Impaired visual object processing across an occipital-frontal-hippocampal brain network in schizophrenia: an integrated neuroimaging study.
Perceptual closure is the ability to identify objects based on partial information and depends on the function of a distributed network of brain regions that include the dorsal and the ventral visual streams, prefrontal cortex (PFC), and hippocampus. To evaluate network-level interactions during perceptual closure in schizophrenia using parallel event-related potential (ERP), functional magnetic resonance imaging (fMRI), and neuropsychological assessment. Case-control study. Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. Patients Twenty-seven patients with schizophrenia or schizoaffective disorder and 23 healthy controls. Intervention Event-related potentials were obtained from 24 patients and 20 healthy volunteers in response to fragmented (closeable) and control-scrambled (noncloseable) line drawings. Functional MRI was performed in 11 patients and 12 controls. Main Outcome Measure Patterns of between-group differences for predefined ERP components and fMRI regions of interest were determined using both analysis of variance and structural equation modeling. Global neuropsychological performance was assessed using standard neuropsychological batteries. Patients showed impaired generation of event-related components reflecting early sensory and later closure-related activity. In fMRI, patients showed impaired activation of the dorsal and ventral visual regions, PFC, and hippocampus. Impaired activation of dorsal stream visual regions contributed significantly to impaired PFC activation, which contributed significantly to impaired activation of the hippocampus and ventral visual stream. Impaired ventral stream and hippocampal activation contributed significantly to deficits on neuropsychological measures of perceptual organization. Schizophrenia is associated with severe activation deficits across a distributed network of sensory and higher order cognitive regions. Deficit in early visual processing within the dorsal visual stream contributes significantly to impaired frontal activation, which, in turn, leads to dysregulation of the hippocampus and ventral visual stream. Dysfunction within this network underlies deficits in more traditional neurocognitive measures, supporting distributed models of brain dysfunction in schizophrenia.


Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.
D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. clinicaltrials.gov Identifier: NCT01134068.


Point-of-care prognosis for common musculoskeletal pain in older adults.
Many site-specific, multivariable risk models for predicting the outcome of musculoskeletal pain problems have been published. The overlapping content in these models suggests a common set of generic indicators suitable for use in primary care. To investigate whether a brief set of generic prognostic indicators can predict the outcome of musculoskeletal pain in older patients presenting to general practitioners. A prospective observational cohort study conducted from September 1, 2006, through March 31, 2007, of consecutive patients 50 years or older presenting with noninflammatory musculoskeletal pain to 1 of the 5 participating general practices in the United Kingdom. During consultation, the treating physician assessed and recorded 5 brief generic items (duration of present pain episode, current pain intensity, pain interference with daily activities, presence of multiple-site pain, and ultrashort depression screen) and recorded their overall prognostic judgment. The primary outcome was patient-rated improvement, which was measured 6 months after consultation and cross-validated with repeated measures up to 3 years. A total of 194 (48.1%) of 403 participants were classified as having an unfavorable outcome at 6 months. Inclusion of 3 generic prognostic indicators (duration of present pain episode, pain interference with daily activities, and presence of multiple-site pain) in the prognostic model improved on reliance on physicians' prognostic judgment alone (C statistic = 0.72 vs 0.62; net reclassification index = 0.136; proportion correctly classified = 69%). The improvement in prognostic accuracy was attributable to correcting physicians' tendency toward overoptimistic expectations of outcome. Three easy-to-obtain pieces of information followed by systematic recording of the general practitioners' prognostic judgment provide a simple generic assessment of prognosis at point of care in older persons presenting with musculoskeletal problems to primary care practices in the United Kingdom. Such an assessment offers a common foundation for investigating the usefulness of prognostic stratification for guiding management in the consultation across a range of common painful conditions.


Phase separation of TPX2 enhances and spatially coordinates microtubule nucleation.
Phase separation of substrates and effectors is proposed to enhance biological reaction rates and efficiency. Targeting protein for Xklp2 (TPX2) is an effector of branching microtubule nucleation in spindles and functions with the substrate tubulin by an unknown mechanism. Here we show that TPX2 phase separates into a co-condensate with tubulin, which mediates microtubule nucleation in vitro and in isolated cytosol. TPX2-tubulin co-condensation preferentially occurs on pre-existing microtubules, the site of branching microtubule nucleation, at the endogenous and physiologically relevant concentration of TPX2. Truncation and chimera versions of TPX2 suggest that TPX2-tubulin co-condensation enhances the efficiency of TPX2-mediated branching microtubule nucleation. Finally, the known inhibitor of TPX2, the importin-α/β heterodimer, regulates TPX2 condensation in vitro and, consequently, branching microtubule nucleation activity in isolated cytosol. Our study demonstrates how regulated phase separation can simultaneously enhance reaction efficiency and spatially coordinate microtubule nucleation, which may facilitate rapid and accurate spindle formation.


Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells.
Here, we show that bacteria induce de novo synthesis of both major histocompatability complex (MHC) class I and II molecules in a mouse dendritic cell culture system. The neo-biosynthesis of MHC class I molecules is delayed as compared with that of MHC class II. Furthermore, bacteria stabilize MHC class I molecules by a 3-fold increase of their half-life. This has important consequences for the capacity of dendritic cells to present bacterial antigens in the draining lymph nodes. In addition, a model antigen, ovalbumin, expressed on the surface of recombinant Streptococcus gordonii is processed and presented on MHC class I molecules. This presentation is 10(6) times more efficient than that of soluble OVA protein. This exogenous pathway of MHC class I presentation is transporter associated with antigen processing (TAP)-dependent, indicating that there is a transport from phagolysosome to cytosol in dendritic cells. Thus, bacteria are shown to be a potentially useful mean for the correct delivery of exogenous antigens to be presented efficiently on MHC class I molecules.


Causes and management of hyponatremia.
To review clinical information on the incidence and causes of hyponatremia (defined as a serum sodium level <130 mEq/L), the most common electrolyte abnormality seen in general hospital patients, and to discuss the diagnosis and treatment of hyponatremia in relation to these factors. Primary sources and review articles were identified via MEDLINE (1981-July 2003) for entries on hyponatremia. We limited the search to specific topics including incidence, risk factors, diagnosis, treatment, and clinical disorders and medications associated with hypotonic hyponatremia. All of the articles identified were evaluated, and relevant and representative information was included in this review. Hyponatremia can result from several disease states, injury, surgery, physical exercise, or the administration of certain drugs (e.g., antidepressants, antiepileptics) and is associated with advanced age. Drug-induced hyponatremia is often asymptomatic and usually resolves following water restriction and monitoring of medication. Symptoms of hyponatremia are primarily neurologic; the principal danger of hyponatremia relates to effects on central nervous system function due to changes in brain size. Although hyponatremia can be a serious condition, appropriate measures for the management of at-risk and affected patients will lead to full recovery in most cases.


Highly selective and rapidly activatable fluorogenic Thrombin sensors and application in human lung tissue.
A library of FRET-based peptides were prepared and studied as Thrombin substrates. This identified probes that showed selective activation by Thrombin, low fluorescent background signals, stability to Factor Xa, matrix metalloproteases, and primary human inflammatory cell lysates and supernatant. These were selected for further optimization, creating a second generation of fluorogenic probes with improved solubility and Plasmin resistance. The optimised probe allowed the detection of Thrombin activity in ex vivo fibrotic human tissue.


Multisystem outcomes and predictors of mortality in critically ill patients with COVID-19: Demographics and disease acuity matter more than comorbidities or treatment modalities.
We sought to describe characteristics, multisystem outcomes, and predictors of mortality of the critically ill COVID-19 patients in the largest hospital in Massachusetts. This is a prospective cohort study. All patients admitted to the intensive care unit (ICU) with reverse-transcriptase-polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 14, 2020, and April 28, 2020, were included; hospital and multisystem outcomes were evaluated. Data were collected from electronic records. Acute respiratory distress syndrome (ARDS) was defined as PaO2/FiO2 ratio of ≤300 during admission and bilateral radiographic pulmonary opacities. Multivariable logistic regression analyses adjusting for available confounders were performed to identify predictors of mortality. A total of 235 patients were included. The median (interquartile range [IQR]) Sequential Organ Failure Assessment score was 5 (3-8), and the median (IQR) PaO2/FiO2 was 208 (146-300) with 86.4% of patients meeting criteria for ARDS. The median (IQR) follow-up was 92 (86-99) days, and the median ICU length of stay was 16 (8-25) days; 62.1% of patients were proned, 49.8% required neuromuscular blockade, and 3.4% required extracorporeal membrane oxygenation. The most common complications were shock (88.9%), acute kidney injury (AKI) (69.8%), secondary bacterial pneumonia (70.6%), and pressure ulcers (51.1%). As of July 8, 2020, 175 patients (74.5%) were discharged alive (61.7% to skilled nursing or rehabilitation facility), 58 (24.7%) died in the hospital, and only 2 patients were still hospitalized, but out of the ICU. Age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.04-1.12), higher median Sequential Organ Failure Assessment score at ICU admission (OR, 1.24; 95% CI, 1.06-1.43), elevated creatine kinase of ≥1,000 U/L at hospital admission (OR, 6.64; 95% CI, 1.51-29.17), and severe ARDS (OR, 5.24; 95% CI, 1.18-23.29) independently predicted hospital mortality.Comorbidities, steroids, and hydroxychloroquine treatment did not predict mortality. We present here the outcomes of critically ill patients with COVID-19. Age, acuity of disease, and severe ARDS predicted mortality rather than comorbidities. Prognostic, level III.


Potentials of mean force for protein structure prediction vindicated, formalized and generalized.
Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge-based potentials based on pairwise distances--so-called "potentials of mean force" (PMFs)--have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state--a necessary component of these potentials--is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities "reference ratio distributions" deriving from the application of the "reference ratio method." This new view is not only of theoretical relevance but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures.


Weight-related concerns and diet behaviors among urban young females: A cross-sectional study.
Females are more likely than males to perceive themselves as too heavy, this has been explained in terms of the equation of "female beauty with extreme thinness." Therefore, females are in general prone to develop unhealthy behaviors for weight management. Wrong weight control behaviors have significant health consequences. To investigate the body weight concerns, body satisfaction, and weight control behaviors among young females and their association with age and socioeconomic status (SES). A cross-sectional study conducted in urban areas from a major city in South India. About 650 healthy unmarried females aged 15-25 years formed the study population. Self-reporting questionnaires were used to obtain relevant data. The categorical data were analyzed using Chi-square, correlation, and regression analyses by SPSS version 16. Most overweight and obese subjects perceived themselves as overweight. Adolescents were more likely to report themselves as overweight. The perceived weight, body satisfaction, and weight control behaviors are influenced by weight status and age of the subjects. However, SES of the participants did not exhibit effect of others' opinion about their weight and body satisfaction as well as weight management behaviors. The high prevalence of weight-related concerns suggests that all females should be reached with appropriate information and interventions. Healthy weight control practices need to be explicitly promoted and unhealthy practices discouraged. Young females need special attention toward weight management.


Electromagnetic force and torque in ponderable media.
Maxwell's macroscopic equations combined with a generalized form of the Lorentz law of force are a complete and consistent set of equations. Not only are these five equations fully compatible with special relativity, they also conform with conservation laws of energy, momentum, and angular momentum. We demonstrate consistency with the conservation laws by showing that, when a beam of light enters a magnetic dielectric, a fraction of the incident linear (or angular) momentum pours into the medium at a rate determined by the Abraham momentum density, E x H/c(2), and the group velocity V(g) of the electromagnetic field. The balance of the incident, reflected, and transmitted momenta is subsequently transferred to the medium as force (or torque) at the leading edge of the beam, which propagates through the medium with velocity V(g). Our analysis does not require "hidden" momenta to comply with the conservation laws, nor does it dissolve into ambiguities with regard to the nature of electromagnetic momentum in ponderable media. The linear and angular momenta of the electromagnetic field are clearly associated with the Abraham momentum, and the phase and group refractive indices (n(p) and n(g)) play distinct yet definitive roles in the expressions of force, torque, and momentum densities.


Estimating the burden of the COVID-19 pandemic on mortality, life expectancy and lifespan inequality in England and Wales: a population-level analysis.
Deaths directly linked to COVID-19 infection may be misclassified, and the pandemic may have indirectly affected other causes of death. To overcome these measurement challenges, we estimate the impact of the COVID-19 pandemic on mortality, life expectancy and lifespan inequality from week 10 of 2020, when the first COVID-19 death was registered, to week 47 ending 20 November 2020 in England and Wales through an analysis of excess mortality. We estimated age and sex-specific excess mortality risk and deaths above a baseline adjusted for seasonality with a systematic comparison of four different models using data from the Office for National Statistics. We additionally provide estimates of life expectancy at birth and lifespan inequality defined as the SD in age at death. There have been 57 419 (95% prediction interval: 54 197, 60 752) excess deaths in the first 47 weeks of 2020, 55% of which occurred in men. Excess deaths increased sharply with age and men experienced elevated risks of death in all age groups. Life expectancy at birth dropped 0.9 and 1.2 years for women and men relative to the 2019 levels, respectively. Lifespan inequality also fell over the same period by 5 months for both sexes. Quantifying excess deaths and their impact on life expectancy at birth provide a more comprehensive picture of the burden of COVID-19 on mortality. Whether mortality will return to-or even fall below-the baseline level remains to be seen as the pandemic continues to unfold and diverse interventions are put in place.


Effects of Damnacanthal and Nordamnacanthal on Proliferation, Apoptosis, and Migration of Oral Squamous Cell Carcinoma Cells
Cancer is one of the most common causes of death in the developed world, with one-third of people diagnosed with cancer during their lifetime. Oral cancer commonly occurs involving the buccal mucosa (cheeks), tongue, floor of the mouth and lip. It is one of the most devastating and disfiguring of malignancies. Morinda citrifolia L., commonly known as 'noni', belongs to the Rubiaceae family. It is native to the Pacific islands, Hawaii, Caribbean, Asia and Australia. The plant displays broad curative effects in pharmacological studies. Damnacanthal (DAM) and Nordamnacanthal (NDAM), anthraquinone compounds isolated from the roots of Morinda citrifolia L., has been used for the treatment of several chronic diseases including cancer. The objectives of this study were to evaluate cytotoxicity, morphological changes, cell death mode (apoptosis/necrosis), and cell migration induced by DAM and NDAM on the most common type of oral cancer, oral squamous cell carcinoma (OSCC)cells. Anti-proliferative effects of these compounds against OSCC cell lines were determined by MTT assay. The mode of cell death was analysed by phase contrast and fluorescent microscopy as well as flow cytometry. In addition, cell migration was assessed. The results showed that DAM and NDAM exerted cytotoxicity against OSCC cells with IC50 values of 1.9 to >30 μg/ml after 72 h treatment. Maximum growth inhibition among the tested cell lines for both compounds was observed in H400 cells, and thus it was selected for further study. The study demonstrated inhibition of H400 OSCC cell proliferation, marked apoptotic morphological changes, induction of early apoptosis, and inhibition of cell migration by DAM and NDAM. Therefore, this information suggests that these compounds from noni have potential for used as anti tumor agents for oral cancer therapy.


Less than Expected? How Media Cover Demonstration Turnout.
Demonstration turnout is a crucial political resource for social movements. In this article, we investigate how mass media cover demonstration size. We develop a typology of turnout coverage and scrutinize the factors that drive turnout coverage. In addition, we test whether media coverage underestimates, reflects, or exaggerates "guesstimates" by organizers and police forces. Together, these analyses shed light on whether turnout coverage fits a logic of normalization or marginalization. We rely on a unique dataset of 428 demonstrations organized in Brussels (2003-2010). For these demonstrations, we have information on the turnout as reported in national television news, as counted by the police, and as expected by the organizers. We find that media present turnout most often as a fact, rarely as contentious (10 percent). Although few demonstrations pass the media gates, our study yields little to no evidence for a logic of turnout marginalization. Media coverage does not systematically underestimate demonstration size, nor does it blindly follow police counts. Rather, turnout coverage attests of a logic of normalization, following standard news-making practices. The more important the demonstration (size, lead item) and the larger the gap between police and organizer guesstimates, the more attention is paid to turnout in the news. Discussion centers on the generalizability and normative interpretation of the results.


Area variation in recreational cycling in Melbourne: a compositional or contextual effect?
To examine whether compositional and/or contextual area characteristics are associated with area socioeconomic inequalities and between-area differences in recreational cycling. The city of Melbourne, Australia. 2349 men and women residing in 50 areas (58.7% response rate). Cycling for recreational purposes (at least once a month vs never). In a cross-sectional survey participants reported their frequency of recreational cycling. Objective area characteristics were collected for their residential area by environmental audits or calculated with Geographic Information Systems software. Multilevel logistic regression models were performed to examine associations between recreational cycling, area socioeconomic level, compositional characteristics (age, sex, education, occupation) and area characteristics (design, safety, destinations or aesthetics). After adjustment for compositional characteristics, residents of deprived areas were less likely to cycle for recreation (OR 0.66; 95% CI 0.43 to 1.00), and significant between-area differences in recreational cycling were found (median odds ratio 1.48 (95% credibility interval 1.24 to 1.78). Aesthetic characteristics tended to be worse in deprived areas and were the only group of area characteristics that explained some of the area deprivation differences. Safety characteristics explained the largest proportion of between-area variation in recreational cycling. Creating supportive environments with respect to safety and aesthetic area characteristics may decrease between-area differences and area deprivation inequalities in recreational cycling, respectively.


New therapeutic targets for the treatment of high-risk neuroblastoma.
High-risk neuroblastoma remains a major problem in pediatric oncology, accounting for 15% of childhood cancer deaths. Although incremental improvements in outcome have been achieved with the intensification of conventional chemotherapy agents and the addition of 13-cis-retinoic acid, only one-third of children with high-risk disease are expected to be long-term survivors when treated with current regimens. In addition, the cost of cure can be quite high, as surviving children remain at risk for additional health problems related to long-term toxicities of treatment. Further advances in therapy will require the targeting of tumor cells in a more selective and efficient way so that survival can be improved without substantially increasing toxicity. In this review we summarize ongoing clinical trials and highlight new developments in our understanding of the molecular biology of neuroblastoma, emphasizing potential targets or pathways that may be exploitable therapeutically.


Early identification of patients at risk for acute respiratory distress syndrome among severe pneumonia: a retrospective cohort study.
Severe pneumonia is the predominant cause for acute respiratory distress syndrome (ARDS). Identification of ARDS from patients with severe pneumonia remains a significant clinical problem due to the overlap of clinical presentations and symptoms. Early recognition of risks for ARDS from severe pneumonia is of great clinical value. From April 2014 to December 2015, patients with severe pneumonia at admission were retrieved from the hospital database, of which ARDS developed within 7 days were further identified. We compared the demographic and clinical characteristics at admission between severe pneumonia patients with and without ARDS development, followed by analysis of potential predictors for ARDS development and mortality. Multivariate logistic regression and receiver operating characteristic (ROC) curves were performed to screen independent risk factors and identify their sensitivity in predicting ARDS development and prognosis. Compared with severe pneumonia without ARDS development, patients with ARDS development had shorter disease duration before admission, higher lung injury score (LIS), serum fibrinogen (FiB), and positive end-expiratory pressure (PEEP), lower Marshall score, sequential organ failure assessment score and proportion of cardiovascular and gastrointestinal diseases, but similar mortality. Serum FiB >5.15 g/L [adjusted odds ratio (OR) 1.893, 95% confidence interval (CI): 1.141-3.142, P=0.014] and PEEP >6.5 cmH2O (adjusted OR 1.651, 95% CI: 1.218-2.237, P=0.001) were independent predictors for ARDS development with a sensitivity of 58.3% and 87.5%, respectively, and pH <7.35 (adjusted OR 0.832, 95% CI: 0.702-0.985, P=0.033) was an independent risk factor for ARDS mortality with a sensitivity of 95.2%. ARDS development risk could be early recognized by PEEP >6.5 cmH2O and serum FiB >5.15 g/L in severe pneumonia patients, and pH <7.35 is a reliable prognostic factor in predicting ARDS mortality risk.


Amino-terminal extension generated from an upstream AUG codon is not required for mitochondrial import of yeast N2,N2-dimethylguanosine-specific tRNA methyltransferase.
The TRM1 gene of Saccharomyces cerevisiae is necessary for the N2,N2-dimethylguanosine modification of both mitochondrial and cytoplasmic tRNAs. The DNA sequence of the TRM1 locus and the 5' ends of mRNAs expressed from this gene have been determined. The majority of the 5' ends map within a large open reading frame between two in-frame ATGs at positions +1 and +49. A small fraction of the 5' ends are located upstream of the first ATG. Both AUGs of the TRM1 mRNAs are used to initiate translation, and two forms of N2,N2-dimethylguanosine-specific tRNA methyltransferase, which differ by an amino-terminal extension of 16 amino acids, are made. Mitochondrial tRNAs are modified when the initiation of translation is limited to one or the other of the AUGs, suggesting that the amino-terminal extension is not necessary for import of the protein into mitochondria. Mitochondrial targeting information must, therefore, be located in a region of N2,N2-dimethylguanosine-specific tRNA methyltransferase that is found in both forms of the enzyme.


Alcohol consumption and risk of ductal carcinoma in situ of the breast in a cohort of postmenopausal women.
Observational studies have commonly linked higher alcohol consumption with a modest increase in invasive breast cancer risk, but cohort studies have not examined alcohol intake in relation to ductal carcinoma in situ (DCIS). The association between adulthood alcohol consumption assessed at baseline and subsequent DCIS risk was examined in a cohort of postmenopausal women participating in the Women's Health Initiative clinical trials, in which mammography was protocol-mandated. Alcohol intake was assessed by a semiquantitative food-frequency questionnaire. Reported DCIS cases were verified by central pathology report review. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. The cohort consisted of 63,822 women with information on alcohol intake, among whom 489 cases of DCIS were ascertained after a median follow-up of 8.0 years. For the primary analysis, invasive breast cancer was treated as a competing risk, and follow-up time was censored at the date of diagnosis of invasive breast cancer. After adjustment for covariates, the hazard ratio for DCIS among women who consumed 14 or more servings of alcohol per week, relative to nondrinkers, was 0.87 (95% confidence interval, 0.50-1.51). In addition, alcohol intake was not associated with risk of either high-grade or low-/moderate-grade DCIS. In this large cohort study of postmenopausal women, alcohol consumption was not associated with risk of DCIS. If other studies confirm our findings, this would suggest that alcohol may have an effect later in the carcinogenic process.


Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice.
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.


A specifically apical sub-membrane intermediate filament cytoskeleton in non-brush-border epithelial cells.
Although many pieces of evidence support the notion of a role for the cytoskeleton in epithelial polarization, no cytoskeletal component has been found to be specifically apical, except for some actin-binding proteins. Here we report the apical distribution of a 53 kDa cytokeratin. Furthermore, this cytokeratin co-purified with biotinylated apical plasma membrane proteins in high density complexes. Differential biotinylation of the basolateral domain showed that the 53 kDa protein is mainly attached to the apical membrane, although a companion 58 kDa protein attaches to both apical and basolateral membrane proteins. Immunoprecipitation experiments indicated that a number of apical components are directly or indirectly linked to the 53 kDa protein. These results indicate the existence of a terminal web-like structure in non-brush-border cells, which attaches to the apical domain and may play a role in apical polarization, especially during the acquisition of polarity from non-polarized cellular stages.


Urinary prostaglandin E2 metabolite and gastric cancer risk in the Shanghai women's health study.
Chronic inflammation has been implicated in the etiology of gastric cancer. Prostaglandin E(2) (PGE(2)) is one of the major end-products of the cyclooxygenase-2 pathway, an enzyme that is an important mediator of inflammation. Using a novel method of quantifying the primary urinary metabolite of PGE(2) (PGE-M; 11alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranorprostane-1,20-dioic acid), we evaluated urinary PGE-M concentrations in association with subsequent risk of development of gastric cancer in the Shanghai Women's Health Study, a large population-based prospective cohort, using a nested case-control study design. Controls were matched (1:1) to 153 gastric cancer cases by menopausal status; age, time, and date of sample collection; time interval since last meal; and availability of urine sample. Odds ratios (95% confidence intervals) were calculated using conditional logistic regression adjusted for potential confounders. Baseline urinary PGE-M levels were slightly higher among gastric cancer cases with a median of 6.4 ng/mg creatinine (interquartile range, 3.4-11.2) compared with 5.4 ng/mg creatinine among controls (interquartile range, 2.8-9.0), but this difference was not statistically significant (P = 0.34, Wilcoxon). With increasing quartiles of urinary PGE-M levels, the odds ratios (95% confidence intervals) for risk of gastric cancer increased in quartiles 2 to 4: 1.00 (0.48-2.08), 1.40 (0.67-2.91), and 1.98 (0.95-4.13), with a statistically significant test for trend (P = 0.04). The association persisted after additional adjustment for Helicobacter pylori status and was slightly strengthened among non-nonsteroidal anti-inflammatory drug users, subjects with positive H. pylori status, and for cases diagnosed within 46 months after study enrollment. Our findings suggest that higher levels of urinary PGE-M, a marker of inflammation, may be associated with gastric cancer risk.


Deeper below the surface-transcriptional changes in selected genes of Clostridium beijerinckii in response to butanol shock.
The main bottleneck in the return of industrial butanol production from renewable feedstock through acetone-butanol-ethanol (ABE) fermentation by clostridia, such as Clostridium beijerinckii, is the low final butanol concentration. The problem is caused by the high toxicity of butanol to the production cells, and therefore, understanding the mechanisms by which clostridia react to butanol shock is of key importance. Detailed analyses of transcriptome data that were obtained after butanol shock and their comparison with data from standard ABE fermentation have resulted in new findings, while confirmed expected population responses. Although butanol shock resulted in upregulation of heat shock protein genes, their regulation is different than was assumed based on standard ABE fermentation transcriptome data. While glucose uptake, glycolysis, and acidogenesis genes were downregulated after butanol shock, solventogenesis genes were upregulated. Cyclopropanation of fatty acids and formation of plasmalogens seem to be significant processes involved in cell membrane stabilization in the presence of butanol. Surprisingly, one of the three identified Agr quorum-sensing system genes was upregulated. Upregulation of several putative butanol efflux pumps was described after butanol addition and a large putative polyketide gene cluster was found, the transcription of which seemed to depend on the concentration of butanol.


Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.
Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.


"I Was Facilitating Everybody Else's Life. And Mine Had Just Ground to a Halt": The COVID-19 Pandemic and its Impact on Women in the United Kingdom.
A growing body of research has highlighted the disproportionately negative impact of the COVID-19 pandemic on women globally. This article contributes to this work by interrogating the lived realities of sixty-four women in the United Kingdom through semi-structured in-depth interviews, undertaken during the first and second periods of lockdown associated with COVID-19 in 2020. Categorizing the data by subgroup of women and then by theme, this article explores the normative and policy-imposed constraints experienced by women in 2020 with regard to paid and unpaid labor, mental health, access to healthcare services, and government representation and consideration of women. These findings highlight women's varied and gendered experiences of the COVID-19 pandemic and emphasizes the role that government can proactively play in attending to gender inequalities throughout its COVID-19 response.


Expression of p53 protein in rheumatoid arthritis synovium. An immunohistochemical analysis.
Mutation of p53 may play a role in manifestation of rheumatoid arthritis synovium, but several studies on p53 expression in synovial tissues of rheumatoid arthritis showed conflicting results. We investigated the amount and pattern of p53 positive cells in rheumatoid arthritis synovium, in comparison with osteoarthritis synovium, by using immunohistochemistry with two other monoclonal antibodies for p53. Synovial tissues from 9 patients with rheumatoid arthritis and 5 patients with osteoarthritis were examined for p53 expression by immunohistochemistry with 2 monoclonal antibodies for p53, DO-1 and DO-7. Histologic features of inflammation were also scored and compared with p53 expression. There was no significant difference between inflammatory scores in both groups. In the synovial tissues of rheumatoid arthritis patients, p53 positive cells were detected in 3 out of 9 samples(33%) and p53 expressions were restricted to inflammatory mononuclear cells, but synovial lining cells, subsynovial fibroblast-like cells and vascular endothelial cells were p53 negative. p53 expressions in osteoarthritis synovial tissues as control were observed in 2 out of 5 samples(40%) and the amount and pattern of p53 positive cells were comparable to those seen in rheumatoid arthritis synovial tissues. There was no demonstrable correlation between the synovial tissues of both groups with respect to inflammation scores and expression of p53 protein. Our findings suggest that altered p53 expression may not play a significant role in the manifestation of rheumatoid arthritis synovium. However these data need to be strengthened by increasing the number of samples and molecular biology approaches.


Intimate partner violence among rural South African men: alcohol use, sexual decision-making, and partner communication.
Nearly one-third of South African men report enacting intimate partner violence. Beyond the direct health consequences for women, intimate partner violence is also linked to varied risk behaviours among men who enact it, including alcohol abuse, risky sex, and poor healthcare uptake. Little is known about how to reduce violence perpetration among men. We conducted retrospective, in-depth interviews with men (n = 53) who participated in a rural South African programme that targeted masculinities, HIV risk, and intimate partner violence. We conducted computer-assisted thematic qualitative coding alongside a simple rubric to understand how the programme may lead to changes in men's use of intimate partner violence. Many men described new patterns of reduced alcohol intake and improved partner communication, allowing them to respond in ways that did not lead to the escalation of violence. Sexual decision-making changed via reduced sexual entitlement and increased mutuality about whether to have sex. Men articulated the intertwined nature of each of these topics, suggesting that a syndemic lens may be useful for understanding intimate partner violence. These data suggest that alcohol and sexual relationship skills may be useful levers for future violence prevention efforts, and that intimate partner violence may be a tractable issue as men learn new skills for enacting masculinities in their household and in intimate relationships.


Response feedback triggers long-term consolidation of perceptual learning independently of performance gains.
Visual perceptual learning (VPL) is defined as a long-term performance enhancement on a visual task, and is typically thought of as a manifestation of plasticity in visual processing. It is thought that neural representations relevant to a recently learned task are consolidated over the course of hours or days and made robust against the effects of deterioration and interference. However, recent work has shown that when these representations are reactivated by further task exposure, they become plastic again and are vulnerable to deterioration effects. Here we used a perceptual learning paradigm in combination with performance feedback (knowledge of task accuracy provided to the observer in real-time) to investigate behavioral factors that influence consolidation. Subjects were trained to detect two coherent motion directions embedded in noise over several days. It was found that without feedback, performance improvements accrued during training rapidly deteriorated upon exposure to novel, neighboring motion directions. However, when one of the two directions was consistently paired with feedback during training, the paired direction was resilient against the effects of deterioration. This benefit coincides with a gradual inhibition of learning for the unpaired stimuli. Furthermore, this stabilizing effect operates independently of the magnitude of performance gains during training and suggests a useful behavioral marker for the study of consolidation processes.


Application of spray freeze drying to theophylline-oxalic acid cocrystal engineering for inhaled dry powder technology.
Spray freeze drying (SFD) produces suitable particles for the pharmaceutical formulation of dry powders used in dry powder inhalers (DPIs). However, SFD particles have large specific surface area and are partially made up of amorphous solids; this state is hygroscopic and would lead to changes in physicochemical properties by humidity when the particles are stored over the long-term or under high humidity conditions such as in the lungs. This study focused on the application of SFD with a cocrystal technique which can add humidity resistance to the active pharmaceutical ingredients (APIs), and the investigation of the physicochemical properties under high humidity conditions. Cocrystal samples containing theophylline anhydrate (THA) and oxalic acid (OXA) in a molar ratio of 2:1 were prepared by SFD. The crystalline structure, thermal behavior, solid-state, hygroscopicity, stability, and aerodynamic properties were evaluated. Simultaneous in situ measurement by near-infrared and Raman (NIR-Raman) spectroscopy was performed to analyze the humidification process. The SFD sample had a porous particle and an optimal aerodynamic particle size (3.03 µm) although the geometric particle diameter was 7.20 µm. In addition, the sample formed the THAOXA cocrystal with partial coamorphous. The hydration capacity and pseudopolymorphic transformation rate of the SFD sample were much lower than those of THA under conditions of 96.4% relative humidity and 40.0°C temperature because of the cocrystal formation. The reasons were discussed based on the crystalline structure and energy. The SFD technology for cocrystallization would enable the pharmaceutical preparation of DPI products under environmentally friendly conditions.


Are the small human-like fossils found on Flores human endemic cretins?
Fossils from Liang Bua (LB) on Flores, Indonesia, including a nearly complete skeleton (LB1) dated to 18kyr BP, were assigned to a new species, Homo floresiensis. We hypothesize that these individuals are myxoedematous endemic (ME) cretins, part of an inland population of (mostly unaffected) Homo sapiens. ME cretins are born without a functioning thyroid; their congenital hypothyroidism leads to severe dwarfism and reduced brain size, but less severe mental retardation and motor disability than neurological endemic cretins. We show that the fossils display many signs of congenital hypothyroidism, including enlarged pituitary fossa, and that distinctive primitive features of LB1 such as the double rooted lower premolar and the primitive wrist morphology are consistent with the hypothesis. We find that the null hypothesis (that LB1 is not a cretin) is rejected by the pituitary fossa size of LB1, and by multivariate analyses of cranial measures. We show that critical environmental factors were potentially present on Flores, how remains of cretins but not of unaffected individuals could be preserved in caves, and that extant oral traditions may provide a record of cretinism.


Lung hyperinflation and functional exercise capacity in patients with COPD - a three-year longitudinal study.
Lung hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of lung hyperinflation and is associated with exercise intolerance. However, knowledge of its effect on longitudinal change in the 6-min walk distance (6MWD) in patients with COPD is scarce. We aimed to study whether the IC/TLC ratio predicts longitudinal change in 6MWD in patients with COPD. This prospective cohort study included 389 patients aged 40-75 years with clinically stable COPD in Global Initiative for Chronic Obstructive Lung Disease stages II-IV. The 6MWD was measured at baseline, and after one and 3 years. We performed generalized estimating equation regression analyses to examine predictors for longitudinal change in 6MWD. Predictors at baseline were: IC/TLC ratio, age, gender, pack years, fat mass index (FMI), fat-free mass index (FFMI), number of exacerbations within 12 months prior to inclusion, Charlson index for comorbidities, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and light and hard self-reported physical activity. Reduced IC/TLC ratio (p < 0.001) was a statistically significant predictor for decline in 6MWD. With a 0.1-unit decrease in baseline IC/TLC ratio, the annual decline in 6MWD was 12.7 m (p < 0.001). Study participants with an IC/TLC ratio in the upper quartiles maintained their 6MWD from baseline to year 3, while it was significantly reduced for the patients with an IC/TLC ratio in the lower quartiles. Absence of light and hard physical activity, increased age and FMI, decreased FEV1 and FVC, more frequent exacerbations and higher Charlson comorbidity index were also predictors for lower 6MWD at any given time, but did not predict higher rate of decline over the timespan of the study. Our findings demonstrated that patients with less lung hyperinflation at baseline maintained their functional exercise capacity during the follow-up period, and that it was significantly reduced for patients with increased lung hyperinflation.


Psychosocial outcomes of an inclusive adapted sport and adventurous training course for military personnel.
To explore the psychosocial outcomes of an inclusive adapted sport and adventurous training course that aims to support the rehabilitation and personal development of military personnel who have sustained physical and/or psychological disability. Narrative life story interviews were conducted with 11 men aged 20-43 taking part in one of the 5-day courses. A thematic narrative analysis was conducted, focusing on accounts that provided insights into personally meaningful psychosocial outcomes of the course. We identified six themes, falling into two distinct clusters. "Bringing me back to myself" was achieved through the themes of (1) returning to activity, (2) rediscovering a sense of purpose, and (3) reconnecting to others. "New rooms to explore" was realised through (4) experiencing new activities, (5) being valued/respected/cared for and (6) being inspired by other people. Involvement in the course stimulated a balance of present- and future-oriented psychosocial outcomes through which participants both recreated aspects of themselves that had been lost through injury/trauma and moved forward with their lives as a result of new horizons of possibility. This 5-day inclusive adapted sport and adventurous training course offered meaningful psychosocial outcomes among military personnel who had experienced physical and/or psychological disability. The course helped participants recover aspects of their previous life and self through becoming physically active again, rediscovering a sense of purpose and reconnecting to others. Participants describe a broadening of life horizons as a result of the course, through new activities, being valued/respected/cared for, and being inspired by other people.


Gait energetic efficiency in older adults with and without knee pain: results from the Baltimore Longitudinal Study of Aging.
With aging, customary gait patterns change and energetic efficiency declines, but the relationship between these alterations is not well understood. If gait characteristics that develop with aging explain part of the decline in energetic efficiency that occur in most aging individuals, then efforts to modify these characteristics could delay or prevent mobility limitation. This study characterizes gait patterns in older persons with and without knee pain and tests the hypothesis that changes in gait characteristics due to knee pain are associated with increased energetic cost of walking in older adults. Study participants were 364 men and 170 women aged 60 to 96 years enrolled in the Baltimore Longitudinal Study of Aging (BLSA), of whom 86 had prevalent knee pain. Gait patterns were assessed at participant self-selected usual pace in the gait laboratory, and the energetic cost of walking was assessed by indirect calorimetry during self-selected usual pace walking over 2.5 min in a tiled corridor using a portable equipment. Participants with knee pain were less energetically efficient than those without pain (oxygen consumption 0.97 vs. 0.88 ml/(10 m · 100 kg); p = 0.002) and had slower gait speed and smaller range of motion (ROM) at the hip and knee joints (p < 0.05, for all). Slower gait speed and lower knee ROM in participants with knee pain and longer double support time and higher ankle ROM in participants without knee pain were associated with lower energetic efficiency (p < 0.05, for all). Slower gait speed and lower knee ROM were correlates of knee pain and were found to mediate the association between age and oxygen consumption. Although knee pain is associated with a higher energetic cost of walking, gait characteristics associated with energetic efficiency differ by pain status which suggests that compensatory strategies both in the presence and absence of pain may impact gait efficiency.


The effect of saline lock on phlebitis rates of patients in cardiac care units.
Despite advances in the field of intravenous therapy, phlebitis is still a common complication of peripheral venous catheter and finding an appropriate solution to prevent and reduce the incidence of this complication remains challenging. One of the methods used in reducing the incidence of phlebitis is the use of saline lock, which is forgotten in most hospitals. Therefore, this study aimed to evaluate its impact on the incidence and severity of phlebitis. In a single-blind (the researcher) clinical trial, 88 patients with peripheral venous catheter admitted in cardiac care units in selected hospitals of Isfahan University of Medical Sciences, Iran, were selected through convenient sampling method. They were randomly divided into two groups of intervention and control groups using random number table. The intervention group received 3 ml of 0.9% normal saline sterilized before and after each intravenous drug or every 12 h. However, in the control group, the intravenous drugs were given as routine and saline lock was not used. The evaluation of intravenous catheter regarding the incidence of phlebitis and its degrees using Jackson's Visual Infusion Phlebitis Scale was performed 6 times within 72 h (every 12 h). Results were evaluated by SPSS software using descriptive statistics, Chi-square test, t-test, and Mann-Whitney test. Results showed that there was a statistically significant difference between the two groups regarding the degree of phlebitis (P = 0.003). The percentage of phlebitis incidence in the control group was 88.6% and in the intervention group was 43.2%. There was a statistically significant difference between the two groups (P < 0.001). The risk of incidence of phlebitis in the group without saline lock (control), compared to the intervention group, was 10.3 times greater (CI = 95%). The incidence of phlebitis in both groups increased with increase in the duration of catheter placement. The results of this study showed that the use of saline lock in the intervention group compared to the control group, in which saline lock was not used, can have a significant impact on reducing the incidence of phlebitis and its degree.


No time to grieve: Inuit loss experiences and grief practices in Nunavik, Quebec.
This article presents an overview of past and current grief rituals and practices and existing grassroots and institutional initiatives seeking to address the complex, prolonged, and traumatic grief experienced by many Inuit living in Quebec. While conducting a study seeking to identify the strengths, resources, and challenges for Nunavik's Inuit communities related to end-of-life care, results emerged concerning how family caregivers' grief related to the dying process was compounded by the sequelae of historic loss experiences (e.g., losses related to Canada's federal policies, including residential schools, forced relocations, and dog slaughters) and by present loss experiences (e.g., tragic and sudden deaths in local communities). To better support caregivers, an understanding of these grief experiences and a vision of bereavement care inclusive of community mobilization efforts to develop bereavement training and support is needed. We conclude with a discussion of a community capacity approach to bereavement care.


Neurootological aspects of juvenile vertigo.
Pathologies from childhood to adolescence carry physical, cognitive, motor, linguistic, perceptual, social, emotional, and neurosensory characteristics. The ages between 8 and 14 or 15 especially carry very special traits of a rollover in data processing with respect to balance regulation. Data acquisition of neurootological function provides us with a network of information about the sensory status of our young patients. Major neurootological complaints leading to functional neurootological investigations are vertigo (including giddiness), dizziness, and nausea. These complaints may occur acutely but also are present in some patients at a young age as longer-lasting complaints. Physiological and clinical vertigo syndromes are commonly found as a combination of four principal phenomena: perceptual (vertigo), oculomotor (nystagmus), postural (dystaxia), and vegetative (nausea, vomiting). These four cardinal manifestations of vertigo are related to different levels of the vestibular analyzer and require different methods of investigation. The focus of our study is the phase of restructuring of equilibrium regulation in children between the ages of 8 and 15 years.


Impact of elevated temperature on the physiological and biochemical responses of Kappaphycus alvarezii (Rhodophyta).
The eucheumatoids Kappaphycus and Eucheuma are cultivated in tropical or subtropical regions for the production of carrageenan, a hydrocolloid widely used in the food and cosmetic industries. Kappaphycus alvarezii is a highly valued economic crop in the Coral Triangle, with the Philippines, Indonesia and Malaysia ranked among the largest producers. In the absence of measures to mitigate climate change, extreme events including heatwaves, typhoons, severe El Niño and La Niña, are expected to increase in frequency and magnitude. This inadvertently brings adverse effects to the seaweed cultivation industry, especially in the tropics. Temperatures are rapidly reaching the upper limit of biologically tolerable levels and an increase in reports of ice-ice and pest outbreaks is attributable to these shifts of environmental parameters. Nevertheless, few reports on the response of eucheumatoids to a changing environment, in particular global warming, are available. Understanding the responses and possible mechanisms for acclimation to warming is crucial for a sustainable seaweed cultivation industry. Here, the physiological and biochemical responses of K. alvarezii to acute warming indicated that the strain used in the current study is unlikely to survive sudden increases in temperature above 36°C. As temperature increased, the growth rates, photosynthetic performance, phycocolloid quality (carrageenan yield, gel strength and gel viscosity) and pigment content (chlorophyll-a, carotenoid and phycobiliproteins) were reduced while the production of reactive oxygen species increased indicating the occurrence of stress in the seaweeds. This study provides a basis for future work on long term acclimation to elevated temperature and mesocosm-based multivariate studies to identify heat-tolerant strains for sustainable cultivation.


Postoperative red blood cell transfusion and morbid outcome in uncomplicated cardiac surgery patients.
To evaluate postoperative red blood cell (RBC) transfusion and its association with postoperative cardiac events and multiorgan morbidity in uncomplicated cardiac surgery patients. A cohort of 945 patients from the 5,436 coronary artery bypass grafting patients enrolled in the international Multicenter Study of Perioperative Ischemia (McSPI) Epidemiology II (EPI II) study was investigated. Inclusion criteria were low to moderate risk profile, postoperative hemoglobin level ≥ 10 g/dl, minimal postoperative blood loss, and no evidence of any morbid event on the day of surgery. RBC transfusion was assessed during the first 24 postoperative hours and cardiac as well as multiorgan outcomes from postoperative day 2 to hospital discharge. Multivariate analysis was applied to assess the effect of RBC transfusion on multiorgan outcomes. A secondary propensity score analysis was performed in 4,465 patients without early postoperative morbid outcomes. Transfused patients (193/945, 20.4%) were more likely to suffer cardiac events (P = 0.03), harvest-site infection (P = 0.002), and composite morbidity outcome (P = 0.04). RBC transfusion was associated with cardiac events on multivariate as well as on propensity score analysis (adjusted odds ratio, 1.39; 95% confidence interval, 1.01-1.92; P = 0.04), and with harvest-site infection on multivariate analysis. Additionally, propensity score analysis suggested possible associations of RBC transfusion with increased risks for composite morbidity outcome and in-hospital mortality, renal morbidity, pneumonia, and mediastinitis. The data suggest a potential association between postoperative RBC transfusion and increased morbidity for cardiac surgery patients with low to moderate mortality risk profiles, adequate hemoglobin levels, and low bleeding rates.


Short persistence of bendiocarb sprayed on pervious walls and its implication for the indoor residual spray program in Ethiopia.
With the emergence and spread of vector resistance to pyrethroids and DDT in Africa, several countries have recently switched or are considering switching to carbamates and/or organophosphates for indoor residual spraying (IRS). However, data collected on the residual life of bendiocarb used for IRS in some areas indicate shorter than expected bio-efficacy. This study evaluated the effect of pH and wall type on the residual life of the carbamates bendiocarb and propoxur as measured by the standard World Health Organization (WHO) cone bioassay test. In phase I of this study, bendiocarb and propoxur were mixed with buffered low pH (pH 4.3) local water and non-buffered high pH (pH 8.0) local water and sprayed on two types of wall surface, mud and dung, in experimental huts. In the six month phase II study, the two insecticides were mixed with high pH local water and sprayed on four different surfaces: painted, dung, mud and mud pre-wetted with water. The residual bio-efficacy of the insecticides was assessed monthly using standard WHO cone bioassay tests. In phase I, bendiocarb mixed with high pH water killed more than 80% of susceptible Anopheles arabiensis mosquitoes for two months on both dung and mud surfaces. On dung surfaces, the 80% mortality threshold was achieved for three months when the bendiocarb was mixed with low pH water and four months when it was mixed with high pH water. Propoxur lasted longer than bendiocarb on dung surfaces, staying above the 80% mortality threshold for four and five months when mixed with high and low pH water, respectively. Phase II results also showed that the type of surface sprayed has a significant impact on the bio-efficacy of bendiocarb. Keeping the spray water constant at the same high pH of 8.0, bendiocarb killed 100% of exposed mosquitoes on impervious painted surfaces for the six months of the study period compared with less than one month on mud surfaces. Mixing the insecticides in alkaline water did not reduce the residual bio-efficacy of bendiocarb. However, bendiocarb performed much better on impervious (painted) surfaces than on porous dung or mud ones. Propoxur was less affected by wall type than was bendiocarb. Studies on the interaction between wall materials, soil, humidity, temperature and pH and the residual bio-efficacy of new and existing insecticides are recommended prior to their wide use in IRS.


Multiple successful desensitizations to brentuximab vedotin: a case report and literature review.
Brentuximab vedotin is an antibody-drug conjugate FDA-approved for the treatment of systemic anaplastic large-cell lymphoma (ALCL) that has relapsed after multiagent chemotherapy. At least 2 cases of hypersensitivity reactions to brentuximab vedotin have been reported, without attempted desensitization. This report describes a morbidly obese 32-year-old woman with ALCL that relapsed after autologous stem cell transplantation, who was treated on a phase II clinical study with brentuximab vedotin. After 1 dose, she experienced near-complete remission, but therapy was stopped because of severe drug-related toxicity. She then received 5 cytotoxic treatments and radiation, and ultimately experienced disease progression. The patient was rechallenged with brentuximab vedotin approximately 28 months after initial exposure and tolerated the dose well, but experienced a significant allergic reaction with the next dose. High-dose steroid and antihistamine prophylaxis administered 50 minutes before the subsequent brentuximab vedotin infusion was unsuccessful in mitigating this reaction. Brentuximab vedotin was successfully infused according to a rapid desensitization protocol. With progressive dose titration and supportive care, the patient tolerated this therapy. She received 11 doses through a rapid desensitization protocol and experienced a durable disease remission.


Land-use allocation protects the Peruvian Amazon.
Disturbance and deforestation have profound ecological and socioeconomic effects on tropical forests, but their diffuse patterns are difficult to detect and quantify at regional scales. We expanded the Carnegie forest damage detection system to show that, between 1999 and 2005, disturbance and deforestation rates throughout the Peruvian Amazon averaged 632 square kilometers per year and 645 square kilometers per year, respectively. However, only 1 to 2% occurred within natural protected areas, indigenous territories contained only 11% of the forest disturbances and 9% of the deforestation, and recent forest concessions effectively protected against clear-cutting. Although the region shows recent increases in disturbance and deforestation rates and leakage into forests surrounding concession areas, land-use policy and remoteness are serving to protect the Peruvian Amazon.


The burden of sickle cell disease in Cape Town.
South Africa has a low incidence of sickle cell disease (SCD). However, its demographics are changing because of immigration from sub-Saharan African countries where SCD is prevalent. We aimed to determine the frequency of SCD presenting to the Haematology/Oncology Service at Red Cross War Memorial Children's Hospital in Cape Town and to measure the associated disease burden. This was a retrospective cross-sectional study of patients first attending the Haematology Service between January 2001 and June 2010. A total of 58 SCD patients were identified, with an annual frequency that increased over the study period by 300 - 400%. Up to 93.1% (n=54) were originally from other African countries, mainly the Democratic Republic of Congo (62.1%, n=36). One patient had sickle D-Punjab genotype, and all the other patients had the homozygous sickle cell anaemia genotype (Hb SS). Their haematological parameters demonstrated a normocytic anaemia with high white cell counts. The mean number of clinic visits per patient per year was 22.2 (range 0 - 64), and the mean number of hospital admissions per patient per year was 1.2 (range 0 - 5). All the patients were on antibiotic prophylaxis. The majority had at least one blood transfusion (65.5%, n=38), and a significant proportion required intravenous analgesia on admission (29.3%, n=17) and hydroxyurea treatment (36.2%, n=21). Over the past 10 years the frequency of SCD has increased considerably, imposing a significant burden and new challenges to the health services in Cape Town.


Non-ionic dendronized multiamphiphilic polymers as nanocarriers for biomedical applications.
A new class of non-ionic dendronized multiamphiphilic polymers is prepared from a biodegradable (AB)n-type diblock polymer synthesized from 2-azido-1,3-propanediol (azido glycerol) and polyethylene glycol (PEG)-600 diethylester using Novozym-435 (Candida antarctica lipase) as a biocatalyst, following a well-established biocatalytic route. These polymers are functionalized with dendritic polyglycerols (G1 and G2) and octadecyl chains in different functionalization levels via click chemistry to generate dendronized multiamphiphilic polymers. Surface tension measurements and dynamic light scattering studies reveal that all of the multiamphiphilic polymers spontaneously self-assemble in aqueous solution. Cryogenic transmission electron microscopy further proves the formation of multiamphiphiles towards monodisperse spherical micelles of about 7-9 nm in diameter. The evidence from UV-vis and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests like pyrene and 1-anilinonaphthalene-8-sulfonic acid within the hydrophobic core of the micelles. These results demonstrate the potential of these dendronized multiamphiphilic polymers for the development of prospective drug delivery systems for the solubilization of poorly water soluble drugs.


Assessment of the cerebral pressure-flow relationship using psychological stress to manipulate blood pressure.
Recent evidence indicates that cerebral autoregulation (CA) might be more pressure passive than previously thought. That is, cerebral blood flow, traditionally thought to be regulated independently of prevailing mean arterial pressure (MAP), might fluctuate, to some extent, as a function of MAP. However, due to limitations associated with experimental usage of pharmaceuticals to manipulate MAP and inconsistent control of arterial carbon dioxide, questions remain regarding the MAP-cerebral blood flow relationship, especially during typical daily activities that alter MAP. Therefore, the current study aimed to assess CA using a nonpharmacological acute psychological stress task to augment MAP, while at the same time controlling for end-tidal carbon dioxide (PET CO2 ). Twenty-five healthy young adults completed a stressful task while continuous measures of MAP, middle cerebral artery blood flow velocity (MCAv), and PET CO2 were recorded. Slope values obtained from hierarchical linear regression were used to assess the strength of the MAP-MCAv relationship and control for PET CO2 . The stress task significantly increased MAP (p < 0.001) and MCAv (p < 0.001), and decreased PET CO2 (p = 0.05). For every 10 mmHg task-induced increase in MAP, MCAv increased by ≈3.5%; task-induced changes in PET CO2 did not appreciably change the MAP-MCAv relationship. Greater task-induced MAP responses were significantly related to decreased MAP-MCAv slope values, consistent with CA. These data support the hypothesis that CA is more pressure passive than previously thought and provide initial evidence indicating that a pressure-passive MAP-MCAv relationship may play a role in the observed associations between MAP stress responses, stroke, and cerebrovascular disease.


In vitro efficacy of a gene-activated nerve guidance conduit incorporating non-viral PEI-pDNA nanoparticles carrying genes encoding for NGF, GDNF and c-Jun.
Despite the success of tissue engineered nerve guidance conduits (NGCs) for the treatment of small peripheral nerve injuries, autografts remain the clinical gold standard for larger injuries. The delivery of neurotrophic factors from conduits might enhance repair for more effective treatment of larger injuries but the efficacy of such systems is dependent on a safe, effective platform for controlled and localised therapeutic delivery. Gene therapy might offer an innovative approach to control the timing, release and level of neurotrophic factor production by directing cells to transiently sustain therapeutic protein production in situ. In this study, a gene-activated NGC was developed by incorporating non-viral polyethyleneimine-plasmid DNA (PEI-pDNA) nanoparticles (N/P 7 ratio, 2 μg dose) with the pDNA encoding for nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) or the transcription factor c-Jun. The physicochemical properties of PEI-pDNA nanoparticles, morphology, size and charge, were shown to be suitable for gene delivery and demonstrated high Schwann cell transfection efficiency (60 ± 13%) in vitro. While all three genes showed therapeutic potential in terms of enhancing neurotrophic cytokine production while promoting neurite outgrowth, delivery of the gene encoding for c-Jun showed the greatest capacity to enhance regenerative cellular processes in vitro. Ultimately, this gene-activated NGC construct was shown to be capable of transfecting both Schwann cells (S42 cells) and neuronal cells (PC12 and dorsal root ganglia) in vitro, demonstrating potential for future therapeutic applications in vivo. The basic requirements of biomaterial-based nerve guidance conduits have now been well established and include being able to bridge a nerve injury to support macroscopic guidance between nerve stumps, while being strong enough to withstand longitudinal tension and circumferential compression, in addition to being mechanically sound to facilitate surgical handling and implantation. While meeting these criteria, conduits are still limited to the treatment of small defects clinically and might benefit from additional biochemical stimuli to enhance repair for the effective treatment of larger injuries. In this study, a gene activated conduit was successfully developed by incorporating non-viral nanoparticles capable of efficient Schwann cell and neuronal cell transfection with therapeutic genes in vitro, which showed potential to enhance repair in future applications particularly when taking advantage of the transcription factor c-Jun. This innovative approach may provide an alternative to conduits used as platforms for the delivery neurotrophic factors or genetically modified cells (viral gene therapy), and a potential solution for the unmet clinical need to repair large peripheral nerve injury effectively.


Polyaniline films photoelectrochemically reduce CO2 to alcohols.
In this communication, we demonstrate that polyaniline, the very first example of an organic semiconductor, is a promising photocathode material for the conversion of carbon dioxide (CO2) to alcohol fuels. CO2 is a greenhouse gas; thus using solar energy to convert CO2 to transportation fuels (such as methanol or ethanol) is a value-added approach to simultaneous generation of alternative fuels and environmental remediation of carbon emissions. Insights into its unique behavior obtained from photoelectrochemical measurements and adsorption studies, together with spectroscopic data, are presented. Through a comparative study involving various conducting polymers, a set of criteria is developed for an organic semiconductor to function as a photocathode for generation of solar fuels from CO2.


Ventilatory and cardiometabolic responses to unilateral sanding in elderly women with ischemic heart disease: a pilot study.
This study was undertaken to investigate how 8 elderly women with ischemic heart disease would respond to a unilateral sanding activity. Three ventilatory measures-expiratory tidal volume, respiratory rate, and expiratory volume--and four cardiometabolic measures--metabolic equivalent, systolic blood pressure, heart rate, and pressure rate product--were continuously recorded during the sanding activity. The two independent variables were angle of the sanding board and sanding velocity. The activity was graded to yield five conditions: (a) sitting at rest; (b) 0 degrees at 15 cycles per min (cpm); (c) 0 degrees at 30 cpm; (d) 15 degrees at 15 cpm; and (e) 15 degrees at 30 cpm. The findings indicated that increasing the angle of the board while holding the velocity constant did not always increase the mean values of the ventilatory and cardiometabolic measures. However, increasing the velocity while holding the angle constant always increased the mean values of the dependent variables. The data also indicated that the metabolic equivalent reached during the sanding activity was no greater than 2, which corresponds to a light activity, such as playing a musical instrument. Replication of the study with a larger sample size may further elucidate the behavior of these two functions during a graded sanding activity. In the present study, a unilateral sanding activity by elderly patients with cardiac impairment was shown to provide valuable data on ventilatory and cardiometabolic functions. The study also demonstrated that a unilateral sanding activity can be safely used as a graded activity in occupational therapy for the cardiac rehabilitation of elderly women.


Letters from relatives: a source of information providing rich insight into the experience of the family in palliative care.
Studies on the effectiveness and efficiency of palliative care (PC) services that use a methodology similar to that used by studies in other medical specialties face serious limitations, since the goals of PC are substantially different. Qualitative research methods can make an important contribution to our understanding of the features of palliative care (PC) that are most relevant to patients and their relatives. The goal of this study was to understand the reasons behind the gratitude shown in letters from bereaved relatives sent to two PC units, one in Spain and one in Portugal. A thematic analysis of the content of the letters was independently carried out by three researchers, who later collaborated to write up the results. Relatives appeared grateful primarily for the humane attitude, professional treatment, and emotional support that their loved ones received from the PC team; they thanked the team for creating a special atmosphere and offering holistic care, and they talked about the contrast between PC and other forms of care. The unsolicited gratitude expressed in their letters constitutes a valid and particularly rich source of information about the contribution that a PC team can make.


Low pre-exercise muscle glycogen availability offsets the effect of post-exercise cold water immersion in augmenting PGC-1α gene expression.
We assessed the effects of post-exercise cold-water immersion (CWI) in modulating PGC-1α mRNA expression in response to exercise commenced with low muscle glycogen availability. In a randomized repeated-measures design, nine recreationally active males completed an acute two-legged high-intensity cycling protocol (8 × 5 min at 82.5% peak power output) followed by 10 min of two-legged post-exercise CWI (8°C) or control conditions (CON). During each trial, one limb commenced exercise with low (LOW: <300 mmol·kg-1 dw) or very low (VLOW: <150 mmol·kg-1 dw) pre-exercise glycogen concentration, achieved via completion of a one-legged glycogen depletion protocol undertaken the evening prior. Exercise increased (P < 0.05) PGC-1α mRNA at 3 h post-exercise. Very low muscle glycogen attenuated the increase in PGC-1α mRNA expression compared with the LOW limbs in both the control (CON VLOW ~3.6-fold vs. CON LOW ~5.6-fold: P = 0.023, ES 1.22 Large) and CWI conditions (CWI VLOW ~2.4-fold vs. CWI LOW ~8.0 fold: P = 0.019, ES 1.43 Large). Furthermore, PGC-1α mRNA expression in the CWI-LOW trial was not significantly different to the CON LOW limb (P = 0.281, ES 0.67 Moderate). Data demonstrate that the previously reported effects of post-exercise CWI on PGC-1α mRNA expression (as regulated systemically via β-adrenergic mediated cell signaling) are offset in those conditions in which local stressors (i.e., high-intensity exercise and low muscle glycogen availability) have already sufficiently activated the AMPK-PGC-1α signaling axis. Additionally, data suggest that commencing exercise with very low muscle glycogen availability attenuates PGC-1α signaling.


Lipid nanoscaffolds in carbon nanotube arrays.
We present the fabrication of lipid nanoscaffolds inside carbon nanotube arrays by employing the nanostructural self-assembly of lipid molecules. The nanoscaffolds are finely tunable into model biomembrane-like architectures (planar), soft nanochannels (cylindrical) or 3-dimensionally ordered continuous bilayer structures (cubic). Carbon nanotube arrays hosting the above nanoscaffolds are formed by packing of highly oriented multiwalled carbon nanotubes which facilitate the alignment of lipid nanostructures without requiring an external force. Furthermore, the lipid nanoscaffolds can be created under both dry and hydrated conditions. We show their direct application in reconstitution of egg proteins. Such nanoscaffolds find enormous potential in bio- and nano-technological fields.


Integrated urban malaria control: a case study in dar es salaam, Tanzania.
The rapid growth of cities in sub-Saharan Africa, much of it driven by rural-urban migration, is associated with complex transformations of these ecosystems and an intricate set of challenges for malaria control. Urban malaria transmission is substantially less intense and much more focal than in rural and peri-urban settings. However, the danger of epidemics is higher and the presence of substantial non-immune populations places people of all ages at comparable levels of risk. The limited number of breeding sites in urban centers suggests that prevention strategies based on vector control, with emphasis on environmental management, should be a central feature of urban malaria control programs. We focus on malaria in the city of Dar es Salaam, Tanzania. Following a brief review of the 100-year history of malaria control in this urban center, we describe and evaluate a control program that operated from 1988 to 1996 as a consequence of a bilateral agreement between the governments of Tanzania and Japan. We present an innovative urban malaria risk mapping methodology based on high-resolution aerial photography with ground-based validation. This strategy clarifies that remote sensing technology at a level of resolution of one meter is essential if this kind of information is to play a role in guiding the detailed specification of intervention strategies for urban malaria control. The Tanzania-Japan multiple-intervention malaria control program, adaptively implemented over time, is described and evaluated with implications for urban malaria control in sub-Saharan Africa more generally.


Stand structure, recruitment and growth dynamics in mixed subalpine spruce and Swiss stone pine forests in the Eastern Carpathians.
Natural subalpine forests are considered to be sensitive to climate change, and forest characteristics are assumed to reflect the prevalent disturbance regime. We hypothesize that stand history determines different stand structures. Based on large full inventory datasets (including tree biometric data, spatial coordinates, tree age, and basal area increment) we assessed the size structure, tree recruitment dynamics and radial growth patterns in three permanent plots along an altitudinal gradient in a mixed coniferous forest (Picea abies and Pinus cembra) in the Eastern Carpathians. Both discrete disturbances (large scale or small scale) and chronic disturbances (climate change) were identified as drivers of stand structure development in the studied plots. A stand replacing wind disturbance generated a unimodal bell-shaped size and age distribution for both species characterized by a sharp increase in post-disturbance recruitment. By contrast, small-scale wind-caused gaps led to a negative exponential diameter distribution for spruce and a left-asymmetric unimodal for pine. Climate-driven infilling processes in the upper subalpine forest were reflected as J-shaped size and age distributions for both species, but with pine predating spruce. The growth patterns for both species demonstrated an increased basal area increment since the early 1900s, with an emphasis in the last few decades, irrespective of stand history. Pine demonstrated a competitive advantage compared to spruce due to the higher growth rate and size at the same age. Recognition of combined discrete and chronic disturbances as drivers of the tree layer characteristics in a subalpine coniferous forest is essential in both stand history analyses and growth predictions.


Spatiotemporal expression of Prdm genes during Xenopus development.
Epigenetic regulation is known to be important in embryonic development, cell differentiation and regulation of cancer cells. Molecular mechanisms of epigenetic modification have DNA methylation and histone tail modification such as acetylation, phosphorylation and ubiquitination. Until now, many kinds of enzymes that modify histone tail with various functional groups have been reported and regulate the epigenetic state of genes. Among them, Prdm genes were identified as histone methyltransferase. Prdm genes are characterized by an N-terminal PR/SET domain and C-terminal some zinc finger domains and therefore they are considered to have both DNA-binding ability and methylation activity. Among vertebrate, fifteen members are estimated to belong to Prdm genes family. Even though Prdm genes are thought to play important roles for cell fate determination and cell differentiation, there is an incomplete understanding of their expression and functions in early development. Here, we report that Prdm genes exhibit dynamic expression pattern in Xenopus embryogenesis. By whole mount in situ hybridization analysis, we show that Prdm genes are expressed in spatially localized manners in embryo and all of Prdm genes are expressed in neural cells in developing central nervous systems. Our study suggests that Prdm genes may be new candidates to function in neural cell differentiation.


Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages.
Epidemiological studies suggest a correlation between severity of acquired immunodeficiency syndrome (AIDS) and selenium deficiency, indicating a protective role for this anti-oxidant during HIV infection. Here we demonstrate that thioredoxin reductase-1 (TR1), a selenium-containing pyridine nucleotide-disulfide oxidoreductase that reduces protein disulfides to free thiols, negatively regulates the activity of the HIV-1 encoded transcriptional activator, Tat, in human macrophages. We used a small interfering RNA approach as well as a high affinity substrate of TR1, ebselen, to demonstrate that Tat-dependent transcription and HIV-1 replication were significantly increased in human macrophages when TR1 activity was reduced. The increase in HIV-1 replication in TR1 small interfering RNA-treated cells was independent of the redox-sensitive transcription factor, NF-kappaB. These studies indicate that TR-1 acts as a negative regulator of Tat-dependent transcription. Furthermore, in vitro biochemical assays with recombinant Tat protein confirmed that TR1 targets two disulfide bonds within the Cys-rich motif required for efficient HIV-1 transactivation. Increasing TR1 expression along with other selenoproteins by supplementing with selenium suggests a potential inexpensive adjuvant therapy for HIV/AIDS patients.


Applying causal mediation methods to clinical trial data: What can we learn about why our interventions (don't) work?
Many randomized controlled trials (RCTs) of psychosocial interventions for low back pain (LBP) have been found to have only small effects on disability outcomes. Investigations of the specific mechanisms that may lead to an improvement in outcome have therefore been called for. We present an application of the causal inference approach to mediation analysis using the example of a cluster RCT in a primary care population with (sub)acute LBP randomized to either usual GP care (n = 171) or a minimal psychosocial intervention (n = 143). Mediation analysis explored the causal pathway between treatment allocation and disability at 3 months by considering pain catastrophizing, fear-avoidance beliefs, distress and receiving and following advice as potential mediators, all measured at 6 weeks. We have attempted to explain this approach to mediation analysis in a step-by-step manner to help clinical researchers apply this method more easily. In unadjusted mediation analyses, fear-avoidance beliefs were identified as a mediator of treatment on disability, with an indirect effect of -0.30 (95% CI: -0.86, -0.03), although this relationship was found to be non-significant after adjusting for age, gender and baseline scores. This finding supports the trial authors' hypothesis that while fear-avoidance beliefs are important, this intervention may not have targeted them strongly enough to lead to change. The use of mediation analysis to identify what factors may be part of the causal pathway between intervention and outcome, regardless of whether the intervention was successful, can provide useful information and insight into how to improve future interventions. This study presents a step-by-step approach to mediation analysis using the causal inference framework to investigate why a psychosocial intervention for LBP was unsuccessful. Fear-avoidance beliefs were found to mediate the relationship between treatment and disability, although not when controlling for baseline scores.


Shotgun identification of protein modifications from protein complexes and lens tissue.
Large-scale genomics has enabled proteomics by creating sequence infrastructures that can be used with mass spectrometry data to identify proteins. Although protein sequences can be deduced from nucleotide sequences, posttranslational modifications to proteins, in general, cannot. We describe a process for the analysis of posttranslational modifications that is simple, robust, general, and can be applied to complicated protein mixtures. A protein or protein mixture is digested by using three different enzymes: one that cleaves in a site-specific manner and two others that cleave nonspecifically. The mixture of peptides is separated by multidimensional liquid chromatography and analyzed by a tandem mass spectrometer. This approach has been applied to modification analyses of proteins in a simple protein mixture, Cdc2p protein complexes isolated through the use of an affinity tag, and lens tissue from a patient with congenital cataracts. Phosphorylation sites have been detected with known stoichiometry of as low as 10%. Eighteen sites of four different types of modification have been detected on three of the five proteins in a simple mixture, three of which were previously unreported. Three proteins from Cdc2p isolated complexes yielded eight sites containing three different types of modifications. In the lens tissue, 270 proteins were identified, and 11 different crystallins were found to contain a total of 73 sites of modification. Modifications identified in the crystallin proteins included Ser, Thr, and Tyr phosphorylation, Arg and Lys methylation, Lys acetylation, and Met, Tyr, and Trp oxidations. The method presented will be useful in discovering co- and posttranslational modifications of proteins.


The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.
Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001). A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.


Amyloid imaging in dementias with atypical presentation.
With the potential emergence of disease specific therapies, an accurate biomarker of Alzheimer's Disease pathology is needed in cases in which the underlying etiology is uncertain. We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Twenty-eight patients with atypical dementia underwent positron emission tomography imaging with the amyloid imaging tracer Pittsburgh compound B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible Alzheimer's disease (AD), focal dementias (e.g., posterior cortical atrophy [PCA]), or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology). Patients were classified as PiB-positive, PiB-negative, or PiB-intermediate, based on objective criteria. Anterior-posterior and left-right indices of PiB and [18F]fluoro-2-deoxy-D-glucose uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Eleven patients (39%) were PiB positive, 16 were PiB negative (57%), and one (4%) was PiB intermediate. By diagnostic category, three of 10 patients (30%) with dementia of uncertain etiology, one of five (20%) with primary progressive aphasia, three of five (60%) with PCA, and four of seven (57%) with possible AD were PiB positive. Brain metabolism of both PiB-positive and PiB-negative patients was generally similar by phenotype, but appeared to differ from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared with typical AD, consistent with their atypical phenotype. AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.