpartum), and secondary education (prenatal, only by multivariate analysis). Significant risk factors found solely by univariate analysis were family history of depression in both parents of the expectant mother (prenatal and 6 weeks postpartum), family history of depression from subject's maternal side (6 months postpartum), unintentional pregnancy (prenatal and 6 weeks postpartum), feelings of unhappiness about being pregnant (prenatal and 6 weeks postpartum), primary education (prenatal and 6 weeks postpartum), mothers who opted not to breastfeed (6 months postpartum) and mothers living without partners (prenatal and 6 months postpartum). Family savings were identified as protective factor (prenatal and 6 months postpartum). We identified significant predictors of PPD. These predictors can be easily detected in clinical practice, and systematic screening can lead to identifying potentially at risk mothers. Since the risk is linked with experience of psychosocial stressors it seems that they might benefit from increased psychosocial support to prevent affective pathology.


A temperature-sensitive NUP116 null mutant forms a nuclear envelope seal over the yeast nuclear pore complex thereby blocking nucleocytoplasmic traffic.
NUP116 encodes a 116-kD yeast nuclear pore complex (NPC) protein that is not essential but its deletion (nup116 delta) slows cell growth at 23 degrees C and is lethal at 37 degrees C (Wente, S. R., M. P. Rout, and G. Blobel. 1992. J. Cell Biol. 119:705-723). Electron microscopic analysis of nup116 delta cells shifted to growth at 37 degrees C revealed striking perturbations of the nuclear envelope: a double membrane seal that was continuous with the inner and outer nuclear membranes had formed over the cytoplasmic face of the NPCs. Electron-dense material was observed accumulating between the cytoplasmic face of these NPCs and the membrane seal, resulting in "herniations" of the nuclear envelope around individual NPCs. In situ hybridization with poly(dT) probes showed the accumulation of polyadenylated RNA in the nuclei of arrested nup116 delta cells, sometimes in the form of punctate patches at the nuclear periphery. This is consistent with the electron microscopically observed accumulation of electron-dense material within the nuclear envelope herniations. We propose that nup116 delta NPCs remain competent for export, but that the formation of the membrane seals over the NPCs blocks nucleocytoplasmic traffic.


Selective deficit of mental visual imagery with intact primary visual cortex and visual perception.
There is a vigorous debate as to whether visual perception and imagery share the same neuronal networks, whether the primary visual cortex is necessarily involved in visual imagery, and whether visual imagery functions are lateralized in the brain. Two patients with brain damage from closed head injury were submitted to tests of mental imagery in the visual, tactile, auditory, gustatory, olfactory and motor domains, as well as to an extensive testing of cognitive functions. A computerized mapping procedure was used to localize the site and to assess the extent of the lesions. One patient showed pure visual mental imagery deficits in the absence of imagery deficits in other sensory domains as well as in the motor domain, while the other patient showed both visual and tactile imagery deficits. Perceptual, language, and memory deficits were conspicuously absent. Computerized analysis of the lesions showed a massive involvement of the left temporal lobe in both patients and a bilateral parietal lesion in one patient. In both patients the calcarine cortex with the primary visual area was bilaterally intact. Our study indicates that: (i) visual imagery deficits can occur independently from deficits of visual perception; (ii) visual imagery deficits can occur when the primary visual cortex is intact and (iii) the left temporal lobe plays an important role in visual mental imagery.


Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man.
1. The diphosphonate, disodium etidronate (disodium ethane-1-hydroxy-1, 1-diphosphonate; (EHDP), is known to increase plasma inorganic phosphate in man. The present study examines the mechanism of this effect. 2. When EHDP was given by mouth at a dose of 80 mumol (20 mg) kg-minus 1day-minus 1, plasma phosphate was significantly increased 24 h after the first dose but did not reach its maximum value for 2-3 weeks. When the drug was stopped, plasma phosphate returned to pretreatment values within 3 weeks. 3. Urinary excretion rate of phosphate was not greatly changed during treatment with EHDP despite the large increase in plasma phosphate, suggesting an alteration in renal handling. This was examined directly by infusing phosphate and inulin in six patients off and on EDPH. 4. EHDP had no effect on glomerular filtration rate (GFR) but produced a large increase in the maximum rate of renal tubular reabsorption of phosphate (TmP). The ratio Tm,P/GFR increased from a mean value of 1.15 mmol/1 to 2.10 mmol/1 on EHDP. This increase accounted for the hyperphosphataemia. 5. The same amount of phosphate infused at the same rate produced a greater rise in plasma phosphate when patients were on EHDP than when they were not, indicating a reduced net rate of entry of phosphate into tissues other than kidney. 6. Fasting total plasma calcium concentration and urine calcium excretion rate were not significantly altered by EHDP but the ability of infused phosphate to decrease plasma calcium was diminished. 7. It is suggested that EHDP alters phosphate transport in kidney and other tissues by a mechanism which is probably independent of the known hormonal influences on phosphate metabolism.


Consistencies and terminologies - the use of the International Dysphagia Diet Standardization Initiative.
Introduction: this study aimed to verify the ability of speech therapists to identify, sort and name the different consistencies used in neurogenic oropharyngeal dysphagia (NOD) management, and to compare the results with the terms proposed by the International Dysphagia Diet Standardization Initiative (IDDSI). Methods: this research was approved by the ethics committee. Sixty speech therapists who work with NOD patients sorted 5 commercial foods from thinnest to thickest to match IDDSI levels 0 to 4, and then used a term to designate each consistency. Results: most subjects (76.66%) sorted the foods properly. Terminologies were divergent at all levels. For level 0, practitioners assigned 3 different terms. For level 1, 24 different terms were reported; for level 2 there were 25 terms, 23 terms for level 3, and 18 terms for level 4. Level 0 (IDDSI - thin) was designated by most participants as liquid; level 1 (IDDSI - slightly thick) was referred to as semi-thickened liquid; level 2 (IDDSI - mildly thick) as thickened liquid; level 3 (IDDSI - moderately thick) as honey; and level 4 (IDDSI - extremely thick) as pasty by most subjects. A reduced number of participants used terms in accordance with IDDSI. Level 0 was appropriately named by 5 subjects (8.33%); levels 1, 2 and 4 by 2 practitioners each (3.33%); and level 3 by 1 professional (1.66%). None of the subjects named all 5 IDDSI levels correctly. Conclusion: most practitioners progressed consistencies properly. There was a diversity of terminologies used for the same consistency at all levels, with no standardization.


Formation Damage Induced by Water-Based Alumina Nanofluids during Enhanced Oil Recovery: Influence of Postflush Salinity.
Injecting nanofluids (NFs) has been proven to be a potential method to enhance oil recovery. Stranded oil is produced by wettability alteration where nanoparticles form a wedge film on pore wall surfaces, which is thought to shrink the pore space of the reservoir. Furthermore, ensuring the stability of the injected NF during the application is a major challenge. A low permeability reservoir and salinity of water make the response of NF injection to the formation damage more difficult. This article, therefore, studied the formation damage induced by the injection of alumina nanofluids (Al-NFs) in a relatively low permeability (7.1 mD) sandstone core. The salinity of the postflush water was also considered to mitigate the destructive impact. Al-NF was formulated by dispersing alumina nanoparticles (Al-NPs) in an aqueous solution of sodium dodecylbenzene sulfonate (SDBS) at its critical micelle concentration (CMC, 0.1 wt %). The formation damage, inherent to Al-NF injection, was evaluated by core-flooding tests. The assays consisted of the injection of 1 PV Al-NF (0.05 wt %) at the trail of which postflush at different salinities was flooded. The study found that the salinity of the postflush has an effect on the formation damage and oil recovery factor (RF). A chase water with a salinity concentration of 3 wt % sodium chloride (NaCl) produced an RF of 8.7% compared to a base case of water-flooding with a pressure drop of up to 13 MPa across the core (70 mm in length). These results pertained to the deposition of Al-NPs at the injection end. However, lowering the postflush salinity to 1 wt % NaCl mitigated the formation damage as evidenced by the decrease in pressure (35%) and an increase in RF to 17.2%.


Longitudinal brain changes in MDD during emotional encoding: effects of presence and persistence of symptomatology.
The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are state-dependent and whether they are affected by the persistence of depressive symptoms. Thirty-nine patients with major depressive disorder and 28 healthy controls were included from the longitudinal functional magnetic resonance imaging (fMRI) sub-study of the Netherlands Study of Depression and Anxiety. Participants performed an emotional word-encoding and -recognition task during fMRI at baseline and 2-year follow-up measurement. At baseline, all patients were in a depressed state. We investigated state-dependency by relating changes in brain activation over time to changes in symptom severity. Furthermore, the effect of time spent with depressive symptoms in the 2-year interval was investigated. Symptom change was linearly associated with higher activation over time of the left anterior hippocampus extending to the amygdala during positive and negative word-encoding. Especially during positive word encoding, this effect was driven by symptomatic improvement. There was no effect of time spent with depression in the 2-year interval on change in brain activation. Results were independent of medication- and psychotherapy-use. Using a longitudinal within-subjects design, we showed that hippocampal-amygdalar activation during emotional memory formation is related to depressive symptom severity but not persistence (i.e. time spent with depression or 'load'), suggesting functional activation patterns in depression are not subject to functional 'scarring' although this hypothesis awaits future replication.


Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age.
The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR). We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children. We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (ρ = -0.25; P = 3.3 × 10-5). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module. Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.


DNA repair triggered by sensors of helical dynamics.
Nucleotide excision repair is a constitutive stress response that eliminates DNA lesions induced by multiple genotoxic agents. Unlike the immune system, which generates billions of immunoglobulins and T cell receptors for antigen recognition, the nucleotide excision repair complex uses only a few generic factors to detect an astounding diversity of DNA modifications. New data favor an unexpected strategy whereby damage recognition is initiated by the detection of abnormal oscillations in the undamaged strand opposite to DNA lesions. Another core subunit recognizes the increased susceptibility of DNA to be kinked at injured sites. We suggest that early nucleotide excision repair factors gain substrate versatility by avoiding direct contacts with modified residues and exploiting instead the altered dynamics of damaged DNA duplexes.


Early Season Pediatric Influenza B/Victoria Virus Infections Associated with a Recently Emerged Virus Subclade - Louisiana, 2019.
Multiple genetically distinct influenza B/Victoria lineage viruses have cocirculated in the United States recently, circulating sporadically during the 2018-19 season and more frequently early during the 2019-20 season (1). The beginning of the 2019-20 influenza season in Louisiana was unusually early and intense, with infections primarily caused by influenza B/Victoria lineage viruses. One large pediatric health care facility in New Orleans (facility A) reported 1,268 laboratory-confirmed influenza B virus infections, including 23 hospitalizations from July 31 to November 21, 2019, a time when influenza activity is typically low. During this period, Louisiana also reported one pediatric death associated with influenza B virus infection. An investigation of the influenza B virus infections in Louisiana, including medical and vaccine record abstraction on 198 patients, primarily from facility A, with sporadic cases from other facilities in the state, found that none of the patients had received 2019-20 seasonal influenza vaccine, in part because influenza activity began before influenza vaccination typically occurs. Among 83 influenza B viruses sequenced from 198 patients in Louisiana, 81 (98%) belonged to the recently emerged B/Victoria V1A.3 genetic subclade. Nationally, to date, B/Victoria viruses are the most commonly reported influenza viruses among persons aged <25 years (2). Of the 198 patients in the investigation, 95% were aged <18 years. Although most illnesses were uncomplicated, the number of hospitalizations, clinical complications, and the reported pediatric death in Louisiana serve as a reminder that, even though influenza B viruses are less common than influenza A viruses in most seasons, influenza B virus infection can be severe in children. All persons aged ≥6 months should receive an annual influenza vaccination if they have not already received it (3). Antiviral treatment of influenza is recommended as soon as possible for all hospitalized patients and for outpatients at high risk for influenza complications (including children aged <2 years and persons with underlying medical conditions) (4).


The Economic Impacts of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Australian Cohort.
Objectives: This study aims to estimate direct and indirect health economic costs associated with government and out-of-pocket (OOP) expenditure based on health care service utilization and lost income of participants and carers, as reported by Australian Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patient survey participants. Design: A cost of illness study was conducted to estimate Australian cost data for individuals with a ME/CFS diagnosis as determined by the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the 1994 CDC Criteria (Fukuda). Setting and participants: Survey participants identified from a research registry database provided self-report of expenditure associated with ME/CFS related healthcare across a 1-month timeframe between 2017 and 2019. Main outcome measures: ME/CFS related direct annual government health care costs, OOP health expenditure costs, indirect costs associated with lost income and health care service use patterns. Results: The mean annual cost of health care related expenditure and associated income loss among survey participants meeting diagnostic criteria for ME/CFS was estimated at $14.5 billion. For direct OOP and Government health care expenditure, high average costs were related to medical practitioner attendance, diagnostics, natural medicines, and device expenditure, with an average attendance of 10.6 referred attendances per annum and 12.1 GP visits per annum related specifically to managing ME/CFS. Conclusions: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.


Insurance status influences the rates of reportable quality metrics in brain tumor patients: a nationwide inpatient sample study.
In 2010, the Patient Protection and Affordable Care Act was passed to expand health insurance, narrow health care disparities, and improve health care quality in the United States. As part of this initiative, the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services are now tracking quality metrics. To analyze the effects of insurance on the incidence of patient safety indicators (PSIs) and hospital-acquired conditions (HACs) using the Nationwide Inpatient Sample for patients who have brain tumors. The Nationwide Inpatient Sample was queried for all hospitalizations between 2002 and 2011 involving patients with brain tumors. Because of the confounding age restriction with Medicare, comparisons were made between Medicaid/self-pay and private insurance. To determine which factors contributed to HACs and PSIs, odds ratios were calculated for each risk factor. Logistic regression models were used to assess the effect of payer status on individual PSIs, HACs, and patient outcomes. Medicaid/self-pay patients had a higher PSI and HAC incidence compared with private insurance patients. The greater incidence of PSIs and HACs correlated with increased length of stay, worse discharge outcomes, and increased in-hospital mortality. Variability exists in the incidence of PSIs and HACs in patients with brain tumors based on insurance status. Controlling for both patient and hospital factors can explain these differences. The cause of these disparities should be studied prospectively to begin the process of improving quality metrics in vulnerable patient populations.


Infant developmental milestones and subsequent cognitive function.
Developmental delay is associated with a subsequent diagnosis of learning disability. However, the relationship between the age of reaching infant developmental milestones and later intellectual function within the general population remains unresolved. We hypothesized that earlier attainment of developmental milestones would be associated with better subsequent intellectual performance throughout the range of abilities, rather than confined to extremes. Developmental data were obtained at age 2 years in the National Survey of Health and Development, a representative sample of 5,362 children born in the United Kingdom in 1946. Data on intellectual function and educational attainment at ages 8, 26, and 53 years were also obtained. Multiple linear regression and logistic regression were used to analyze the effect of age of reaching developmental milestones on subsequent cognition and educational attainment. The age of reaching developmental milestones was associated with intellectual performance at ages 8, 26, and 53 years; for every month earlier a child learned to stand, there was, on average, a gain of one half of one intelligence quotient point at age 8. Speech development had a small but statistically significant effect on subsequent educational attainment (later developers were less likely to progress beyond basic education); this effect was not apparent for motor development. Effect sizes were reduced when the slowest developers were excluded, but many effects remained significant. The association between later development and poorer subsequent intellectual function is small, but it does have theoretical implications; we suggest it is secondary to suboptimal cortical-subcortical connectivity.


Variations in ORAI1 Gene Associated with Kawasaki Disease.
Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.


Cortical plaque-like structures identify ribosome-containing domains in the Mauthner cell axon.
The hypothesis that ribosomes are present, but may have a restricted distribution, in the Mauthner (M) axon was evaluated in isolated M-cell axoplasm after (1) staining with YOYO-1 and (2) inspection by electron spectroscopic imaging (ESI) of ribosomal RNA (rRNA) phosphorus (P). Discrete periaxoplasmic plaques, identified by their ribonuclease-sensitive fluorescence, were located circumferentially at the surface boundary of isolated axoplasm and distributed longitudinally at random intervals. Conditions that destabilized plaques, and surface blotting of plaques onto a coverslip, revealed that fluorescent puncta were probably a significant source of plaque fluorescence. Fluorescent puncta were also distributed in a delimited volume of axoplasm, subjacent to the plaque. The notably higher density of F-actin in the latter region suggested that the actin cytoskeleton may govern the spatial distribution of puncta in subcortical axoplasm. Some fluorescent plaques were superficial to the cortical F-actin layer, whereas others formed inclusions within the F-actin layer; however, plaques did not appear to contain F-actin. Periaxoplasmic plaques were also identified in ordinary myelinated axons. ESI, in which rRNA emits bright signals in the phosphorus (P) spectral line against a low-contrast background, showed that isolated axoplasm contained characteristic 25 nm P signals, which were associated or in direct contact with a pleiomorphic structural matrix, located at the surface boundary. Polyribosomal P signals were also distributed in peripheral axoplasm below the matrix. The concept of a distinct polyribosome-populated domain, distributed intermittently in the cortical zone of the axon is described. This domain is spatially defined by a plaque-like periaxoplasmic structural matrix, and a confluent volume of subcortical axoplasm integrated through an actin cytoskeleton.


Eat now or later: self-control as an overlapping cognitive mechanism of depression and obesity.
While overlapping neurobiological mechanisms are known, relatively little is known about how "self-control" and cognitive affective processing of rewards may also influence the bi-directional risk between obesity and depression. The objective of this study was to identify the extent to which "self-control," measured using a delay discounting task is co-related to BMI and Depression diagnostic thresholds. A within-subjects counterbalanced design was used in which 92 participants (Mean ± SD: BMI = 27.9 ± 3.5, HAMD = 14.7 ± 7.7) completed a series of clinical diagnostic, survey, and demographic questionnaires in a behavioral health laboratory setting. For the delay discounting task, participants chose between one large delayed reward and one successively smaller immediate reward for four food types (dessert, fried food, fruit, and vegetable). Results showed that delay discounting scores were predictive of BMI and depression with lower delay discounting scores associated with higher BMI and HAMD for the dessert (HAMD scores (β = -.197, p = .013), BMI (β = -.239, p < .001)) and fried food (HAMD scores (β = -.328, p = .001), BMI (β = -.166, p = .027)). Clinical significance was further evident when HAMD and BMI scores were converted to diagnostic thresholds. Only depression and/or atypical depressive symptoms were related to delay discounting scores with the fruit and vegetable. Thus, reduced cognitive affective self-control for impulsive food choices-particularly for "comfort foods" high in fat and sugar-appears to be a shared cognitive mechanism for both conditions perhaps contributing to the high prevalence of co-morbid mood disorders and weight gain.


Somatostatin contributes to in vivo gamma oscillation modulation and odor discrimination in the olfactory bulb.
Neuropeptides are systematically encountered in local interneurons, but their functional contribution in neural networks is poorly documented. In the mouse main olfactory bulb (MOB), somatostatin is mainly concentrated in local GABAergic interneurons restricted to the external plexiform layer (EPL). Immunohistochemical experiments revealed that the sst2 receptor, the major somatostatin receptor subtype in the telencephalon, is expressed by mitral cells, the MOB principal cells. As odor-activated mitral cells synchronize and generate gamma oscillations of the local field potentials, we investigated whether pharmacological manipulations of sst2 receptors could influence these oscillations in freely behaving mice. In wild-type, but not in sst2 knock-out mice, gamma oscillation power decreased lastingly after intrabulbar injection of an sst2-selective antagonist (BIM-23627), while sst2-selective agonists (octreotide and L-779976) durably increased it. Sst2-mediated oscillation changes were correlated with modifications of the dendrodendritic synaptic transmission between mitral and granule cells. Finally, bilateral injections of BIM-23627 and octreotide respectively decreased and increased odor discrimination performances. Together, these results suggest that endogenous somatostatin, presumably released from EPL interneurons, affects gamma oscillations through the dendrodendritic reciprocal synapse and contributes to olfactory processing. This provides the first direct correlation between synaptic, oscillatory, and perceptual effects induced by an intrinsic neuromodulator.


Stein and Moore Award address. Reconstructing history with amino acid sequences.
The main goal of the protein evolutionist is the reconstruction of past events leading to the structures of contemporary proteins. The common strategy is to align amino acid sequences and make inferences about matters of common ancestry. The rate of change of amino acid sequence varies greatly from protein to protein, and this naturally affects how far back a given protein's ancestry can be traced. Happily, the rate of change of many proteins is slow enough that very ancient events can be inferred. Many mainstream metabolic enzymes, for example, are 40-50% identical in prokaryotes and eukaryotes, groups that diverged from a common ancestor more than 1.5 billion years ago. Moreover, some eukaryotic proteins like actin and tubulin change so slowly that they are seldom less than 60% identical, no matter from what source they are drawn. As it happens, prokaryotic counterparts for many eukaryotic cytoskeletal proteins are unknown. A recent exception involves the finding that a heat shock protein cognate is a relative of actin. The gene duplication that gave rise to these two proteins must have been an ancient event. The more recent invention of other proteins whose distribution is restricted to one or the other of the major kingdoms may be easier to trace. Among the factors that can confound the reconstruction of events, however, are occasional horizontal gene transfers and exon shuffling. The latter has led to a number of mosaic proteins, many of which contain various combinations of a relatively small set of modules like the epidermal growth factor domain.


Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study.
The associations of the C34T polymorphism of the adenosine monophosphate deaminase 1 (AMPD1) gene with cardiorespiratory phenotypes were tested during cycling exercise at absolute and relative power outputs progressing to exhaustion before and after endurance training for 20 wk in the HERITAGE Family Study cohort (n = 779). Since no blacks were mutant homozygotes (TT), only whites were considered for analysis (400 normal homozygotes, CC; 97 heterozygotes, CT; and 6 TT). For sedentary state, cycling at the absolute power output of 50 W resulted in a higher rating of perceived exertion in TT (P < 0.0001). At the relative intensity of 60% of Vo(2 max), stroke volume was lower in TT (P < 0.05). Maximal values for power output, systolic blood pressure, heart rate, Vco(2), and respiratory exchange ratio were lower in TT (P < 0.05). The cardiorespiratory training response at 50 W and at 60% of Vo(2 max) was similar across C34T-AMPD1 genotypes. However, the maximal values for ventilation, Vo(2), and Vco(2) during exercise increased less in TT (P < 0.01). The results indicate that subjects with the TT genotype at the C34T AMPD1 gene have diminished exercise capacity and cardiorespiratory responses to exercise in the sedentary state. Furthermore, the training response of ventilatory phenotypes during maximal exercise is more limited in TT.


Interaction of YOYO-1 with guanine-rich DNA.
The oxazole homodimer YOYO-1 has served as a valuable tool for the detection and quantification of nucleic acids. While the base specificity and selectivity of binding of YOYO-1 has been researched to some extent, the effect of unorthodox nucleic acid conformations on dye binding has received relatively less attention. In this work, we attempt to correlate the quadruplex-forming ability of G-rich sequences with binding of YOYO-1. Oligonucleotides differing in the number of tandem G repeats, total length, and length of loop sequence were evaluated for their ability to form quadruplexes in presence of sodium (Na(+)) or potassium (K(+)) ions. The fluorescence behavior of YOYO-1 upon binding such G-rich sequences was also ascertained. A distinct correlation was observed between the strength and propensity of quadruplex formation, and the affinity of YOYO-1 to bind such sequences. Specifically, as exemplified by the oligonucleotides 5'-G4T2G4-3' and 5'-G3TG3TG3-3', sequences possessing longer G-rich regions and shorter loop sequences formed stronger quadruplexes in presence of K(+) which translated to weaker binding of YOYO-1. The dependence of binding of YOYO-1 on sequence and structural features of G-rich DNA has not been explored previously and such studies are expected to aid in more effective interpretation of applications involving the fluorophore.


Dual negative control of spx transcription initiation from the P3 promoter by repressors PerR and YodB in Bacillus subtilis.
The spx gene encodes an RNA polymerase-binding protein that exerts negative and positive transcriptional control in response to oxidative stress in Bacillus subtilis. It resides in the yjbC-spx operon and is transcribed from at least five promoters located in the yjbC regulatory region or in the yjbC-spx intergenic region. Induction of spx transcription in response to treatment with the thiol-specific oxidant diamide is the result of transcription initiation at the P(3) promoter located upstream of the spx coding sequence. Previous studies conducted elsewhere and analyses of transcription factor mutants using transformation array technology have uncovered two transcriptional repressors, PerR and YodB, that target the cis-acting negative control elements of the P(3) promoter. Expression of an spx-bgaB fusion carrying the P(3) promoter is elevated in a yodB or perR mutant, and an additive increase in expression was observed in a yodB perR double mutant. Primer extension analysis of spx RNA shows the same additive increase in P(3) transcript levels in yodB perR mutant cells. Purified YodB and PerR repress spx transcription in vitro when wild-type spx P(3) promoter DNA was used as a template. Point mutations at positions within the P(3) promoter relieved YodB-dependent repression, while a point mutation at position +24 reduced PerR repression. DNase I footprinting analysis showed that YodB protects a region that includes the P(3) -10 and -35 regions, while PerR binds to a region downstream of the P(3) transcriptional start site. The binding of both repressors is impaired by the treatment of footprinting reactions with diamide or hydrogen peroxide. The study has uncovered a mechanism of dual negative control that relates to the oxidative stress response of gram-positive bacteria.


NMR spectroscopy in bioinorganic chemistry.
Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function and structure of large biomolecules. Specifically, NMR is used i) to investigate how metal ions bind to nucleic acids and thereby control the folding and structure of RNAs, ii) to characterize how metal ions are able to stabilize modified nucleic acids to be used as potential nanowires, and iii) to characterize the formation, structure, and role of the diverse metal clusters within plant metallothioneins. In this review we summarize the various NMR experiments applied and the information obtained, demonstrating the important and fascinating part NMR spectroscopy plays in the field of bioinorganic chemistry.


Recent advances in posterior meniscal root repair techniques.
Posterior root avulsions of the medial and lateral menisci result in decreased areas of tibiofemoral contact and increased tibiofemoral contact pressures. These avulsions may lead to the development of osteoarthritis. Therefore, two surgical techniques, the transtibial pullout repair and the suture anchor repair, have recently been developed to restore the native structure and function of the meniscal root attachment. Compared with the historical alternative of partial or total meniscectomy, these techniques allow for meniscal preservation and anatomic reduction of the meniscal roots, with the goal of preventing the development and progression of osteoarthritis. However, early biomechanical and clinical studies have reported conflicting results on the effectiveness of both techniques with regard to resisting displacement and facilitating healing. Although there is currently a lack of consensus on which is the superior technique, transtibial pullout and suture anchor repairs are increasingly used in clinical practice.