[A discrete type of potassium channel conductance in snail neurons].
The results of further investigations on a single potential dependent K+ channel are described. It was shown that ionic selectivity of the channel for monovalent ions is too high: Li+, Na+, and Cs+ are practically impermeant ions. Permeability of the channel for Rb+ is approximately 10 times less, and for Tl+ it is 2 times more than permeability for K+. Besides, it was found that open K+ channel has 16 multiple conductance levels.


Variations and inter-relationship in outcome from emergency admissions in England: a retrospective analysis of Hospital Episode Statistics from 2005-2010.
The quality of care delivered and clinical outcomes of care are of paramount importance. Wide variations in the outcome of emergency care have been suggested, but the scale of variation, and the way in which outcomes are inter-related are poorly defined and are critical to understand how best to improve services. This study quantifies the scale of variation in three outcomes for a contemporary cohort of patients undergoing emergency medical and surgical admissions. The way in which the outcomes of different diagnoses relate to each other is investigated. A retrospective study using the English Hospital Episode Statistics 2005-2010 with one-year follow-up for all patients with one of 20 of the commonest and highest-risk emergency medical or surgical conditions. The primary outcome was in-hospital all-cause risk-standardised mortality rate (in-RSMR). Secondary outcomes were 1-year all-cause risk-standardised mortality rate (1 yr-RSMR) and 28-day all-cause emergency readmission rate (RSRR). 2,406,709 adult patients underwent emergency medical or surgical admissions in the groups of interest. Clinically and statistically significant variations in outcome were observed between providers for all three outcomes (p < 0.001). For some diagnoses including heart failure, acute myocardial infarction, stroke and fractured neck of femur, more than 20% of hospitals lay above the upper 95% control limit and were statistical outliers. The risk-standardised outcomes within a given hospital for an individual diagnostic group were significantly associated with the aggregated outcome of the other clinical groups. Hospital-level risk-standardised outcomes for emergency admissions across a range of specialties vary considerably and cross traditional speciality boundaries. This suggests that global institutional infra-structure and processes of care influence outcomes. The implications are far reaching, both in terms of investigating performance at individual hospitals and in understanding how hospitals can learn from the best performers to improve outcomes.


Quantitative grip force assessment of muscular weakness in chronic inflammatory demyelinating polyneuropathy.
In patients suffering from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) disease severity is assessed by Medical Research Counsil (MRC) Scale or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. However, none of these methods is appropriate to objectively assess muscle weakness or to detect very small subclinical changes. More objective and quantitative measures are needed in order to evaluate treatment efficiency or to detect subclinical affection of upper limps for early diagnosis. The goal of our study was to objectively quantify muscular weakness in CIDP patients with the non-invasive Quantitative Motor (Q-Motor) test of Grip Force Assessment (QGFA) as well as the Involuntary Movement Assessment (QIMA) and to search for differences between typical and atypical CIDP variants. In addition, we hypothesized that Q-Motor findings correlate with disease severity scales such as MRC or INCAT score. In this cross-sectional exploratory proof-of-concept study subjects with confirmed diagnosis of typical or atypical CIDP were examined and compared to healthy controls (HC). For Q-Motor tests all subjects had to lift a device (250 g and 500 g) equipped with an electromagnetic sensor that measured grip force (GF) and three-dimensional changes in position and orientation. The measures "grip force variability" (GFV), "position index" (PI) and "orientation index" (OI) were provided to assess involuntary movements due to muscular weakness. 33 patients with CIDP and 28 HC were included. All measures were significantly elevated in CIDP patients for both devices in the right and left hand compared to healthy controls. Subgroup analysis revealed no differences between typical and atypical CIDP variants. INCAT score only weakly correlated with OI and PI. However, there was a stronger correlation between MRC and QIMA parameters in both hands. Q-Motor assessments were capable to objectively assess muscular weakness in CIDP. In particular, QIMA measures detected subclinical generalized muscle weakness even in patients with milder disability. Sensitivity and rater-independence of Q-Motor assessments support a further exploration of QIMA measures as potential endpoints for future clinical trials in CIDP.


Self-Similar Processes Follow a Power Law in Discrete Logarithmic Space.
Cities, wealth, and earthquakes follow continuous power-law probability distributions such as the Pareto distribution, which are canonically associated with scale-free behavior and self-similarity. However, many self-similar processes manifest as discrete steps that do not produce a continuous scale-free distribution. We construct a discrete power-law distribution that arises naturally from a simple model of hierarchical self-similar processes such as turbulence and vasculature, and we derive the maximum-likelihood estimate (MLE) for its exponent. Our distribution is self-similar, in contrast to previously studied discrete power laws such as the Zipf distribution. We show that the widely used MLE derived from the Pareto distribution leads to inaccurate estimates in systems that lack continuous scale invariance such as branching networks and data subject to logarithmic binning. We apply our MLE to data from bronchial tubes, blood vessels, and earthquakes to produce new estimates of scaling exponents and resolve contradictions among previous studies.


Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells.
Two different CpG oligonucleotides (ODN) were used to study the regulation of type I IFN in human plasmacytoid dendritic cells (PDC): ODN 2216, a CpG-A ODN, known to induce high amounts of IFN-alpha in PDC, and ODN 2006, a CpG-B ODN, which is potent at stimulating B cells. CpG-A ODN showed higher and prolonged kinetics of type I IFN production compared with that of CpG-B ODN. In contrast, CpG-B ODN was more active than CpG-A ODN in stimulating IL-8 production and increasing costimulatory and Ag-presenting molecules, suggesting that CpG-A and CpG-B trigger distinct regulatory pathways in PDC. Indeed, CpG-A ODN, but not CpG-B ODN, activated the type I IFNR-mediated autocrine feedback loop. PDC were found to express high constitutive levels of IFN regulatory factor (IRF)7. IRF7 and STAT1, but not IRF3, were equally up-regulated by both CpG-A and CpG-B. CD40 ligand synergistically increased CpG-B-induced IFN-alpha independent of the IFNR but did not affect CpG-B-induced IFN-beta. In conclusion, our studies provide evidence for the existence of two distinct regulatory pathways of type I IFN synthesis in human PDC, one dependent on and one independent of the IFNR-mediated feedback loop. The alternate use of these pathways is based on the type of stimulus rather than the quantity of IFN-alphabeta available to trigger the IFNR. Constitutive expression of IRF7 and the ability to produce considerable amounts of IFN-alpha independent of the IFNR seem to represent characteristic features of PDC.


Alzheimer's Disease in the Latino Community: Intersection of Genetics and Social Determinants of Health.
Alzheimer's disease (AD) is the most common type of dementia among individuals 65 or older. There are more than 5 million diagnosed cases in the US alone and this number is expected to triple by 2050. Therefore, AD has reached epidemic proportions with significant socioeconomic implications. While aging in general is the greatest risk factor for AD, several additional demographic factors that have contributed to the rise in AD in the US are under study. One such factor is associated with the relatively fast growth of the Latino population. Several reports indicate that AD is more prevalent among blacks and Latinos. However, the reason for AD disparity among different ethnic groups is still poorly understood and highly controversial. The Latino population is composed of different groups based on nationality, namely South and Central America, Mexico, and Caribbean Hispanics. This diversity among the Latino population represents an additional challenge since there are distinct characteristics associated with AD and comorbidities. In this review, we aim to bring attention to the intersection between social determinants of health and genetic factors associated with AD within the Latino community. We argue that understanding the interplay between identified social determinants of health, co-morbidities, and genetic factors could lead to community empowerment and inclusiveness in research and healthcare services, contributing to improved diagnosis and treatment of AD patients. Lastly, we propose that inserting a neuroethics perspective could help understand key challenges that influence healthcare disparities and contribute to increased risk of AD among Latinos.


[Use of tremonorm in treatment of Parkinson's disease: outpatient experience of Moscow Municipal Health Care Service].
The efficacy of domestic drug tremonorm (levadopa-carbidopa) for Parkinson's disease (PD) treatment was studied. The treatment was conducted in neurological outpatient departments in several Moscow administrative regions and was administered to 142 PD patients, 15 being assigned to this drug for the first time and 127 being previously treated with other medications containing levadopa/carbidopa. A minimal effective dose (up to 500 mg) was selected for each patient and was not changed during 2 months. For patients previously switched to levadopa, the change for tremonorm has been done during 1 day if the dose of levadopa did not exceed 500 mg, and during 2 months in case a patient received over 500 mg per day. Modified Hoehn&Yahr scale, UPDRS, MMSE, PDQ-39 and other scales were used in complex evaluation of the disease stage. Positive effect of tremonorm was detected for 94 patients (66.2%), all of them continued tremonorm therapy after the end of the study. The most frequent side-effects proved to be dyspeptic symptoms. Tremonorm caused statistically significant positive changes in patient's movement scaled by UPDRS and the QL indexes in all PDQ-39 subscales. Positive changes in movement activity were accompanied by decrease of bradykinesia, tremor, better walking, writing and every day activity of PD patients. A change of nacom for tremonorm did not result in significant alteration of symptoms and Quality of Life indexes that suggest similar influence of these drugs on PD symptomatology. At the same time, a substantially lower price of tremonorm allows reducing of treatment costs.


Stroke lesion size - Still a useful biomarker for stroke severity and outcome in times of high-dimensional models.
The volumetric size of a brain lesion is a frequently used stroke biomarker. It stands out among most imaging biomarkers for being a one-dimensional variable that is applicable in simple statistical models. In times of machine learning algorithms, the question arises of whether such a simple variable is still useful, or whether high-dimensional models on spatial lesion information are superior. We included 753 first-ever anterior circulation ischemic stroke patients (age 68.4±15.2 years; NIHSS at 24 h 4.4±5.1; modified Rankin Scale (mRS) at 3-months median[IQR] 1[0.75;3]) and traced lesions on diffusion-weighted MRI. In an out-of-sample model validation scheme, we predicted stroke severity as measured by NIHSS 24 h and functional stroke outcome as measured by mRS at 3 months either from spatial lesion features or lesion size. For stroke severity, the best regression model based on lesion size performed significantly above chance (p < 0.0001) with R2 = 0.322, but models with spatial lesion features performed significantly better with R2 = 0.363 (t(752) = 2.889; p = 0.004). For stroke outcome, the best classification model based on lesion size again performed significantly above chance (p < 0.0001) with an accuracy of 62.8%, which was not different from the best model with spatial lesion features (62.6%, p = 0.80). With smaller training data sets of only 150 or 50 patients, the performance of high-dimensional models with spatial lesion features decreased up to the point of being equivalent or even inferior to models trained on lesion size. The combination of lesion size and spatial lesion features in one model did not improve predictions. Lesion size is a decent biomarker for stroke outcome and severity that is slightly inferior to spatial lesion features but is particularly suited in studies with small samples. When low-dimensional models are desired, lesion size provides a viable proxy biomarker for spatial lesion features, whereas high-precision prediction models in personalised prognostic medicine should operate with high-dimensional spatial imaging features in large samples.


Safety and efficacy of intrastromal injection of 5% natamycin in experimental fusarium keratitis.
To compare the efficacy of combined intrastromal injection and topical natamycin 5% to standard topical therapy alone in an experimental rabbit model of Fusarium keratitis. Fungal keratitis was induced in the right eyes of 12 New Zealand rabbits by stromal injection of Fusarium solani spore suspension into the cornea. Four days after inoculation, animals were randomly assigned to 2 different treatment groups (n=6 in each group). The study group received intrastromal injections of natamycin 5% on treatment day 1 and 4, combined with topical natamycin 5% eye drops given hourly between 8:00 and 20:00 for the first 2 days, followed by 4 times daily on days 3-11. The control group received only topical natamycin 5% at identical intervals. Eyes were examined clinically on days 1, 4, 7, and 11 for status of corneal healing, corneal vascularization, and hypopyon. Animals were sacrificed on day 11, and corneas were subjected to histopathological examination. Both groups showed significant improvement in terms of conjunctival hyperemia, size and density of corneal infiltrate, corneal edema, and total clinical score. In the study group, there was a significant improvement in the height of hypopyon in the anterior chamber, while there was also an increased amount of vascularization. This study showed that intrastromal injection of natamycin 5% combined with topical treatment has little beneficial effect over topical therapy in a Fusarium keratitis rabbit model. The addition of intrastromal injection should be reserved to the most severe or recalcitrant cases.


Quantitative digital angiography as an adjunct to the intraoperative placement of endovascular stents in congenital heart disease.
Clearly identifiable intraoperative landmarks render the placement of intraoperative stents difficult. Preoperative use of quantitative digital angiography helps the surgeon accurately insert endovascular stents intraoperatively. By using defined points of reference, we were able to carefully select the size and lengths of stents before the operation and precisely place these stents in the operating room. Furthermore, we have been able to redilate these stents using the same techniques at subsequent operations. Our results reflect the efficacy of this technique.


A riboswitch gives rise to multi-generational phenotypic heterogeneity in an auxotrophic bacterium.
Auxotrophy, the inability to produce an organic compound essential for growth, is widespread among bacteria. Auxotrophic bacteria rely on transporters to acquire these compounds from their environment. Here, we study the expression of both low- and high-affinity transporters of the costly amino acid methionine in an auxotrophic lactic acid bacterium, Lactococcus lactis. We show that the high-affinity transporter (Met-transporter) is heterogeneously expressed at low methionine concentrations, resulting in two isogenic subpopulations that sequester methionine in different ways: one subpopulation primarily relies on the high-affinity transporter (high expression of the Met-transporter) and the other subpopulation primarily relies on the low-affinity transporter (low expression of the Met-transporter). The phenotypic heterogeneity is remarkably stable, inherited for tens of generations, and apparent at the colony level. This heterogeneity results from a T-box riboswitch in the promoter region of the met operon encoding the high-affinity Met-transporter. We hypothesize that T-box riboswitches, which are commonly found in the Lactobacillales, may play as-yet unexplored roles in the predominantly auxotrophic lifestyle of these bacteria.


Clinical evaluation of a new polymerase chain reaction assay for detection of Chlamydia trachomatis in endocervical specimens.
A clinical evaluation of the Amplicor polymerase chain reaction (PCR) assay for the detection of Chlamydia trachomatis in endocervical swabs (Roche Molecular Systems, Branchburg, N.J.) is described. This new clinical system used one-step sample preparation, amplification with biotinylated cryptic plasmid primer pairs (CP24-CP27), uracil-N-glycosylase (AmpErase), and a microtiter format for amplicon capture and detection. Culture with McCoy cells in duplicate 1-dram (3.697-ml) vials with fluorescent immunostaining was the reference system. Endocervical swab samples from 945 women provided 74 culture-positive specimens, of which PCR detected 71. The initial PCR result was positive for 12 additional specimens. Arbitration of the PCR-positive, culture-negative samples by PCR with major outer membrane protein primers, duplicate culture, elementary body direct fluorescent-antibody staining, and DNA extraction PCR showed that all 12 samples were positive for chlamydia, raising the number of truly positive samples from 74 to 86. After arbitration the true sensitivities of PCR and culture were 96.5 and 86%, respectively (P = 0.02). Specificities for both were 100%. For PCR, the positive and negative predictive values were 100 and 99.7%, respectively. Total test efficiency was 99.7%. A high-test-volume (121 samples) timing study with all items included in the College of American Pathologists work load method indicated that this PCR format took approximately 3 min per sample. Because of the high sensitivity, specificity, and improved ease of handling, we found PCR to be a good alternative to culture for detection of C. trachomatis.


Guillain-Barre syndrome: A possibility in a spinal cord injured patient.
A 28-year-old male had paraplegia as a result of fracture dislocation of T12/L1 six years ago. He was functioning independently until four weeks ago, when he started complaining of trunkal paraesthesia which later progressed to include the upper extremities. The initial diagnosis was that of posttraumatic syringomyelia (PTS). While awaiting the MRI scan he developed weakness of upper limbs. The weakness restricted his self-care activities including transfers. The MRI did not show any evidence of syringomyelia. Neurological consultation and assessment yielded provisional diagnosis of Guillain-Barre syndrome (GBS). The patient was treated with immunoglobulins and regained 90% of his previous neurological status. This case is reported to raise awareness among clinicians to include the possibility of the GBS in the differential diagnosis of progressive neurological loss on top of existing neurological deficiency in spinal cord injured patients.


What are the risk factors for admission to the pediatric intensive unit among pediatric patients with COVID-19?
Although with exceptions, evidence seems to indicate that children have lower susceptibility than adults to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. When infected, children generally remain asymptomatic or develop mild disease. A small number of pediatric cases required admission to the pediatric intensive care unit (PICU), respiratory support with a mechanical ventilation and additional life-saving interventions. Even if rarely, death can occur. Aim of this manuscript is to highlight the risk factors associated with severe outcome among pediatric patients with COVID-19. Early identification of SARS-CoV-2-infected children at risk of developing severe COVID-19 is vital for service planning, as severely affected pediatric patients require high-quality care and should be followed only where an adequately structured PICU is available. However, early identification of children who must be carefully monitored for substantial risk of severe COVID-19 remains difficult. An underlying comorbidity and heart involvement are frequently observed in severe paediatric cases. Reduced left ventricular systolic function with an ejection fraction < 60%; diastolic dysfunction; and arrhythmias, including ST segment changes, QTc prolongation, and premature atrial or ventricular beat, are the earliest manifestations of heart involvement. Inclusion of heart enzyme serum levels and evaluation of ventricular function among predictive markers could lead to a more effective evaluation of children at risk with proper selection of those to admit to the PICU and with more adequate treatment in case of more severe clinical manifestations. To appropriately manage severe pediatric COVID-19 cases, greater attention should be paid to risk factors in children and adolescents, especially to cardiovascular alterations (e.g., heart enzyme serum levels and evaluation of ventricular function). Further studies are needed and the development of a validated score based on all the most common presumed markers of disease severity seems essential.


Coronavirus disease 2019 (COVID-19) and simultaneous acute anteroseptal and inferior ST-segment elevation myocardial infarction.
Coronavirus disease 2019 (COVID-19) is a recently recognised pandemic spreading rapidly from Wuhan, Hubei, to other provinces in China and to many countries around the world. The number of COVID-19-related deaths is steadily increasing. Acute ST-segment elevation myocardial infarction (STEMI) is a disease with high morbidity and mortality rates, and primary percutaneous coronary intervention is usually recommended for the treatment. A patient with diabetes mellitus and hypertension for five years was admitted to the emergency unit with symptoms of fever, cough and dyspnoea. These symptoms were consistent with viral pneumonia and a COVID PCR test was performed, which tested positive three days later. The patient had chest pain on the eighth day of hospitalisation. On electrocardiography, simultaneous acute inferior and anterior STEMI were identified. High levels of stress and increased metabolic demand in these patients may lead to concomitant thrombosis of different coronary arteries, presenting with two different STEMIs.


Nuclear compartmentalization of α1-adrenergic receptor signaling in adult cardiac myocytes.
Although convention dictates that G protein-coupled receptors localize to and signal at the plasma membrane, accumulating evidence suggests that G protein-coupled receptors localize to and signal at intracellular membranes, most notably the nucleus. In fact, there is now significant evidence indicating that endogenous alpha-1 adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. Cumulatively, the data suggest that α1-ARs localize to the inner nuclear membrane, activate intranuclear signaling, and regulate physiologic function in adult cardiac myocytes. Although α1-ARs signal through Gαq, unlike other Gq-coupled receptors, α1-ARs mediate important cardioprotective functions including adaptive/physiologic hypertrophy, protection from cell death (survival signaling), positive inotropy, and preconditioning. Also unlike other Gq-coupled receptors, most, if not all, functional α1-ARs localize to the nuclei in adult cardiac myocytes, as opposed to the sarcolemma. Together, α1-AR nuclear localization and cardioprotection might suggest a novel model for compartmentalization of Gq-coupled receptor signaling in which nuclear Gq-coupled receptor signaling is cardioprotective.


Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.
African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.


Topical Corticosteroid Therapy for Psoriasis-A Review of Clobetasol Propionate 0.025% Cream and the Clinical Relevance of Penetration Modification.
Topical corticosteroids (TCs) have played a central role, over the past several decades, as a treatment for many dermatologic disorders. A number of factors, including potency, anticipated efficacy, vehicle formulation, and patient preference, directly influence the success or failure of any TC. In this article, the author reviews and discusses the current literature on various aspects of TCs for the treatment of plaque psoriasis, including an overview of product selection tendencies of patients, conventional use and formulations of topical clobetasol propionate (CP) 0.05%, and the use of special additives (e.g., penetration enhancers) to increase CP potency. The author highlights data from recent studies that evaluated a new CP cream formulation that incorporates half the concentration of traditional CP (0.025%) without the loss of super-potency (Class I) status and without the use of traditional potency enhancement with propylene glycol.


Nonclinical Safety Assessment of an Inhaled Formulation of Serelaxin: A Recombinant Human Protein in Rats and Cynomolgus Monkeys (Macaca fascicularis).
Serelaxin is a recombinant human relaxin-2 intended for cardiovascular indications. Inhalation was chosen as alternative route to intravenous to allow daily administration for chronic applications and home treatment. A total of 4 short-term studies were conducted in rats and cynomolgus monkeys with inhaled formulation of serelaxin at dose up to 10 mg/kg/d. All rats and cynomolgus macaques receiving serelaxin were exposed to the test item. One rat and approximately 50% of macaques developed immunogenicity, which did not appear to affect exposure. No adverse effect on respiratory function or systemic changes was noted. Both species developed similar microscopic lesions characterized by eosinophilic cell infiltration around bronchi; however, in the rat, this was more pronounced and extended to a perivascular location. In addition, in the rat, serelaxin showed eosinophilic crystalline material associated with macrophages in the alveoli and bronchioles. In macaques, serelaxin induced minimal macrophage infiltrates in alveoli and perivascular/peribronchiolar mononuclear cell infiltrations. The minimal airway eosinophilic/mononuclear inflammatory cell infiltrations were considered to be nonadverse in macaques due to the minimal severity and the lack of any other alterations in the lung parenchyma. In the rat, the presence of eosinophilic crystalline material and macrophage response, characterized as precipitated test article, was considered adverse.


Baclofen, motion sickness susceptibility and the neural basis for velocity storage.
Reduction of the dominant time constant (T(VOR)) of the angular vestibulo-ocular reflex (aVOR) by habituation is associated with a decrease in motion sickness susceptibility. Baclofen, a GABA(b) agonist, reduces the time constant of the velocity storage integrator in the aVOR in a dose-dependent manner. The high frequency aVOR gain is unaltered by baclofen. Here we demonstrate that the reduction in T(VOR) produced by oral administration of 20 mg of baclofen causes a significant reduction in motion sickness susceptibility, tested with roll while rotating (RWR). These data show that motion sickness susceptibility can be pharmacologically manipulated with a GABA(b) agonist and support our conclusion that motion sickness is generated through velocity storage. We also show how baclofen acts on velocity storage at the neural level. A vestibular-plus-saccade (VPS) neuron was recorded in the rostral medial vestibular nucleus (rMVN) of a cynomolgus monkey, an area where we postulate that velocity storage is generated. The cell had a time constant during steps of velocity that was close to that of the T(VOR). After parenteral administration of baclofen, there was a similar decrease in the time constants of the VPS neuron and the T(VOR). This is the first demonstration of the concurrence of unit and aVOR time constants before and after baclofen. The data support the hypothesis that the velocity storage integrator is generated through activity of vestibular-only (VO) and VPS neurons in rMVN and suggest that GABA(b) synapses on VO and VPS neurons are likely to be involved in the baclofen-induced reduction in motion sickness susceptibility.


Nonsurgical weight loss for extreme obesity in primary care settings: results of the Louisiana Obese Subjects Study.
Effective primary care practice (PCP) treatments are needed for extreme obesity. The Louisiana Obese Subjects Study (LOSS) tested whether, with brief training, PCPs could effectively implement weight loss for individuals with a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 40 to 60. The LOSS, a 2-year (July 5, 2005, through January 30, 2008) randomized, controlled, "pragmatic clinical trial" trained 7 PCPs and 1 research clinic in obesity management. Primary outcome measure was year-2 percentage change from baseline weight. Volunteers (597) were screened and randomized to intensive medical intervention (IMI) (n = 200) or usual care condition (UCC) (n = 190). The UCC group had instruction in an Internet weight management program. The IMI group recommendations included a 900-kcal liquid diet for 12 weeks or less, group behavioral counseling, structured diet, and choice of pharmacotherapy (sibutramine hydrochloride, orlistat, or diethylpropion hydrochloride) during months 3 to 7 and continued use of medications and maintenance strategies for months 8 to 24. The mean age of participants was 47 years; 83% were women, and 75% were white. Retention rates were 51% for the IMI group and 46% for the UCC group (P = .30). After 2 years, the results were as follows: (1) among 390 randomized participants, 31% in the IMI group achieved a 5% or more weight loss and 7% achieved a 20% weight loss or more, compared with 9% and 1% of those in the UCC group. (2) The mean +/- SEM baseline observation carried forward analysis showed a weight loss of -4.9% +/- 0.8% in IMI and -0.2 +/- 0.3% in UCC. (3) Last observation carried forward analysis showed a weight loss of -8.3% +/- 0.79% for IMI, whereas UCC was -0.0% +/- 0.4%. (4) A total of 101 IMI completers lost -9.7% +/- 1.3% (-12.7 +/- 1.7 kg), whereas 89 UCC completers lost -0.4% +/- 0.7% (-0.5 +/- 0.9 kg); (P < .001 for all group differences). Many metabolic parameters improved. Primary care practices can initiate effective medical management for extreme obesity; future efforts must target improving retention and weight loss maintenance. clinicaltrials.gov Identifier: NCT00115063.


Predictors of metabolic syndrome in community-dwelling older adults.
The metabolic syndrome has been associated with a variety of individual variables, including demographics, lifestyle, clinical measures and physical performance. We aimed to identify independent predictors of the prevalence and incidence of metabolic syndrome in a large cohort of older adults. The Longitudinal Aging Study Amsterdam is a prospective cohort including community-dwelling adults aged 55-85 years. Metabolic syndrome was defined according to criteria of the National Cholesterol Education Program Adult Treatment Panel III. The incidence of metabolic syndrome was calculated over a period of three years. Stepwise backward logistic regression analyses were used to identify predictors, including variables for demographics, lifestyle, clinical measures and physical performance, both in a cross-sectional cohort (n = 1292) and a longitudinal sub-cohort (n = 218). Prevalence and incidence of metabolic syndrome were 37% (n = 479) and 30% (n = 66), respectively. Cross-sectionally, heart disease (OR: 1.91, 95% CI: 1.37-2.65), peripheral artery disease (OR: 2.13, 95% CI: 1.32-3.42), diabetes (OR: 4.74, 95% CI: 2.65-8.48), cerebrovascular accident (OR: 1.92, 95% CI: 1.09-3.37), and a higher Body Mass Index (OR: 1.32, 95% CI: 1.26-1.38) were significant independent predictors of metabolic syndrome. Longitudinally, Body Mass Index (OR: 1.16, 95% CI: 1.05-1.27) was an independent predictor of metabolic syndrome. Four age related diseases and a higher Body Mass Index were the only predictors of metabolic syndrome in the cross-sectional cohort, despite the large variety of variables included in the multivariable analysis. In the longitudinal sub-cohort, a higher Body Mass Index was predictive of developing metabolic syndrome.


circHIPK3 Promotes Cell Proliferation and Migration of Gastric Cancer by Sponging miR-107 and Regulating BDNF Expression.
Circular RNAs (circRNAs) play important regulatory roles in cancer development. However, the mechanisms by which circRNAs regulate gene expression in gastric cancer (GC) remain unclear. Human GC samples and their matched normal adjacent tissues were obtained from 30 patients to assess the expression of circHIPK3 and its relationship with GC proliferation and migration. A series of in vitro and in vivo functional experiments were carried out to elucidate the role of circHIPK3 in GC proliferation and migration, and its underlying molecular mechanisms. Using a circRNA microarray we found a circRNA termed circHIPK3 that performed a significant regulatory role in GC. circHIPK3 was further confirmed to be upregulated in all GC tissues and cells tested. Furthermore, circHIPK3 levels were associated with Tumor & Lymph Node & Metastasis(TNM) stage (P = 0.032). The area under the receiver operating characteristic curve (ROC) was 0.743 (95% confidence interval 0.615-0.872; P = 0.001). CCK-8, colony formation, Transwell and EdU assays were performed to evaluate the effects of circHIPK3 on cell proliferation and migration in GC. Moreover, circHIPK3 was identified as a sponge of miR-107, and as such it regulated brain-derived neurotrophic factor (BDNF), which plays a pivotal role in the development of GC. circHIPK3 represents a novel potential biomarker and therapeutic target of GC.


[The value of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG PET-CT) in evaluating the stability of atherosclerotic plaques].
Objective: Positron emission tomography-computed tomography (PET-CT) has been used to quantify inflammatory response in the body. The aim of the present study was to explore the possibility of using this method to evaluate the stability of atherosclerotic plaques and the efficacy of atorvastatin in stabilizing atherosclerotic plaques. Methods: Twenty New Zealand male white rabbits were included and divided into the atorvastatin intervention group and the control group, with 10 rabbits in each group. Rabbits in both groups were fed with a high fat diet for 20 weeks, and treated with thoracoabdominal aortic balloon-pulling to establish atherosclerosis model at the end of the 2nd week. Rabbits in atorvastatin intervention group was given atorvastatin intragastrically once a day. At the 8th week, thoracoabdominal aortic ultrasound was used to detect plaques in all rabbits. Blood was drawn at the 3rd and the 20th week, respectively, to measure blood lipids, high-sensitive C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9). At the end of experiment, survival animals were scanned by (18)F-FDG PET-CT, and the average and maximum standard uptake values (SUVmean, SUVmax) of aortic segments were measured. Thereafter, the animals were sacrificed and aortic specimens of rabbits were taken and examined by immunohistochemistry. The pathological indexes were measured and compared. Results: At the end of experiment, the total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), hs-CRP [ (4.58±0.51) ng/ml vs.(5.87±0.66) ng/ml, P<0.01], MMP-9[ (43.93±2.16) ng/ml vs. (50.77±2.32) ng/ml, P<0.01], SUVmean (0.59±0.15 vs. 0.68±0.20, P<0.05) , SUVmax (0.68±0.20 vs. 0.81±0.27, P<0.05) , plaque area [ (0.36±0.24) mm(2) vs. (0.50±0.34) mm(2), P<0.05) ] and density of macrophage[ (4.34±1.54) % vs. (5.65±1.89) %, P<0.01] in the atorvastatin intervention group were significantly lower than those in the control group. In contrast, fiber cap thickness of the plaque[ (4.12±0.66) μm vs. (2.96±0.37) μm, P<0.01] in the atorvastatin intervention group was higher than that of the control group, and the difference was statistically significant. The arterial plaque areas were positively correlated with SUVmean (r=0.27, P<0.05) and SUVmax (r=0.43, P<0.01) . Fiber cap thickness was negatively correlated with SUVmean (r=-0.38, P<0.05) and SUVmax (r=-0.47, P<0.01) . The density of macrophage were positively correlated with SUVmean (r=0.52, P<0.01) and SUVmax (r=0.51, P<0.01) . Conclusion: (18)F-FDG PET/CT can be used to evaluate the efficacy of atorvastatin by the stability of atherosclerotic plaques.


Role of Tumor Subtypes in Response to Neoadjuvant Chemotherapy in Non-metastatic Breast Cancer.
Neoadjuvant chemotherapy (NAC) is an integral part of breast cancer treatment. Determination of the factors that can distinguish patients who will have best response to NAC is invaluable. In this study, we aimed to elucidate the factors influencing patient response to NAC. We retrospectively collected data of female patients with non-metastatic breast cancer that had received NAC followed by surgery, admitted to Imam Khomeini hospital between 2015-2019. We investigated the association between various tumor and patients' characteristics with pathologic complete response (PCR). Overall data of 205 female patients were collected. PCR was observed in 27.6% of cases. PCR rate in luminal A, luminal B, HER2 enriched, and TNB tumors was reported in 11.1%, 30.2%, 35.7%, and 36.4% of patients respectively (P=0.27). In patients with luminal B tumors, PCR was more prevalent in patients with positive HER2 only (P=0.006). In our study factors which was significantly associated with PCR were: tumor grade, progesterone receptor (PR) status, and HER2 status. In the multiple regression model, positive PR in the tumor lowered the odds of pathologic response 3.6 times (P=0.004). In our study, tumor grade, PR status, and HER2 status was associated with response to NAC. PCR was more prevalent in non-luminal tumors; however, PCR rate in luminal B patients-especially those with HER2 positive status- was slightly less than non-luminals.


The development of a core key word signing vocabulary (Lámh) to facilitate communication with children with down syndrome in the first year of mainstream primary school in Ireland.
Key word signing, an unaided augmentative, and alternative communication (AAC) system is commonly used by children with Down syndrome who attend mainstream primary schools. To ensure the successful use of key word signing within a mainstream environment, a meaningful, contextually appropriate sign vocabulary must be available to all communication partners. The aim of this study was to develop a core school-based key word signing vocabulary to facilitate effective communication between children with Down syndrome and their communication partners in the first year of mainstream primary school. Four key groups-participants with Down syndrome, their peers, teachers, and special needs assistants-and a speech-language pathologist contributed to the vocabulary over the course of an academic year, through observations, semi-structured interviews, and guided tours of the school environment. Based on criteria of frequency and commonality, 140 words were considered to be core vocabulary. The current study provides new insights into the complex process of vocabulary selection for children who use key word signing at school and highlights the importance of access to a functional sign vocabulary in facilitating inclusive education practices.


Designing electronic medication reconciliation for patients: the lead user method.
There is a potential to reduce medication errors by supporting the use of medication reconciliation through electronic Personal Health Records. The lead user method was used to identify specific goals and activities that are required to have in an electronic medication reconciliation tool and to provide a synthesized visual design that would reflect these requirements. Lead users identified two major functionalities of a proposed medication reconciliation tool: ability to view and edit certain medication information when reconciling medication lists and share most current, reconciled medication lists with selected providers.


Physical and Metabolic Integrity of the Blood-Brain Barrier in HIV Infection: A Special Focus on Intercellular Junctions, Influx and Efflux Transporters and Metabolizing Enzymes.
The advent of highly active antiretroviral therapy has significantly reduced morbidity and mortality in human immunodeficiency virus (HIV) infection. Despite this reduction, complete eradication of HIV from the human body is not feasible in the nearly seen future. The central nervous system (CNS) is protected from blood-borne substances by a subtle structure of vascular endothelia known as blood-brain barrier (BBB). The BBB expresses transporters and metabolizing enzymes that modulate drug permeability in the CNS. This paper reviews the changes of the BBB phenotype as a physical and metabolic barrier in HIV infection. The effects of HIV and its proteins on intercellular junctions, influx and efflux transporters and metabolizing enzymes expressed at the BBB are reviewed. In HIV infection, the integrity of the BBB is severely compromised which often leads to serious neuropathological manifestations in the CNS. HIV and its proteins affect signaling pathways leading to oxidative stress, induction of matrix metalloproteinases and cytokines, down-regulation of different structural components of intercellular junctions, transporters and metabolizing enzymes. Taken together, HIV infection severely disrupts the integrity of the BBB and homeostasis of the CNS leading to modulation of drug disposition in the CNS and neurotoxicity. Applying knowledge of these mechanisms may lead to new therapeutic avenues to reduce neurological complications of HIV infection in the CNS.


A Systematic Review and Meta-analysis of Iowa Oral Performance Instrument Measures in Persons with Parkinson's Disease Compared to Healthy Adults.
Measures of tongue strength and endurance using the Iowa Oral Performance Instrument (IOPI) may have diagnostic utility during clinical swallowing evaluations for persons with Parkinson's disease (PwPD). Thus, the objective was to systematically analyze the existing literature comparing IOPI values of tongue strength and endurance between age- and sex-match pairs of PwPD and healthy adults as well as across disease stages. A systematic review of 12 databases and Google Scholar identified five peer-reviewed articles published in English (1990-2019) that compared tongue strength and/or endurance between PwPD and controls. Individual-level data were published in two studies and provided by authors for three studies. Study appraisal included the NIH Quality Assessment Tool and STROBE checklists. Limited data for posterior tongue pressures restricted meta-analyses to anterior pressures. Meta-analyses of group means indicated reduced tongue strength across 106 matched pairs (p < .001, I2 = 0%) and a trend for reduced endurance across 41 matched pairs (p = .07, I2 = 54%). Participant-level analyses found reduced strength (96 pairs, p < .001) and endurance (41 pairs, p = .011) secondary to PD. Tongue strength (n = 68), but not endurance (n = 41), inversely correlated with disease stage when controlling for age (p ≤ .018). Overall, clinicians should be aware that reduced anterior tongue strength and endurance are as follows : expected in approximately one-third and one-fourth of PwPD, respectively, and reduced anterior tongue strength may manifest as early as Hoehn and Yahr stage 2 with continual decline as disease progresses. Further investigation is warranted regarding the relation among tongue strength, tongue endurance, and swallowing physiology as well as applications of tongue pressure training within dysphagia rehabilitation for PwPD.


Alternative splicing and genetic variation of mhc-e: implications for rhesus cytomegalovirus-based vaccines.
Rhesus cytomegalovirus (RhCMV)-based vaccination against Simian Immunodeficiency virus (SIV) elicits MHC-E-restricted CD8+ T cells that stringently control SIV infection in ~55% of vaccinated rhesus macaques (RM). However, it is unclear how accurately the RM model reflects HLA-E immunobiology in humans. Using long-read sequencing, we identified 16 Mamu-E isoforms and all Mamu-E splicing junctions were detected among HLA-E isoforms in humans. We also obtained the complete Mamu-E genomic sequences covering the full coding regions of 59 RM from a RhCMV/SIV vaccine study. The Mamu-E gene was duplicated in 32 (54%) of 59 RM. Among four groups of Mamu-E alleles: three ~5% divergent full-length allele groups (G1, G2, G2_LTR) and a fourth monomorphic group (G3) with a deletion encompassing the canonical Mamu-E exon 6, the presence of G2_LTR alleles was significantly (p = 0.02) associated with the lack of RhCMV/SIV vaccine protection. These genomic resources will facilitate additional MHC-E targeted translational research.


Legionella pneumophila CsrA regulates a metabolic switch from amino acid to glycerolipid metabolism.
Legionella pneumophila CsrA plays a crucial role in the life-stage-specific expression of virulence phenotypes and metabolic activity. However, its exact role is only partly known. To elucidate how CsrA impacts L. pneumophila metabolism we analysed the CsrA depended regulation of metabolic functions by comparative 13C-isotopologue profiling and oxygen consumption experiments of a L. pneumophila wild-type (wt) strain and its isogenic csrA- mutant. We show that a csrA- mutant has significantly lower respiration rates when serine, alanine, pyruvate, α-ketoglutarate or palmitate is the sole carbon source. By contrast, when grown in glucose or glycerol, no differences in respiration were detected. Isotopologue profiling uncovered that the transfer of label from [U-13C3]serine via pyruvate into the citrate cycle and gluconeogenesis was lower in the mutant as judged from the labelling patterns of protein-derived amino acids, cell-wall-derived diaminopimelate, sugars and amino sugars and 3-hydroxybutyrate derived from polyhydroxybutyrate (PHB). Similarly, the incorporation of [U-13C6]glucose via the glycolysis/Entner-Doudoroff (ED) pathway but not via the pentose phosphate pathway was repressed in the csrA- mutant. On the other hand, fluxes due to [U-13C3]glycerol utilization were increased in the csrA- mutant. In addition, we showed that exogenous [1,2,3,4-13C4]palmitic acid is efficiently used for PHB synthesis via 13C2-acetyl-CoA. Taken together, CsrA induces serine catabolism via the tricarboxylic acid cycle and glucose degradation via the ED pathway, but represses glycerol metabolism, fatty acid degradation and PHB biosynthesis, in particular during exponential growth. Thus, CsrA has a determining role in substrate usage and carbon partitioning during the L. pneumophila life cycle and regulates a switch from amino acid usage in replicative phase to glycerolipid usage during transmissive growth.


From homoconjugated push-pull chromophores to donor-acceptor-substituted spiro systems by thermal rearrangement.
Series of homoconjugated push-pull chromophores and donor-acceptor (D-A)-functionalized spiro compounds were synthesized, in which the electron-donating strength of the anilino donor groups was systematically varied. The structural and optoelectronic properties of the compounds were investigated by X-ray analysis, UV/Vis spectroscopy, electrochemistry, and computational analysis. The homoconjugated push-pull chromophores with a central bicyclo[4.2.0]octane scaffold were obtained in high yield by [2+2] cycloaddition of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to N,N-dialkylanilino- or N,N-diarylanilino-substituted activated alkynes. The spirocyclic compounds were formed by thermal rearrangement of the homoconjugated adducts. They also can be prepared in a one-pot reaction starting from DDQ and anilino-substituted alkynes. Spiro products with N,N-diphenylanilino and N,N-diisopropylanilino groups were isolated in high yields whereas compounds with pyrrolidino, didodecylamino, and dimethylamino substituents gave poor yields, with formation of insoluble side products. It was shown by in situ trapping experiments with TCNE that cycloreversion is possible during the thermal rearrangement, thereby liberating DDQ. In the low-yielding transformations, DDQ oxidizes the anilino species present, presumably via an intermediate iminium ion pathway. Such a pathway is not available for the N,N-diphenylanilino derivative and, in the case of the N,N-diisopropylanilino derivative, would generate a strained iminium ion (A1,3 strain). The mechanism of the thermal rearrangement was investigated by EPR spectroscopy, which provides good evidence for a proposed biradical pathway starting with the homolytic cleavage of the most strained (CN)C-C(CN) bond between the fused four- and six-membered rings in the homoconjugated adducts.


Cost effectiveness of zoledronic acid in the management of skeletal metastases in hormone-refractory prostate cancer patients in France, Germany, Portugal, and the Netherlands.
Zoledronic acid (ZOL) reduces the risk of skeletal related events (SREs) in hormone-refractory prostate cancer (HRPC) patients with bone metastases. This study assessed the cost effectiveness of ZOL for SRE management in French, German, Portuguese, and Dutch HRPC patients. This analysis was based on the results of a randomized phase III clinical trial wherein HRPC patients received up to 15 months of ZOL (n = 214) or placebo (n = 208). Clinical inputs were obtained from the trial. Costs were estimated using hospital tariffs, published, and internet sources. Quality adjusted life-years (QALYs) gained were estimated from a separate analysis of EQ-5D scores reported in the trial. Uncertainty surrounding outcomes was addressed via univariate sensitivity analyses. ZOL patients experienced an estimated 0.759 fewer SREs and gained an estimated 0.03566 QALYs versus placebo patients. ZOL was associated with reduced SRE-related costs [net costs] (-€2396 [€1284] in France, -€2606 [€841] in Germany, -€3326 [€309] in Portugal and -€3617 [€87] in the Netherlands). Costs per QALY ranged from €2430 (Netherlands) to €36,007 (France). This analysis is subject to the limitations of most cost-effectiveness analyses: it combines data from multiple sources. Nevertheless, the results strongly suggest that ZOL is cost effective versus placebo in French, German, Portuguese, and Dutch HRPC patients.


Modified kinetics and selectivity of sodium channels in frog skeletal muscle fibers treated with aconitine.
The effect of the plant alkaloid aconitine on sodium channel kinetics, ionic selectivity, and blockage by protons and tetrodotoxin (TTX) has been studied in frog skeletal muscle. Treatment with 0.25 or 0.3 mM aconitine alters sodium channels so that the threshold of activation is shifted 40-50 mV in the hyperpolarized direction. In contrast to previous results in frog nerve, inactivation is complete for depolarizations beyond about -60 mV. After aconitine treatment, the steady state level of inactivation is shifted approximately 20 mV in the hyperpolarizing direction. Concomitant with changes in channel kinetics, the relative permeability of the sodium channel to NH4,K, and Cs is increased. This altered selectivity is not accompanied by altered block by protons or TTX. The results suggest that sites other than those involved in channel block by protons and TTX are important in determining sodium channel selectivity.


Increased concentration of an indigenous proviral mouse mammary tumor virus long terminal repeat-containing transcript is associated with neoplastic transformation of mammary epithelium in C3H/Sm mice.
Increased amounts of mouse mammary tumor virus (MMTV) proviral transcripts were found in RNA dot blots from MMTV-negative, C3H/Sm mouse mammary tumors which arose spontaneously or were induced by hormonal or chemical carcinogens or both. Other dot blots probed with a long terminal repeat (LTR) probe showed that LTR (MMTV)-containing transcripts were disproportionately represented in these tumor RNAs. Different segments of the MMTV genome were used in sequential hybridizations to Northern blots to determine relative sequence content and size of MMTV transcripts in transformed mammary tissues, as compared with those in lactating mammary glands. Increased amounts of 4.4-kilobase env and 8.1-kilobase genomic MMTV transcripts were detected with an env probe in many of the tumor RNAs examined. Hybridization of the same Northern blots containing tumor RNAs with an LTR probe revealed a 2.2-kilobase transcript which was prominent in RNAs from chemically-induced, hormonally-induced, and spontaneous mammary tumors relative to those from lactating mammary glands. The LTR-containing transcript did not possess significant homology to either env or gag-pol probes. This distinctive, transformation-enhanced, 2.2-kilobase transcript may contain mouse cellular sequences in addition to LTR sequences or it may represent the message for a nonstructural viral protein encoded within the LTR open reading frame of one or more of the four C3H/Sm MMTV proviral genes.


The 'Maltreatment and Abuse Chronology of Exposure' (MACE) scale for the retrospective assessment of abuse and neglect during development.
There is increasing interest in childhood maltreatment as a potent stimulus that may alter trajectories of brain development, induce epigenetic modifications and enhance risk for medical and psychiatric disorders. Although a number of useful scales exist for retrospective assessment of abuse and neglect they have significant limitations. Moreover, they fail to provide detailed information on timing of exposure, which is critical for delineation of sensitive periods. The Maltreatment and Abuse Chronology of Exposure (MACE) scale was developed in a sample of 1051 participants using item response theory to gauge severity of exposure to ten types of maltreatment (emotional neglect, non-verbal emotional abuse, parental physical maltreatment, parental verbal abuse, peer emotional abuse, peer physical bullying, physical neglect, sexual abuse, witnessing interparental violence and witnessing violence to siblings) during each year of childhood. Items included in the subscales had acceptable psychometric properties based on infit and outfit mean square statistics, and each subscale passed Andersen's Likelihood ratio test. The MACE provides an overall severity score and multiplicity score (number of types of maltreatment experienced) with excellent test-retest reliability. Each type of maltreatment showed good reliability as did severity of exposure across each year of childhood. MACE Severity correlated 0.738 with Childhood Trauma Questionnaire (CTQ) score and MACE Multiplicity correlated 0.698 with the Adverse Childhood Experiences scale (ACE). However, MACE accounted for 2.00- and 2.07-fold more of the variance, on average, in psychiatric symptom ratings than CTQ or ACE, respectively, based on variance decomposition. Different types of maltreatment had distinct and often unique developmental patterns. The 52-item MACE, a simpler Maltreatment Abuse and Exposure Scale (MAES) that only assesses overall exposure and the original test instrument (MACE-X) with several additional items plus spreadsheets and R code for scoring are provided to facilitate use and to spur further development.


FIVE-YEAR INCIDENCE AND VISUAL ACUITY OUTCOMES FOR INTRAVITREAL THERAPY IN BILATERAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Fight Retinal Blindness! Project.
To compare treatment intensity and mean visual acuity gains for first- and second-affected eyes with age-related macular degeneration nAMD over 5 years of treatment. The cumulative incidence of second-eye involvement was assessed. We analyzed data from the Fight Retinal Blindness! project database, a prospectively designed registry of "real-world" outcomes from Australia, New Zealand, Switzerland, and Singapore. Patients with bilateral age-related macular degeneration with ≥5 years of follow-up on treatment were included. Six thousand five hundred and forty-two eyes being treated for age-related macular degeneration were tracked from 2005 to 2017. Thousand two hundred and sixty-one patients had bilateral age-related macular degeneration; of whom, 302 had 5 years of follow-up. Of these, 170 patients started treatment for each eye at least 2 months apart. The mean baseline visual acuity of second-affected eyes was significantly higher than that of first-eyes (20/50 + 2 vs. 20/80; P < 0.01). Second-affected eyes lost a mean of 5.8 (-9.1 to -2.6) logarithm of the minimum angle of resolution letters after 5 years of treatment, whereas the vision of the first-affected eyes remained stable (P = 0.01). Second-affected eyes received fewer injections than the first-affected eyes after the first year of treatment (6.2/year vs. 7.8/year; P < 0.01) and reactivated earlier (376 vs. 507 days; P = 0.04). The cumulative incidence of second eye involvement was 54% over 5 years. Second-affected eyes received fewer treatments and reactivated earlier. Care should be taken to avoid undertreating second-affected eyes.


Immunoassay for glial fibrillary acidic protein: antigen recognition is affected by its phosphorylation state.
Glial fibrillary acid protein (GFAP) is used commonly as a marker of astrogliosis and astrocyte activation in several situations involving brain injury. Its content may be measured by immunocytochemistry, immunoblotting or enzyme-linked immunosorbent assay (ELISA), usually employing commercial antibodies. Two major post-translational modifications in GFAP (phosphorylation and proteolysis) may alter the interpretation of results or for immunoassay standardization. This study using a non-sandwich ELISA aimed to investigate the putative changes in the immunorecognition due to the phosphorylated state of the antigen by a routinely used polyclonal anti-GFAP antibody from DAKO. Results involving in vitro phosphorylation of purified GFAP or biological samples (brain tissue, cell culture and cerebrospinal fluid) mediated by protein kinase dependent on cAMP indicate that GFAP phosphorylation improves the recognition by the used antibody. These results provide support to the understanding of fast changes in the GFAP-immunoreactivity and suggest that caution is necessary in the interpretation of results using this antibody, as well as indicate that the effect of post-translational modifications must be considered during the standardization of immunoassays with other antibodies.


Determination of cadmium, lead, copper and zinc in Yemeni khat by anodic stripping voltammetry.
Trace element concentrations in khat were investigated as they can disturb trace element levels in the body. Cadmium (Cd), lead (Pb), copper (Cu) and zinc (Zn) levels in khat and 6 leafy vegetables commonly consumed in the Republic of Yemen were determined by differential pulse anodic stripping voltammetry after wet digestion of the organic matter. Khat had significantly higher concentrations of Cu and Zn than did the leafy vegetables, but similar amounts of Cd and Pb. The average daily intake of khat consumers of Cd, Pb, Cu and Zn from khat only was estimated to be 2.0-10.2 microg/day, 23.6-118.0 microg/day, 530-2654 microg/day and 662-3311 microg/day respectively. Although high, these values were within Food and Agriculture Organization/World Health Organization tolerance limits.


How do people with dementia respond to different types of art? An explorative study into interactive museum programs.
Various art programs are available for people with dementia. These have been shown to contribute to the patient's quality of life. But are all types of art suitable for this purpose and for the target group? This study investigated whether responsiveness during museum programs depends on the type of art work shown and/or characteristics of the person with dementia, such as severity of dementia or specific cognitive impairments. A cross-sectional observational study was conducted in which the responsiveness of people with dementia to different types of art was investigated as part of a study into the implementation of the Unforgettable program, an interactive guided museum tour program in Dutch museums for people with dementia. The appreciative and active responsiveness and interaction with others during the program appeared related to the severity of dementia, to specific cognitive impairments, and to type of artworks. People with more severe dementia responded less to art than people with mild dementia. Artworks with more natural elements revealed less interaction with others. Artifacts (i.e., objects not originally meant as artworks) evoked more reactions than artworks. The study results are important to take into account when designing and offering art programs for people with dementia. Knowing which type of art works appeals most to (subgroups of) people with dementia will contribute to the optimization of art programs for this target group and to their active participation in such programs.


Long-term swallowing, trismus, and speech outcomes after combined chemoradiotherapy and preventive rehabilitation for head and neck cancer; 10-year plus update.
The objective of this study was to explore the 10-year plus outcomes of Intensity Modulated Radiotherapy with concomitant chemotherapy (CRT) combined with preventive swallowing rehabilitation (CRT+) for head and neck cancer (HNC). Subjective and objective swallowing, trismus, and speech related outcomes were assessed at 10-year plus after CRT+. Outcomes were compared to previously published 6-year results of the same cohort. Fourteen of the 22 patients at 6-year follow-up were evaluable. Although objective swallowing-related outcomes showed no deterioration (eg, no feeding tube dependency and no pneumonia), swallowing-related quality of life slightly deteriorated over time. No patients had or perceived trismus. Voice and speech questionnaires showed little problems in daily life. Overall quality of life (QOL) was good. After CRT with preventive rehabilitation exercises for advanced HNC, swallowing, trismus, and speech related outcomes moderately deteriorated from 6 to 10 years, with an on average good overall QOL after.


Identification of a heparin-binding region of rat thyroglobulin involved in megalin binding.
We recently showed that thyroglobulin (Tg) is a heparin-binding protein and that heparin inhibits binding of Tg to its endocytic receptor megalin (gp330). Here we have identified a heparin-binding region in the carboxyl-terminal portion of rat Tg and have studied its involvement in megalin binding. Rat thyroid extracts, obtained by ammonium sulfate precipitation, were separated by column fractionation into four Tg polypeptides, with apparent masses of 660, 330, 210, and 50 kDa. As assessed by enzyme-linked immunoadsorbent assays and ligand blot binding assays, megalin bound to intact Tg (660 and 330 kDa) and, to a even greater extent, to the 210-kDa Tg polypeptide. Furthermore, the 210-kDa Tg polypeptide inhibited megalin binding to intact Tg by approximately 70%. Solid phase assays showed binding of biotin-labeled heparin to intact Tg and to the 210-kDa Tg polypeptide. We characterized the 210-kDa Tg polypeptide by matrix-assisted laser desorption/ionization mass spectrometry analysis and found that it corresponds to the carboxyl-terminal portion of rat Tg. We developed a synthetic peptide corresponding to a 15-amino acid sequence in the carboxyl-terminal portion of rat Tg (Arg(689)-Lys(703)), containing a heparin-binding consensus sequence (SRRLKRP) and demonstrated heparin binding to this peptide. A rabbit antibody raised against the peptide recognized intact Tg in its native conformation and under denaturing conditions. This antibody markedly reduced heparin-binding to intact Tg, indicating that the region of native Tg corresponding to the peptide is involved in heparin binding. Furthermore, the anti-Tg peptide antibody almost completely inhibited binding of megalin to Tg, suggesting that the Tg region containing the peptide sequence is required for megalin binding. Physiologically, Tg binding to megalin on thyroid cells may be facilitated by Tg interaction with heparin-like molecules (heparan sulfate proteoglycans) via adjacent binding sites.


[Thyroid disorders in spontaneous chronic urticaria].
Chronic spontaneous urticaria (CSU) is linked to thyroid disease in up to 54%, with predominance of hypothyroidism. To describe the impairments of the thyroid function in patients with CSU in a third level of care. A cross-sectional, observational, and descriptive study in which we have included men and women over 18-year-old with CSU; in which TSH and free T4 were quantified. According to the results, they were classified as euthyroid, hyperthyroid, and hypothyroid; in the latter ones, the presence of antithyroid antibodies was intentionally sought. The demographic and biochemical characteristics of the results were assessed. The clinical characteristics of 127 patients with CSU were analyzed. Women accounted for 78%. The average age was 44.5 ± 15.1 years. Impairments of the thyroid function were identified in 50 patients (39%), and subclinical hypothyroidism (SH) occurred in 41 (82%) of them; patients with hyperthyroidism were not found. Of the patients with hypothyroidism, 14 (28%) presented positive antibodies; all of them were women. More than a third of the analyzed patients with CSU presented impairments of the thyroid function; subclinical hypothyroidism (SH) was more common. The importance of identifying this entity lies in the possibility of a multidisciplinary treatment with endocrinology. Subsequent studies may establish whether the presence of hypothyroidism influences the activity of CSU.


FAIR: a fast algorithm for document image restoration.
We present, in this paper, the FAIR algorithm: a fast algorithm for document image restoration. This algorithm has been submitted to different contests where it showed good performance in comparison to the state of the art. In addition, this method is scale invariant and fast enough to be used in real-time applications. The method is based on a double-threshold edge detection approach that makes it possible to detect small details while remaining robust against noise. The performance of the proposition is evaluated on several types of degraded document images where considerable background noise or variation in contrast and illumination exist.


Cuba's National Health Sciences Prizes 2007.
In December 2007, Cuba's National Health Science Prizes were awarded for outstanding contributions to basic science, clinical medicine, and population health. The prizes, first bestowed in 1976, are sponsored by Cuba's Ministry of Public Health and the National Council of Scientific Societies. Works are selected based on excellence, scientific rigor, and relevance. In 2007, one Grand Prize, 13 additional prizes, and 11 special mentions were awarded from among 244 entries forwarded from the provincial level.


Psychophysical and neurophysiological responses to acupuncture stimulation to incorporated rubber hand.
From a neuroscientific perspective, the sensations induced by acupuncture are not only the product of the bottom-up modulation of simple needling at somatosensory receptors, but also of the reciprocal interaction of top-down modulation from the brain. The present study investigated whether acupuncture stimulation to incorporated body parts produces brain responses that are similar to the responses observed following acupuncture stimulation to the real hand. The present study included 17 participants who watched a rubber hand being synchronously stroked with their unseen left hand to induce incorporation of the rubber hand into their body. After the experimental modification of body ownership, acupuncture needle stimulation was applied to the LI4 acupoint on the incorporated rubber hand while brain activity was measured with functional magnetic resonance imaging (fMRI). When the rubber hand was fully incorporated with the real body, acupuncture stimulation to the rubber hand resulted in the experience of the DeQi sensation as well as brain activations in the dorsolateral prefrontal cortex (DLPFC), insula, secondary somatosensory cortex (SII), and medial temporal (MT) visual area. The insular activation was associated with the DeQi sensation from the rubber hand. The psychophysical and neurophysiological responses associated with acupuncture stimulation to the incorporated rubber hand were influenced by an enhanced bodily awareness of the hand, which was likely due to top-down modulation from the interoceptive system in the brain.


Space Emerges from What We Know-Spatial Categorisations Induced by Information Constraints.
Seeking goals carried out by agents with a level of competency requires an "understanding" of the structure of their world. While abstract formal descriptions of a world structure in terms of geometric axioms can be formulated in principle, it is not likely that this is the representation that is actually employed by biological organisms or that should be used by biologically plausible models. Instead, we operate by the assumption that biological organisms are constrained in their information processing capacities, which in the past has led to a number of insightful hypotheses and models for biologically plausible behaviour generation. Here we use this approach to study various types of spatial categorizations that emerge through such informational constraints imposed on embodied agents. We will see that geometrically-rich spatial representations emerge when agents employ a trade-off between the minimisation of the Shannon information used to describe locations within the environment and the reduction of the location error generated by the resulting approximate spatial description. In addition, agents do not always need to construct these representations from the ground up, but they can obtain them by refining less precise spatial descriptions constructed previously. Importantly, we find that these can be optimal at both steps of refinement, as guaranteed by the successive refinement principle from information theory. Finally, clusters induced by these spatial representations via the information bottleneck method are able to reflect the environment's topology without relying on an explicit geometric description of the environment's structure. Our findings suggest that the fundamental geometric notions possessed by natural agents do not need to be part of their a priori knowledge but could emerge as a byproduct of the pressure to process information parsimoniously.


[Complete elimination of cytomegalovirus without antiviral therapy after systemic transplantation of mesenchymal bone marrow stromal cells in a patient with ulcerative colitis].
Cytomegalovirus infection (CMV) has become in the last 15-20 years one of the most important problems of scientific research and clinical high attention. This is due to new information discovered about its leading role in the origin, development, and the outcome of a large group of serious diseases. Cytomegalovirus (CMV) is one of the most common causative agents of opportunistic infections (OI) in patients with IBD, which are mandatory feature of the state of immunodeficiency. Numerous studies in vivo and in vitro studies have demonstrated that mesenchymal stromal cells (MSCs) suppress immune reactions to allogeneic stimulation, but not the invasion of infection, as well as themselves possess antiviral and antimicrobial activity, as demonstrated in this clinical case.


The DNA damage response in mammalian oocytes.
DNA damage is one of the most common insults that challenge all cells. To cope, an elaborate molecular and cellular response has evolved to sense, respond to and correct the damage. This allows the maintenance of DNA fidelity essential for normal cell viability and the prevention of genomic instability that can lead to tumor formation. In the context of oocytes, the impact of DNA damage is not one of tumor formation but of the maintenance of fertility. Mammalian oocytes are particularly vulnerable to DNA damage because physiologically they may lie dormant in the ovary for many years (>40 in humans) until they receive the stimulus to grow and acquire the competence to become fertilized. The implication of this is that in some organisms, such as humans, oocytes face the danger of cumulative genetic damage for decades. Thus, the ability to detect and repair DNA damage is essential to maintain the supply of oocytes necessary for reproduction. Therefore, failure to confront DNA damage in oocytes could cause serious anomalies in the embryo that may be propagated in the form of mutations to the next generation allowing the appearance of hereditary disease. Despite the potential impact of DNA damage on reproductive capacity and genetic fidelity of embryos, the mechanisms available to the oocyte for monitoring and repairing such insults have remained largely unexplored until recently. Here, we review the different aspects of the response to DNA damage in mammalian oocytes. Specifically, we address the oocyte DNA damage response from embryonic life to adulthood and throughout oocyte development.


Unsupported labeling of race as a risk factor for certain diseases in a widely used medical textbook.
Confounding of racial, socioeconomic, and behavioral characteristics may lead to the misidentification of race as a risk factor for certain diseases. The authors evaluated the validity of attributing race as a risk factor in a widely used pathology textbook. In 2009-2010, the authors searched Robbins and Cotran Pathologic Basis of Disease, Professional Edition (8th ed) for assertions that African Americans have a different disease profile than do individuals of other races. They evaluated the references cited in the textbook, assessing the quality of the sources and whether those authors controlled for confounding variables, such as socioeconomic status and behavioral characteristics. For statements that remained unconfirmed, the authors searched the literature for evidence supporting or contradicting the claims made in the textbook. The authors classified each statement from the textbook as supported, unconfirmed, or contradicted. Of the 31 relevant statements, 11 were supported by the literature review, 17 remained unconfirmed, and three were contradicted. About two-thirds of the assertions that different risk factors exist for African Americans found in a widely used pathology textbook could not be supported by the published literature. Failure to separate race from other socioeconomic and behavioral characteristics as risk factors for certain diseases may contribute to the misdiagnosis of patients and interfere with efforts to identify and remove causes of health disparities.


[μ-1,2,3,4-Tetra-kis(pyridin-4-yl)butane-κ(2) N (1):N (4)]bis-[trimeth-yl(thio-cyanato-κN)tin(IV)].
In the title compound, [Sn2(CH3)6(NCS)2(C24H22N4)], the 1,2,3,4-tetra-kis-(pyridin-4-yl)butane ligand uses the pyridine N atoms at the ends of the butyl chain to coordinate to two trimethylthiocyanatotin(IV) units, forming a dinuclear structure. The Sn(IV) atom in the mol-ecule shows a distorted trans-trigonal-bipyramidal coordination with the methyl groups in equatorial positions. The mol-ecule lies on a center of inversion, with the mid-point of the butyl chain coinciding with this symmetry element. In the crystal, weak C-H⋯π inter-actions occur between pyridine rings of adjacent mol-ecules.


Nanometallomics: an emerging field studying the biological effects of metal-related nanomaterials.
Metallomics, focusing on the global and systematic understanding of the metal uptake, trafficking, role and excretion in biological systems, has attracted more and more attention. Metal-related nanomaterials, including metallic and metal-containing nanomaterials, have unique properties compared to their micro-scaled counterparts and therefore require special attention. The small size effect, surface effect, and quantum size effect directly influence the physicochemical properties of nanostructured materials and their fate and behavior in biota. However, to our knowledge, the metallomics itself did not touch this special category of materials yet. Therefore, the term "nanometallomics" is proposed and the systematic study on the absorption, distribution, metabolism, excretion (ADME) behavior of metal-related nanomaterials in biological systems and their interactions with genes, proteins and other biomolecules will be reviewed. The ADME behavior of metal-related nanomaterials in the biological systems is influenced by their physicochemical properties, the exposure route, and the microenvironment of the deposition site. Nanomaterials may not only interact directly or indirectly with genes, proteins and other molecules to cause DNA damage, genotoxicity, immunotoxicity, and cytotoxicity, but also stimulate the immune responses, circumvent tumor resistance and inhibit tumor metastasis. Nanometallomics needs to be integrated with other omics sciences, such as genomics, proteomics and metabolomics, to explore the biomedical data and obtain the overall knowledge of underlying mechanisms, and therefore to improve the application performance and to reduce the potential risk of metal-related nanomaterials.


Photolocalized tinea facialis.
The case of a 34-year-old white woman with tinea facialis that persisted for nine months prior to diagnosis is presented. The confluent plaquelike erythematous eruption of the face with eyelid lichenification that flared outdoors was thought to represent polymorphic light eruption and was refractory to antibiotics, corticosteroids (topical and systemic), and antimalarials. A KOH preparation was positive when the dermatosis spilled onto the mandibular region, and restaining of the initial skin biopsy revealed fungal hyphae. Complete resolution was accomplished with griseofulvin and MicTin. Tinea cab be added to the list of infectious agents that have a photosensitivity component. The fungus possibly "photolocalizes" to sun-damaged areas, ie, areas of increased capillary permeability. This case illustrates the importance of including tinea in considering diagnoses of sun-exposed lesions of the face.


Bystanding an abused child: testing the applicability of the stages of change construct.
A minority of child abuse cases is recognized by professionals, making the role of non-professional bystanders essential. The stages of change construct, as proposed by the Transtheoretical Model, may provide a useful approach to explain non-professional helping behavior. The objective of this study was to test the applicability of the stages of change construct by (i) assessing whether cognitive determinants distinguish between the stages, (ii) testing the predictive value of the stages for future helping behavior and (iii) examining the mediating role of the stages in the relation between previous and future helping behavior. Data of 126 adult non-professional bystanders were analyzed. Respondents were questioned by telephone or via an Internet questionnaire, at baseline and after a follow-up of about two months later. Attitude toward helping was significantly less positive in pre-contemplation than in the other stages, and self-efficacy expectations were significantly higher in preparation compared with the other stages. Moreover, baseline preparators were more likely to conduct future helping behavior than those in the two earlier stages. Finally, the stages of change mediated the relation between previous and future helping behavior. Initial support was found for the applicability of the stages of change construct for helping behavior by non-professional bystanders.


Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA.
Analysis of mitochondrial DNA (mtDNA) in muscle and blood from 72 patients with mitochondrial myopathy showed that 30 had major deletions of a variable proportion of muscle mtDNA. All of these 30 patients presented with progressive external ophthalmoplegia and limb weakness, and 8 had the additional features of the Kearns-Sayre syndrome. Of the 42 patients without detectable muscle mtDNA deletions, 10 had progressive external ophthalmoplegia and limb weakness, 2 had the Kearns-Sayre syndrome, 11 had limb weakness without extraocular involvement, and 19 had multisystem disorders predominantly affecting the central nervous system. Only 2 patients with mtDNA deletions had clinically affected relatives, compared with 10 of those without deletions. In the 4 patients with polarographic defects exclusively involving complex I (NADH coenzyme Q reductase), the deleted protein-coding genes were confined to those for complex I subunits. Thirteen other patients with apparently identical deletions had variable clinical and biochemical features. Immunoblots of complex I polypeptides from patients with deletions were either indistinguishable from controls or showed only a mild generalized decrease in all identifiable subunits.


Larval anopheline mosquito recta exhibit a dramatic change in localization patterns of ion transport proteins in response to shifting salinity: a comparison between anopheline and culicine larvae.
Mosquito larvae live in dynamic aqueous environments, which can fluctuate drastically in salinity due to environmental events such as rainfall and evaporation. Larval survival depends upon the ability to regulate hemolymph osmolarity by absorbing and excreting ions. A major organ involved in ion regulation is the rectum, the last region for modification of the primary urine before excretion. The ultrastructure and function of culicine larval recta have been studied extensively; however, very little published data exist on the recta of anopheline larvae. To gain insight into the structure and functions of this organ in anopheline species, we used immunohistochemistry to compare the localization of three proteins [carbonic anhydrase (CA9), Na+/K+ P-ATPase and H+ V-ATPase] in the recta of anopheline larvae reared in freshwater and saline water with the localization of the same proteins in culicine larvae reared under similar conditions. Based on the following key points, we concluded that anophelines differ from culicines in larval rectal structure and in regulation of protein expression: (1) despite the fact that obligate freshwater and saline-tolerant culicines have structurally distinct recta, all anophelines examined (regardless of saline-tolerance) have a structurally similar rectum consisting of distinct DAR (dorsal anterior rectal) cells and non-DAR cells; (2) anopheline larvae undergo a dramatic shift in rectal Na+/K+-ATPase localization when reared in freshwater vs saline water. This shift is not seen in any culicine larvae examined. Additionally, we use these immunohistochemical analyses to suggest possible functions for the DAR and non-DAR cells of anopheline larvae in freshwater and saline conditions.


Griffithsin and Carrageenan Combination Results in Antiviral Synergy against SARS-CoV-1 and 2 in a Pseudoviral Model.
Over 182 million confirmed cases of COVID-19 and more than 4 million deaths have been reported to date around the world. It is essential to identify broad-spectrum antiviral agents that may prevent or treat infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but also by other coronaviruses that may jump the species barrier in the future. We evaluated the antiviral selectivity of griffithsin and sulfated and non-sulfated polysaccharides against SARS-CoV-1 and SARS-CoV-2 using a cytotoxicity assay and a cell-based pseudoviral model. The half-maximal cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were determined for each compound, using a dose-response-inhibition analysis on GraphPad Prism v9.0.2 software (San Diego, CA, USA). The therapeutic index (TI = CC50/EC50) was calculated for each compound. The potential synergistic, additive, or antagonistic effect of different compound combinations was determined by CalcuSyn v1 software (Biosoft, Cambridge, UK), which estimated the combination index (CI) values. Iota and lambda carrageenan showed the most potent antiviral activity (EC50 between 3.2 and 7.5 µg/mL). Carrageenan and griffithsin combinations exhibited synergistic activity (EC50 between 0.2 and 3.8 µg/mL; combination index <1), including against recent SARS-CoV-2 mutations. The griffithsin and carrageenan combination is a promising candidate to prevent or treat infections by SARS-CoV-1 and SARS-CoV-2.


Gradual reduction of supracondylar fracture of the humerus in children reporting late with a swollen elbow.
To study the outcome of gradual reduction by skin traction of supracondylar fracture of the humerus in children with swollen elbow, who seek treatment two days or longer after the injury. Fifteen children aged between 4 and 11 years (average 7 years 11 months), who had initially consulted a traditional practitioner, reported between 2 and 21 days (average 7.5) after the injury were treated by skin traction with the elbow kept straight and the forearm in position of comfort. The average duration of stay in hospital was 14 days. All fractures healed; there was no incidence of myositis ossificans or neurovascular deficit. All patients had functional range of movements at the elbow within 6 months. Five patients developed cubitus varus deformity greater than 5 degrees, they were classified as poor result. Four out of these 5 patients had sought treatment after a delay of 7 days or longer. There were 9 good (60%), 1 fair (7%) and 5 poor (33%) results. Gradual reduction by skin traction is safe. It is possible to achieve satisfactory reduction if the delay is up to 7 days. The results with regards to deformity and function were comparable with those obtained following open or closed Kirschner wire fixation.


Voluntary and Involuntary Control of Attention in Adolescents Born Very Preterm: A Study of Eye Movements.
Very preterm birth is associated with attention deficits that interfere with academic performance. A better understanding of attention processes is necessary to support very preterm born children. This study examined voluntary and involuntary attentional control in very preterm born adolescents by measuring saccadic eye movements. Additionally, these control processes were related to symptoms of inattention, intelligence, and academic performance. Participants included 47 very preterm and 61 full-term born 13-years-old adolescents. Oculomotor control was assessed using the antisaccade and oculomotor capture paradigm. Very preterm born adolescents showed deficits in antisaccade but not in oculomotor capture performance, indicating impairments in voluntary but not involuntary attentional control. These impairments mediated the relation between very preterm birth and inattention, intelligence, and academic performance.


Density of epidermal Langerhans cells in psoriasis patients treated with an aromatic retinoid (RO 10-9359). An immunoperoxidase study using anti-T6 and anti-Ia monoclonal antibodies.
Immunocytochemical techniques using antibodies to the specific T6 and Ia (Major Histocompatibility Complex, class II, human HLA-Dr) antigens were used to determine the densities of epidermal Langerhans cells (LC) in psoriasis patients treated with the aromatic retinoid RO 10-9359. Fourteen patients were treated with the aromatic retinoid and were skin biopsied before, during and after therapy. Two psoriasis patients receiving PUVA (systemic 8-methoxypsoralen + UVA irradiation) were included in the study. The results showed an increase in LC numbers during aromatic retinoid administration, which coincided with an improvement in the clinical severity of the lesions. At the end of retinoid administration the LC numbers were similar to those found in the initial psoriatic plaques. The density of Ia+ LC, in comparison with T6+ LC in the epidermis of psoriatic plaques were significantly different. Dendritic and non-dendritic Ia+ cells were also observed in the dermis of the plaques. Unlike aromatic retinoid treated patients, PUVA treated patients showed a decrease of both T6+ and Ia+ epidermal LC by the middle of therapy, a total absence of immunoreaction by the end of therapy, and a return to normal skin values a few weeks after treatment. This immunocytochemical study helps in distinguishing between dendritic and other possible Ia-expressing cells from the infiltrate that may penetrate the epithelium. These results do not conclusively demonstrate the role of LC in the pathogenesis of psoriasis. Other factors, such as the interrelationship with other immune response cell types and alterations in the lymphokine cascade may be important.


Dysregulated gene expression networks in human acute myelogenous leukemia stem cells.
We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). Comparing the expression signature of normal HSC to that of LSC, we identified 3,005 differentially expressed genes. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources applied to highly enriched normal and malignant stem cell populations, can yield an understanding of the critical pathways regulating cancer stem cells.


Long-term survival after transplantation of unrelated donor peripheral blood or bone marrow hematopoietic cells for hematologic malignancy.
We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.


Optical properties of gadolinium gallium garnet.
The refractive index, the temperature coefficient of the refractive index, and the optical transparency of gadolinium gallium garnet are reported as a function of wavelength from the near UV to the middle IR. The materialis transparent enough for good optical components between 0.36 and 6.0 microm, and the refractive index ranges from 2.0 at the UV end to 1.8 at the IR end of the spectrum. The wavelength dependence of index is expressed as a three-term Sellmeier formula with agreement better than two parts in the fourth decimal between calculated and experimental values. Variations in composition depending on growth from various melts (e.g., stoichiometric vs congruent) have no effect on the optical parameters at this level of precision.


Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects.
Ozone (O3) is a criteria air pollutant that is associated with numerous adverse health effects, including altered respiratory immune responses. Despite its deleterious health effects, possible epigenetic mechanisms underlying O3-induced health effects remain understudied. MicroRNAs (miRNAs) are epigenetic regulators of genomic response to environmental insults and unstudied in relationship to O3 inhalation exposure. Our objective was to test whether O3 inhalation exposure significantly alters miRNA expression profiles within the human bronchial airways. Twenty healthy adult human volunteers were exposed to 0.4 ppm O3 for 2 h. Induced sputum samples were collected from each subject 48 h preexposure and 6 h postexposure for evaluation of miRNA expression and markers of inflammation in the airways. Genomewide miRNA expression profiles were evaluated by microarray analysis, and in silico predicted mRNA targets of the O3-responsive miRNAs were identified and validated against previously measured O3-induced changes in mRNA targets. Biological network analysis was performed on the O3-associated miRNAs and mRNA targets to reveal potential associated response signaling and functional enrichment. Expression analysis of the sputum samples revealed that O3 exposure significantly increased the expression levels of 10 miRNAs, namely miR-132, miR-143, miR-145, miR-199a*, miR-199b-5p, miR-222, miR-223, miR-25, miR-424, and miR-582-5p. The miRNAs and their predicted targets were associated with a diverse range of biological functions and disease signatures, noted among them inflammation and immune-related disease. The present study shows that O3 inhalation exposure disrupts select miRNA expression profiles that are associated with inflammatory and immune response signaling. These findings provide novel insight into epigenetic regulation of responses to O3 exposure.


Fecal shedding of non-O157 serogroups of Shiga toxin-producing Escherichia coli in feedlot cattle vaccinated with an Escherichia coli O157:H7 SRP vaccine or fed a Lactobacillus-based direct-fed microbial.
The objectives of this study were to determine whether fecal shedding of non-O157 Shiga toxin-producing Escherichia coli (STEC) in feedlot cattle was affected by the use of an E. coli O157:H7 vaccine or a direct-fed microbial (DFM) and whether the shedding of a particular non-O157 STEC serogroup within feces was associated with shedding of O157 or other non-O157 STEC serogroups. A total of 17,148 cattle in 40 pens were randomized to receive one, both, or neither (control) of the two interventions: a vaccine based on the siderophore receptor and porin proteins (E. coli SRP vaccine, two doses) and a DFM product (low-dose Bovamine). Fresh fecal samples (30 samples per pen) were collected weekly from pen floors for four consecutive weeks beginning approximately 56 days after study allocation. DNA extracted from enriched samples was tested for STEC O157 and non-O157 serogroups O26, O45, O103, O111, O121, and O145 and for four major virulence genes (stx1, stx2, eae, and ehxA) using an 11-gene multiplex PCR assay. Generalized linear mixed models were used to analyze the effects of treatments and make within-sample comparisons of the presence of O-serogroup-specific genes. Results of cumulative prevalence measures indicated that O157 (14.6%), O26 (10.5%), and O103 (10.3%) were the most prevalent STEC O serogroups. However, the vaccine, DFM, or both had no significant effect (P > 0.05) on fecal prevalence of the six non-O157 STEC serogroups in feedlot cattle. Within-sample comparisons of the presence of STEC serogroup-specific genes indicated that fecal shedding of E. coli O157 in cattle was associated with an increased probability (P < 0.05) of fecal shedding of STEC O26, O45, O103, and O121. Our study revealed that neither the E. coli O157:H7 vaccine, which reduced STEC O157 fecal shedding, nor the DFM significantly affected fecal shedding of non-O157 STEC serogroups, despite the fact that the most prevalent non-O157 STEC serogroups tended to occur concurrently with O157 STEC strains within fecal samples.