Lupus myelopathy.
Although neurological manifestations of systemic lupus erythematosus (SLE) are well recognised, myelopathy complicating SLE is rare. A 35-year-old woman presented with non-specific symptoms and a respiratory tract infection but had serological evidence of SLE. She subsequently deteriorated rapidly, developing a catastrophic spinal cord syndrome. Her initial MRI was normal; but after 1 month, her encephalopathy having progressed, repeat imaging showed characteristic myelitic changes. She responded only slowly to a combination of cyclophosphamide and corticosteroids. This case exemplifies the mixed presentations of SLE, including the under-recognised 'subpial leukomyelopathy' of central nervous system lupus. It highlights the challenges in managing lupus-related myelopathy and the benefits of a multidisciplinary approach to care.


Audio-visual interactions uniquely contribute to resolution of visual conflict in people possessing absolute pitch.
Individuals possessing absolute pitch (AP) are able to identify a given musical tone or to reproduce it without reference to another tone. The present study sought to learn whether this exceptional auditory ability impacts visual perception under stimulus conditions that provoke visual competition in the form of binocular rivalry. Nineteen adult participants with 3-19 years of musical training were divided into two groups according to their performance on a task involving identification of the specific note associated with hearing a given musical pitch. During test trials lasting just over half a minute, participants dichoptically viewed a scrolling musical score presented to one eye and a drifting sinusoidal grating presented to the other eye; throughout the trial they pressed buttons to track the alternations in visual awareness produced by these dissimilar monocular stimuli. On "pitch-congruent" trials, participants heard an auditory melody that was congruent in pitch with the visual score, on "pitch-incongruent" trials they heard a transposed auditory melody that was congruent with the score in melody but not in pitch, and on "melody-incongruent" trials they heard an auditory melody completely different from the visual score. For both groups, the visual musical scores predominated over the gratings when the auditory melody was congruent compared to when it was incongruent. Moreover, the AP participants experienced greater predominance of the visual score when it was accompanied by the pitch-congruent melody compared to the same melody transposed in pitch; for non-AP musicians, pitch-congruent and pitch-incongruent trials yielded equivalent predominance. Analysis of individual durations of dominance revealed differential effects on dominance and suppression durations for AP and non-AP participants. These results reveal that AP is accompanied by a robust form of bisensory interaction between tonal frequencies and musical notation that boosts the salience of a visual score.


The IMPROVE study: background and study design. Impact of Managed Pharmaceutical Care on Resource Utilization and Outcomes in Veterans Affairs Medical Centers.
An ongoing study of the impact of ambulatory care clinical pharmacists on patient outcomes at selected Veterans Affairs medical centers (VAMCs) is described. The IMPROVE (Impact of Managed Pharmaceutical Care on Resource Utilization and Outcomes in Veterans Affairs Medical Centers) study will examine the effects of referring patients at high risk for drug-related problems to a pharmacist-managed monitoring program. Nine study sites from diverse geographic locations and small and large urban areas have been selected. Investigators visited each site to evaluate the structure of care, observe pharmacist-patient interactions, and assess the level and documentation of pharmacists' activities. A coordinating center will collect and process patient-specific data from the study sites to identify high-risk patients. It is expected that 500 intervention patients and 500 control patients from the nine VAMCs will complete all portions of the study. Intervention patients will be scheduled for medication assessments by ambulatory care pharmacists and will be monitored by pharmacists for at least 12 months. The coordinating center will track refill histories for intervention patients. Investigators will assess the activities performed by ambulatory care pharmacists to determine predictors of successful patient outcomes. The two groups will be compared with respect to change from baseline in quality of life and satisfaction with health care providers. A cost-benefit analysis will be undertaken to determine the impact of pharmaceutical care relative to total patient care costs. The main outcome results of the IMPROVE study are expected to be available in 1999. The IMPROVE project will be the first study of the impact of ambulatory care clinical pharmacists on patient outcomes.


Determination of ifosfamide, 2- and 3-dechloroethyifosfamide using gas chromatography with nitrogen-phosphorus or mass spectrometry detection.
A comparison was made between methods for determining ifosfamide (IF), 2- (2DCE) and 3-dechloroethylifosfamide (3DCE) using gas chromatography with nitrogen-phosphorus detection (GC-NPD) versus positive ion electron-impact ion-trap mass spectrometry (GC-MS2). Sample pretreatment involved liquid-liquid extraction with ethyl acetate after adding trofosfamide as internal standard and alkalinization. The GC-NPD was linear, specific, and sensitive for all analytes in the range of 0.0500-100 microg/mL with lower limits of quantification (LLQ) of 0.0500 microg/mL using a 50-microgL plasma sample. The GC-MS2 was linear, specific, and sensitive for IF, 2DCE, and 3DCE in the ranges of 0.250-100, 0.500-25.0, and 0.500-25.0 microg/mL, respectively, with LLQs of 0.250, 0.500, and 0.500 microg/mL. The ranges of accuracy, within-day precision, and between-day precision for analysis of all compounds with GC-NPD did not exceed 93.3% to 105.4%, 8.0% and 9.8%, respectively. The ranges of accuracy, within-day precision, and between-day precision for analysis of all compounds with GC-MS2 did not exceed 86.5% to 99.0%, 9.0% and 12.7%, respectively. In conclusion, GC-NPD proved to be superior to GC-MS2 in sensitivity, detection range, accuracy, and precisions. Therefore GC-NPD is the method of choice for fast un-derivatized determination of IF, 2DCE, and 3DCE in human plasma, and it can readily be used for clinical pharmacokinetic studies and routine monitoring of IF-treated patients in a hospital setting.


Highly biocompatible TiO₂:Gd³⁺ nano-contrast agent with enhanced longitudinal relaxivity for targeted cancer imaging.
We report the development of a novel magnetic nano-contrast agent (nano-CA) based on Gd(3+) doped amorphous TiO(2) of size ∼25 nm, exhibiting enhanced longitudinal relaxivity (r(1)) and magnetic resonance (MR) contrasting together with excellent biocompatibility. Quantitative T1 mapping of phantom samples using a 1.5 T clinical MR imaging system revealed that the amorphous phase of doped titania has the highest r(1) relaxivity which is ∼2.5 fold higher than the commercially used CA Magnevist™. The crystalline (anatase) samples formed by air annealing at 250 °C and 500 °C showed significant reduction in r(1) values and MR contrast, which is attributed to the loss of proton-exchange contribution from the adsorbed water and atomic re-arrangement of Gd(3+) ions in the crystalline host lattice. Nanotoxicity studies including cell viability, plasma membrane integrity, reactive oxygen stress and expression of pro-inflammatory cytokines, performed on human primary endothelial cells (HUVEC), human blood derived peripheral blood mononuclear cells (PBMC) and nasopharyngeal epidermoid carcinoma (KB) cell line showed excellent biocompatibility up to relatively higher doses of 200 μg ml(-1). The potential of this nano-CA to cause hemolysis, platelet aggregation and plasma coagulation were studied using human peripheral blood samples and found no adverse effects, illustrating the possibility of the safe intravenous administration of these agents for human applications. Furthermore, the ability of these agents to specifically detect cancer cells by targeting molecular receptors on the cell membrane was demonstrated on folate receptor (FR) positive oral carcinoma (KB) cells, where the folic acid conjugated nano-CA showed receptor specific accumulation on cell membrane while leaving the normal fibroblast cells (L929) unstained. This study reveals that the Gd(3+) doped amorphous TiO(2) nanoparticles having enhanced magnetic resonance contrast and high biocompatibility is a promising candidate for molecular receptor targeted MR imaging.


A Comparative Analysis of the Injury Patterns and In-Hospital Mortality Rates of Belted and Unbelted Motor-Vehicle Occupants - Puerto Rico, January 2000 to December 2014.
Motor vehicle collisions (MVCs) constitute a leading source of morbidity and mortality worldwide. Seatbelt use has been associated with reduced mortality in MVCs. In Puerto Rico, the impact of seatbelt use on MVC deaths has not been evaluated, although they represent a major public health threat. Therefore, this study aimed to assess the association between seatbelt use and in-hospital mortality at Puerto Rico Trauma Hospital (PRTH). A retrospective cohort study of 2,685 MVC patients aged 1 to 96 years was conducted using the Trauma Registry at PRTH, with data collected from 2000 through 2014. The patient data included sociodemographic and clinical variables and outcomes. Logistic regression analyses were used to evaluate the mortality risk of patients of severe MVC-related trauma who had been wearing seatbelts and compare it to the risk sustained by their unbelted counterparts. Seatbelt use was more common in females than it was in males (71% vs.62%; p < 0.001) and more prevalent in older as opposed to younger patients (p < 0.001). Belted severe trauma victims suffered less frequently from head injuries than did their unbelted counterparts (p < 0.001). The proportions of patients with Glasgow coma scale (GCS) scores of 8 or lower (17% vs. 6%; p < 0.001) and Injury Severity Scores (ISSs) of 25 or higher (24% vs. 15%; p < 0.001) were greater for the unbelted group. Belted severe trauma victims had a 30% lower in-hospital mortality risk compared to their unbelted peers (ORunadj = 0.70; 95% CI: 0.52-0.92). After adjusting for confounders, this difference in risk was eliminated (ORadj = 1.04; 95% CI: 0.72-1.52). Our findings demonstrate that seatbelt use is associated with fewer head injuries, lower ISSs, and higher GCS scores. This suggests that using seatbelts mitigates trauma severity, thereby reducing the likelihood of in-hospital mortality for those MVC victims who were wearing seatbelts at the time of their accident.


[Vitamin D and metabolic, autoimmunologic and neoplasm diseases].
At the turn of the 19th and 20th century McColum made the discovery of vitamin D as a result of the research on cod liver oil, in order to identify substances having anti ricets effect. Since that time, knowledge of its role in the human body systematically increases. For many years it was thought that it only plays a role in regulating calcium economy. The discovery in the mid-1970s of the presence of VDR- Vitamin D Receptor in most cells of the human body have turned attention to its pleiotropic effect. Special attention deserves wit. D impact on the risk of metabolic diseases and of pre-neoplasia as well as the long-term effects of the treatment of these diseases. The article presents a short review of the results of previously conducted studies on these issues.


Anxiety, Depression, Quality of Life, Caregiver Burden, and Perceptions of Caregiver-Centered Communication among Black and White Hospice Family Caregivers.
Background: Anxiety, depression, and reduced quality of life (QOL) are common problems for hospice family caregivers, but it is unknown if disparities in these experiences exist among Black and White caregivers. Objectives: To compare anxiety, depression, QOL, caregiver burden, and perceptions of caregiver-centered hospice team communication between Black and White hospice family caregivers. Design: Secondary analysis of baseline data from two randomized clinical trials. Setting/Subjects: Seven hundred twenty-two Black and White hospice family caregivers ages 18+ from Midwestern and Northeastern United States. Measurements: Measures included the Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire (PHQ-9), Caregiver Quality-of-Life Index-Revised (CQLI-R), Zarit Burden Interview (ZBI-7), and Caregiver-Centered Communication Questionnaire (CCCQ). Results: Black and White caregivers differed across demographic and socioeconomic variables. Nearly one-third of hospice family caregivers reported moderate-to-severe anxiety (32.1%) and moderate-to-severe depressive symptoms (32.0%). White caregivers reported lower QOL than Black caregivers (p = 0.04), specifically in emotional (p = 0.02) and social (p = 0.0005) domains. In multiple regression analyses controlling for caregiver and patient factors, we found no racial differences in depression, anxiety, QOL, caregiver burden, or perceptions of caregiver-centered hospice communication. Conclusions: Despite demographic and socioeconomic differences, Black and White hospice family caregivers experience similarly high levels of anxiety, depression, burden, and perceptions of hospice communication. Interventions to support hospice family caregivers across racial groups and research that identifies factors that mediate social determinants of health in this population are needed. The development and validation of culture-concordant mental health screening tools in racially diverse populations is recommended. Trial registration: ClinicalTrials.gov NCT02929108 and ClinicalTrials.gov NCT01444027.


Regulation of meiotic chromatin loop size by chromosomal position.
At meiotic prophase, chromatin loops around a proteinaceous core, with the sizes of these loops varying between species. Comparison of the morphology of sequence-related inserts at different sites in transgenic mice demonstrates that loop size also varies with chromosomal geography. Similarly, chromatin loop lengths differ dramatically for interstitially and terminally located hamster telomeric sequences. Sequences, telomeric or otherwise, located at chromosome termini, closely associate with the meiotic proteinaceous core, forming shorter loops than identical interstitial sequences. Thus, we present evidence that different chromatin packaging mechanisms exist for interstitial versus terminal chromosomal regions, which act separately from those operating at the level of the DNA sequence. Chromosomal position plays the dominant role in chromatin packaging.


Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction.
Positive end-expiratory pressure (PEEP) has generally been withheld from the treatment of patients with chronic airflow obstruction (CAO), in view of the risk of hyperinflation and lack of documented benefit. We studied 10 mechanically ventilated patients with exacerbated CAO and air trapping to determine the impact of PEEP on lung mechanics, alveolar pressure, and the work of breathing. PEEP levels of 5 and 10 cmH2O were applied to patients whose end-expiratory alveolar pressures were documented to be positive when breathing against ambient pressure (the auto-PEEP effect). All patients were studied under two conditions: every breath machine assisted (AMV) and every breath machine controlled (paralyzed, CMV). PEEP improved expiratory resistance without substantially increasing peak static pressure. Inspiratory resistance remained unchanged. The difference between the end-expiratory values of alveolar and central airway pressure narrowed as PEEP increased. Adding PEEP improved the effective triggering sensitivity of the ventilator, diminished ventilatory drive, and reduced the mechanical work of breathing during the machine-assisted ventilatory cycle. Our results indicate that low levels of PEEP may improve lung mechanics and reduce the effort required of mechanically ventilated patients with severe airflow obstruction, without substantially increasing the hazards of hyperinflation.


Feasibility and utility of a cognitive screening for risk stratification in hospitalized older patients.
To determine whether the Mini-Cog can be applied by nursing staff to hospitalized elderly patients for cognitive impairment associated risk stratification. This explorative prospective multicenter cohort study was carried out among 2522 patients aged 70 and older, hospitalized due to physical illness in eight hospitals in Rhineland-Palatinate, Germany. All patients were asked to conduct the Mini-Cog at the day of admission and were clustered into low-performance, intermediate-performance, and good-performance categories by trained nursing staff and two experienced geronto-psychiatrists as gold standard. Complications in the course of the treatment were monitored. The Mini-Cog was conducted in 1398 (54%) out of 2522 eligible patients. Mini-Cog scores assessed by nursing staff differed from the gold standard in 327 cases (23.9%). According to the area under the curve (AUC), nursing staff identified cognitively low-performing patients almost as well as the geronto-psychiatrists (AUC = 0.862; 95% CI, 0.83-0.89; P < 0.001, accuracy 89.6%). Overall, 241 (17.6%) patients were classified as low performing. These patients had a significantly higher probability of suffering from at least one complication (odds ratio [OR] = 3.13; 95% CI, 2.09-4.70; calculated by a logistic regression model, adjusted for age), and they had a higher probability to show behavioral symptoms. Even under naturalistic conditions, nursing staff detected cognitively low-performing inpatients with the Mini-Cog. Using this short screening instrument should enable to predict complications of hospitalized older patients associated with cognitive impairment, a precondition to implement targeted care for this vulnerable patient group.


Characterization of a Na+/H+ antiporter gene of Escherichia coli.
A mutant of Escherichia coli with increased Na+/H+ antiport activity was isolated and found by other workers to harbor two mutations [Niiya, S., Yamasaki, K., Wilson, T.H. & Tsuchiya, T. (1982) J. Biol. Chem. 257, 8902-8906]. The mutation that leads to increased Na+/H+ antiport (antup) has now been separated and mapped. antup maps in the vicinity of 0.5 min on the E. coli map, and the presence of this mutation alone in an isogenic pair raises antiport activity (Vmax) by approximately 4-fold. We also characterized cells hearing plasmids containing fragments of a 15-kilobase-pair segment of DNA between carA and dnaJ. A wild-type gene located within 2 kilobase pairs counterclockwise of rpsT increases the Na+/H+ antiport activity when present in multiple copies.


[Severe coronary artery disease in premenopausal woman with familial hypercholesterolaemia].
We present a case of a 51 year-old, premenopausal, non-smoker for many years woman with severe, two-coronary artery disease in the form of acute coronary syndrome (ACS), and severe hypercholesterolaemia as the predominant risk factor. The first clinical diagnosis of familial hypercholesterolaemia has been established at the time of diagnosis of ACS. Satisfactory effect of pharmacological treatment is achieved by a complex lipid-lowering therapy.


Evidence for an interaction between adducin and Na(+)-K(+)-ATPase: relation to genetic hypertension.
Adducin point mutations are associated with genetic hypertension in Milan hypertensive strain (MHS) rats and in humans. In transfected cells, adducin affects actin cytoskeleton organization and increases the Na(+)-K(+)-pump rate. The present study has investigated whether rat and human adducin polymorphisms differently modulate rat renal Na(+)-K(+)-ATPase in vitro. We report the following. 1) Both rat and human adducins stimulate Na(+)-K(+)-ATPase activity, with apparent affinity in tens of nanomolar concentrations. 2) MHS and Milan normotensive strain (MNS) adducins raise the apparent ATP affinity for Na(+)-K(+)-ATPase. 3) The mechanism of action of adducin appears to involve a selective acceleration of the rate of the conformational change E(2) (K) --> E(1) (Na) or E(2)(K). ATP --> E(1)Na. ATP. 4) Apparent affinities for mutant rat and human adducins are significantly higher than those for wild types. 5) Recombinant human alpha- and beta-adducins stimulate Na(+)-K(+)-ATPase activity, as do the COOH-terminal tails, and the mutant proteins display higher affinities than the wild types. 6) The cytoskeletal protein ankyrin, which is known to bind to Na(+)-K(+)-ATPase, also stimulates enzyme activity, whereas BSA is without effect; the effects of adducin and ankyrin when acting together are not additive. 7) Pig kidney medulla microsomes appear to contain endogenous adducin; in contrast with purified pig kidney Na(+)-K(+)-ATPase, which does not contain adducin, added adducin stimulates the Na(+)-K(+)-ATPase activity of microsomes only about one-half as much as that of purified Na(+)-K(+)-ATPase. Our findings strongly imply the existence of a direct and specific interaction between adducin and Na(+)-K(+)-ATPase in vitro and also suggest the possibility of such an interaction in intact renal membranes.


Comparing the neuropsychiatric inventory and the revised memory and behavior problems checklist for associations with caregiver burden and depressive symptoms.
Few empirical studies compare the ability of prominent measures of behavioral and psychological symptoms of dementia (BPSD) to explain key caregiver outcomes. We compared the respective abilities of the Neuropsychiatric Inventory (NPI) and the Revised Memory and Behavior Problems Checklist (RMBPC) to detect associations between BPSD and caregiver depressive symptoms. Our results may facilitate measurement decisions for researchers and clinicians. The NPI and the RMBPC, which measure BPSD frequency and corresponding caregiver appraisals, were administered to 164 caregivers of persons with dementia to compare the measures' ability to explain caregiver depressive symptoms. Depressive symptoms were measured using the Geriatric Depression Scale (GDS), and caregiver burden was measured (using the Zarit Burden Interview) as a mediator between BPSD frequency/appraisal and caregiver depressive symptoms. Path analysis using Mplus facilitated the comparison between the RMBPC and the NPI. Significant indirect associations were present when NPI frequency, NPI appraisal, RMBPC frequency, and RMBPC appraisal were modeled separately with burden and depressive symptoms, although indirect relationships are not associated with increases in R(2). Only RMBPC appraisal produced both a significant direct association with depressive symptoms and a significant increase in R(2) when modeled separately (β = 0.24, p < 0.01; ΔR(2) = 0.04, p < 0.05). When all independent variables were modeled together, only RMBPC appraisal demonstrated significant direct (β = 0.23, p < 0.01) and indirect associations. The RMBPC might be more suitable than the NPI in studies measuring BPSD to explain key caregiver outcomes such as depressive symptoms.


Historical Overview of the Effect of β-Adrenergic Agonists on Beef Cattle Production.
Postnatal muscle hypertrophy of beef cattle is the result of enhanced myofibrillar protein synthesis and reduced protein turnover. Skeletal muscle hypertrophy has been studied in cattle fed β-adrenergic agonists (β-AA), which are receptor-mediated enhancers of protein synthesis and inhibitors of protein degradation. Feeding β-AA to beef cattle increases longissimus muscle cross-sectional area 6% to 40% compared to non-treated cattle. The β-AA have been reported to improve live animal performance, including average daily gain, feed efficiency, hot carcass weight, and dressing percentage. Treatment with β-AA increased mRNA concentration of the β 2 or β 1-adrenergic receptor and myosin heavy chain IIX in bovine skeletal muscle tissue. This review will examine the effects of skeletal muscle and adipose development with β-AA, and will interpret how the use of β-AA affects performance, body composition, and growth in beef cattle.


The relationships of vascular plants.
Recent phylogenetic research indicates that vascular plants evolved from bryophyte-like ancestors and that this involved extensive modifications to the life cycle. These conclusions are supported by a range of systematic data, including gene sequences, as well as evidence from comparative morphology and the fossil record. Within vascular plants, there is compelling evidence for two major clades, which have been termed lycophytes (clubmosses) and euphyllophytes (seed plants, ferns, horsetails). The implications of recent phylogenetic work are discussed with reference to life cycle evolution and the interpretation of stratigraphic inconsistencies in the early fossil record of land plants. Life cycles are shown to have passed through an isomorphic phase in the early stages of vascular plant evolution. Thus, the gametophyte generation of all living vascular plants is the product of massive morphological reduction. Phylogenetic research corroborates earlier suggestions of a major representational bias in the early fossil record. Mega-fossils document a sequence of appearance of groups that is at odds with that predicted by cladogram topology. It is argued here that the pattern of appearance and diversification of plant megafossils owes more to changing geological conditions than to rapid biological diversification.


Subgrouping a Large U.S. Sample of Patients with Fibromyalgia Using the Fibromyalgia Impact Questionnaire-Revised.
Fibromyalgia (FM) is a heterogeneous and complex syndrome; different studies have tried to describe subgroups of FM patients, and a 4-cluster classification based on the Fibromyalgia Impact Questionnaire-Revised (FIQR) has been recently validated. This study aims to cross-validate this classification in a large US sample of FM patients. A pooled sample of 6280 patients was used. First, we computed a hierarchical cluster analysis (HCA) using FIQR scores at item level. Then, a latent profile analysis (LPA) served to confirm the accuracy of the taxonomy. Additionally, a cluster calculator was developed to estimate the predicted subgroup using an ordinal regression analysis. Self-reported clinical measures were used to examine the external validity of the subgroups in part of the sample. The HCA yielded a 4-subgroup distribution, which was confirmed by the LPA. Each cluster represented a different level of severity: "Mild-moderate", "moderate", "moderate-severe", and "severe". Significant differences between clusters were observed in most of the clinical measures (e.g., fatigue, sleep problems, anxiety). Interestingly, lower levels of education were associated with higher FM severity. This study corroborates a 4-cluster distribution based on FIQR scores to classify US adults with FM. The classification may have relevant clinical implications for diagnosis and treatment response.


Intravenous metoclopramide in the treatment of acute migraines: A randomized, placebo-controlled trial.
The present study aimed to evaluate the efficacy and safety of intravenous metoclopramide for acute migraine treatment. A double-blind, randomized, parallel-group, placebo-controlled trial was carried out in an academic emergency department. After the patients were assessed for eligibility via the International Headache Society criteria for migraines, they were randomized into 10 mg intravenous metoclopramide and normal saline groups. The headache intensity was evaluated using an 11-point numeric rating scale (NRS) score. The primary outcome measure was determined as the median between-group change in the score at the 30th minute. The secondary outcome measures were rescue medication needs, adverse events, and emergency department (ED) revisits after discharge. A total of 148 patients were randomized into two equal groups with similar baseline characteristics, including the baseline NRS scores (8 points). The median reduction in the NRS scores at the 30th minute was 4 [interquartile range (IQR): 2-6)] in the metoclopramide group and 3 (IQR: 1-4) in the normal saline group [median difference: -1.0, 95% confidence interval (CI): -2.1 to 0.1]. No serious adverse events were observed, and the rescue medication needs were similar in both groups. No difference was found between intravenous metoclopramide and placebo regarding efficacy and safety in patients with acute migraines.


Nasality in Taiwanese.
This study used perceptual and articulatory data to investigate a language specific phonemic inventory, and allophonic rules for homorganic initial voiced stops versus homorganic nasal stops, and oral versus nasal vowels in Taiwanese. Four experiments were conducted: concept formation, gating, and two airflow studies. Results of a first nasal airflow study on syllable initial voiced stops and nasal stops showed that initial voiced stops were nasalized when preceded by a nasal consonant across a word boundary. Results of a concept formation experiment indicated that Taiwanese listeners grouped homorganic voiced stops and nasal stops into the same category. A gating experiment showed that subjects were insensitive to the phonetic differences between homorganic voiced stops and nasal stops. The presence or absence of nasality within the vowel nucleus was the crucial cue to the identification of oral and nasal syllables. A second nasal airflow study on vowel nuclei demonstrated that oral vowels were nasalized at their onset and offset when preceded or followed by a nasal consonant respectively. The distinction between oral and nasal vowels was maintained at the center of the vowel nuclei. By classifying homorganic initial voiced stops and nasal stops into the same category, Taiwanese speakers were able to ignore the phonetic difference between them and relied on the distinction between nasal vowel versus oral and nasalized vowel to distinguish between nasal versus oral syllables. Taiwanese speakers produced a clear distinction between oral and nasal vowels to retain the crucial role that oral versus nasal contrasts on vowel nuclei played during perception experiments. This study offers phonetic evidence to answer the controversial nasality issue in Taiwanese. Furthermore, a link was found between perception and extent of application of allophonic rules during production.


Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status.
The PKCβ inhibitor enzastaurin was tested in parental neuroblastoma and rhabdomyosarcoma cell lines, their vincristine-resistant sub-lines, primary neuroblastoma cells, ABCB1-transduced, ABCG2-transduced, and p53-depleted cells. Enzastaurin IC50s ranged from 3.3 to 9.5 μM in cell lines and primary cells independently of the ABCB1, ABCG2, or p53 status. Enzastaurin 0.3125 μM interfered with ABCB1-mediated drug transport. PKCα and PKCβ may phosphorylate and activate ABCB1 under the control of p53. However, enzastaurin exerted similar effects on ABCB1 in the presence or absence of functional p53. Also, enzastaurin inhibited PKC signalling only in concentrations ≥ 1.25 μM. The investigated cell lines did not express PKCβ. PKCα depletion reduced PKC signalling but did not affect ABCB1 activity. Intracellular levels of the fluorescent ABCB1 substrate rhodamine 123 rapidly decreased after wash-out of extracellular enzastaurin, and enzastaurin induced ABCB1 ATPase activity resembling the ABCB1 substrate verapamil. Computational docking experiments detected a direct interaction of enzastaurin and ABCB1. These data suggest that enzastaurin directly interferes with ABCB1 function. Enzastaurin further inhibited ABCG2-mediated drug transport but by a different mechanism since it reduced ABCG2 ATPase activity. These findings are important for the further development of therapies combining enzastaurin with ABC transporter substrates.


Host Range and Population Survey of Spodoptera frugiperda Rhabdovirus.
The Sf9 and Sf21 cell lines derived from ovarian tissues of the wide-host-range phytophagous lepidopteran Spodoptera frugiperda are widely used for research and commercial-scale production of recombinant proteins. These cell lines are chronically infected with a rhabdovirus (Sf-RV) that does not cause any overt cytopathic effects. We demonstrate that wild populations of S. frugiperda in the eastern United States and Caribbean are infected with genetically diverse strains of Sf-RV and that this virus is also capable of infecting cells of Spodoptera exigua, Heliothis subflexa, and Bombyx mori Feeding studies demonstrated the ability of S. frugiperda larvae to deposit Sf-RV onto human-consumed vegetables during feeding. Although no evidence for replication in two species of plant cells was detected, subcellular localization studies demonstrated that the Sf-RV nucleocapsid was targeted to plasmodesmata, while two forms of the accessory protein were differentiated on the basis of their ability to localize to nuclei. Collectively, the results from this study suggest that environmental exposure of humans to Sf-RV is likely to be commonplace and frequent, but its inability to replicate in plant or human cells suggests that there is no substantial risk to human health.IMPORTANCE Insect-derived cell lines are widely used commercially for the production of vaccines and protein-based pharmaceuticals. After decades of safe and beneficial use, it was a surprise to the biotechnology industry to discover an endemic rhabdovirus in Sf9 cells. This discovery was made possible only by the substantial advancements in DNA sequencing technologies. Given the public health concerns associated with many rhabdovirus species, several initiatives were undertaken to establish that Spodoptera frugiperda rhabdovirus (Sf-RV) does not pose a threat to humans. Such actions include the generation of cell lines that have been cleared of Sf-RV. Given that Sf9 is derived from a moth whose larvae feed on human-edible foods, we explored the prevalence of Sf-RV in its wild and lab-grown populations, as well as its ability to be deposited on food items during feeding. Collectively, our data suggest that there is no overt risk from exposure to Sf-RV.


Partial preparation computed tomographic colonography: a feasibility study.
We retrospectively evaluated computed tomographic colonography examinations of patients who have had a partial bowel preparation and compared the quality of their preparation with patients who have had a full bowel preparation. In total, 27 patients undergoing computed tomographic colonography examination (10 patients with partial bowel preparation and 17 with full bowel preparation) had their examinations retrospectively reviewed by three independent radiologists in a blinded manner, with evaluation of residual stool, distention, residual fluid, and overall bowel preparation quality. Six colon segments were evaluated individually and independently for these four variables (a total of 161 segments tested). Comparisons were made with the Mann-Whitney test between the partial preparation group and the full preparation group. Partial preparation included stool and fluid tagging plus 20 mg of bisacodyl orally; full preparation included stool and fluid tagging plus 2 L of polyethylene glycol solution. No significant clinical difference was found in colon preparation between the partial and full bowel preparation groups--when evaluated with individual colon segments or by independent readers. Interreader correlation was high. This pilot study indicates that full bowel preparation is not required for diagnostic-quality computed tomographic colonography examination. Further evaluation of this partial bowel preparation regimen is warranted.


An (n-3) polyunsaturated fatty acid-deficient diet disturbs daily locomotor activity, melatonin rhythm, and striatal dopamine in Syrian hamsters.
Several studies suggest that (n-3) PUFA may play a role in the regulation of cognitive functions, locomotor and exploratory activity, and affective disorders. Additionally, (n-3) PUFA affect pineal function, which is implicated in the sleep-wake rhythm. However, no studies to our knowledge have explored the role of PUFA on the circadian system. We investigated the effect of an (n-3) PUFA-deficient diet on locomotor and pineal melatonin rhythms in Syrian hamsters used as model species in circadian rhythm research. To assess the possible relationship between voluntary wheel running activity and dopaminergic neurotransmission, we also measured endogenous monoamine concentrations in the striatum. Two-month-old male hamsters, fed either an (n-3) PUFA-deficient or an (n-3) PUFA-adequate diet, were housed individually in cages equipped with run wheels. At 3 mo, cerebral structures were extracted for biochemical and cellular analysis. In (n-3) PUFA-deficient hamsters, the induced changes in the pineal PUFA membrane phospholipid composition were associated with a reduction in the nocturnal peak level of melatonin that was 52% lower than in control hamsters (P < 0.001). The (n-3) PUFA-deficient hamsters also had higher diurnal (P < 0.01) and nocturnal (P = 0.001) locomotor activity than the control hamsters, in parallel with activation of striatal dopaminergic function (P < 0.05). The (n-3) PUFA-deficient hamsters exhibited several symptoms: chronic locomotor hyperactivity, disturbance in melatonin rhythm, and striatal hyperdopaminergia. We suggest that an (n-3) PUFA-deficient diet lessens the melatonin rhythm, weakens endogenous functioning of the circadian clock, and plays a role in nocturnal sleep disturbances as described in attention deficit/hyperactivity disorder.


The process of suicidal planning among medical doctors: predictors in a longitudinal Norwegian sample.
The suicidal process is a common underlying perspective on suicidal behaviour, but the process has hardly been empirically studied. This study investigates the process from suicidal thoughts to suicidal planning among physicians; an occupational group with a raised risk of suicide. The process is studied in two ways: First, predictors at medical school of postgraduate suicidal planning are identified. Second, the transition from suicidal thoughts to planning over three to four years is explored. A nationwide cohort of Norwegian medical students (N=631) were approached initially in their final semester (T1), and then again in the first (T2) and fourth (T3) postgraduate years. The average observation time was 3.6 years. Twenty-eight participants (6%) reported suicidal planning in the postgraduate years. Adjusted predictors at T1 were vulnerability trait (neuroticism), severe depressive symptoms, and negative life events. Among those with previous suicidal thoughts at T1, 13 (8%) reported suicidal planning at T2 or T3. Adjusted predictors of transition from thoughts to planning were reality weakness trait, severe depressive symptoms, and a low level of perceived medical school stress. A minority of the postgraduate planners had sought professional care. The effect of severe depressive symptoms may be overestimated, and the sample size is relatively small. Common predictors for both postgraduate suicidal planning and transition from thoughts to planning were depressive symptoms and personality traits. Reality weakness was the most decisive trait for aggravation in suicidal ideation, and this personality trait needs further study in suicidal research and clinical awareness.


The size of the proton.
The proton is the primary building block of the visible Universe, but many of its properties-such as its charge radius and its anomalous magnetic moment-are not well understood. The root-mean-square charge radius, r(p), has been determined with an accuracy of 2 per cent (at best) by electron-proton scattering experiments. The present most accurate value of r(p) (with an uncertainty of 1 per cent) is given by the CODATA compilation of physical constants. This value is based mainly on precision spectroscopy of atomic hydrogen and calculations of bound-state quantum electrodynamics (QED; refs 8, 9). The accuracy of r(p) as deduced from electron-proton scattering limits the testing of bound-state QED in atomic hydrogen as well as the determination of the Rydberg constant (currently the most accurately measured fundamental physical constant). An attractive means to improve the accuracy in the measurement of r(p) is provided by muonic hydrogen (a proton orbited by a negative muon); its much smaller Bohr radius compared to ordinary atomic hydrogen causes enhancement of effects related to the finite size of the proton. In particular, the Lamb shift (the energy difference between the 2S(1/2) and 2P(1/2) states) is affected by as much as 2 per cent. Here we use pulsed laser spectroscopy to measure a muonic Lamb shift of 49,881.88(76) GHz. On the basis of present calculations of fine and hyperfine splittings and QED terms, we find r(p) = 0.84184(67) fm, which differs by 5.0 standard deviations from the CODATA value of 0.8768(69) fm. Our result implies that either the Rydberg constant has to be shifted by -110 kHz/c (4.9 standard deviations), or the calculations of the QED effects in atomic hydrogen or muonic hydrogen atoms are insufficient.


Bioavailability of Orally Delivered Alpha-Tocopherol by Poly(Lactic-Co-Glycolic) Acid (PLGA) Nanoparticles and Chitosan Covered PLGA Nanoparticles in F344 Rats.
It is hypothesized that the bioavailability of αT (alpha-tocopherol), an antioxidant, can be improved when delivered by poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) and chitosan covered PLGA nanoparticles (PLGA-Chi NPs), and that the mucoadhesive properties of chitosan may enhance absorption of αT. PLGA and PLGA-Chi NPs were characterized by measuring entrapment efficiency, size, polydispersity, and zeta potential. Nanoparticle physical stability, chemical stability of entrapped αT, and release kinetics were also measured. Pharmacokinetic studies were conducted by administering PLGA (αT) NPs, PLGA-Chi (αT) NPs, and free αT via oral gavage in rats. The size and zeta potential of the two particle systems were 97.87 ± 2.63 nm and -36.2 ± 1.31 mV for PLGA(αT) NPs, and 134 ± 2.05 nm and 38.0 ± 2.90 mV for PLGA-Chi (αT) nanoparticles in DI water. The particle systems showed to be stable during various in vitro assays. Bioavailability of nanodelivered αT was improved compared to the free αT, by 170% and 121% for PLGA and PLGA-Chi NPs, respectively. It was concluded that while chitosan did not further improved bioavailability of αT, PLGA NPs protected the entrapped drug from the GI environment degradation and proved to be an effective delivery system for αT.


Segmental localization of urea transporter mRNAs in rat kidney.
Renal epithelia express at least two distinct urea transporter mRNAs, termed UT1 and UT2, that are derived from a single UT gene by alternative splicing. Previous immunolocalization studies using a polyclonal antibody that does not distinguish between the protein products of these two transcripts revealed that expression of urea transporter protein is restricted to inner medullary collecting ducts and descending thin limbs of Henle's loop. To identify which transcripts account for protein expression in these two structures, we carried out reverse transcription-polymerase chain reaction studies in microdissected structures using UT1- and UT2-specific primers. UT1 mRNA was detected only in the inner medullary collecting duct, consistent with its identification as the vasopressin-regulated urea transporter. In contrast, UT2-mRNA was detected in the late part of descending thin limbs of short loops of Henle and in the inner medullary part of descending thin limbs of long loops of Henle. This localization is consistent with the predicted role of UT2 in medullary urea recycling. Thus, in conjunction with foregoing physiological studies, our data indicate that these transporters play central roles in the urinary concentrating mechanism.


Extra-phosphoric effects of phytase with and without xylanase in corn-soybean meal-based diets fed to broilers.
Two experiments were conducted to evaluate the extra-phosphoric effects of phytase on amino acid (AA) and energy digestibility (experiments 1 and 2) and growth performance (experiment 2) of broilers fed diets adequate in Ca and nonphytate P supplemented with xylanase. Ross × Ross 708 broiler chicks (864 males in experiment 1 and 1,152 females in experiment 2) were randomly distributed into battery cages (6 replicate cages per treatment) with 12 birds per cage at 1 d of age. In both experiments, factorial arrangements of treatments were evaluated consisting of 6 phytase [0, 1,000, 2,000, 4,000, 8,000, or 16,000 phytase units (FTU)/kg] and 2 xylanase [0 or 16,000 birch xylan units (BXU)/kg] concentrations in experiment 1 and 4 phytase (0, 500, 1,000 or 2,000 FTU/kg) and 4 xylanase (0, 8,000, 16,000, or 32,000 BXU/kg) concentrations in experiment 2. Treatments were provided from 27 to 32 d of age in experiment 1 and from 1 to 32 d of age in experiment 2. Digesta contents of the terminal ileum were collected at 32 d of age (experiment 1 and 2), and growth performance was measured at 1, 14, and 25 d of age in experiment 2. There was no interaction of phytase and xylanase; only main effects of phytase were observed. In experiment 1, broilers fed diets supplemented with phytase at 1,000 FTU/kg had increased (P < 0.05) apparent ileal digestibility (AID) of all AA with the exception of Ala and Met. Diets fed to broilers supplemented with higher concentrations of phytase did not further increase AID of any AA (P > 0.05) above the addition of 1,000 FTU/kg of phytase. Phytase supplementation did not affect ileal digestible energy (P > 0.05). For all variables measured, significant log-linear or log-quadratic effects of phytase (P > 0.05) were not observed. In contrast, broilers fed diets supplemented with phytase in experiment 2 exhibited log-linear (P < 0.05) increases in AID of AA but not apparent ileal digestible energy. However, supplementation with 2,000 FTU/kg of phytase increased (P = 0.05) ileal digestible energy by 36 kcal/kg compared with the basal diet. Broilers fed diets with 1,000 FTU/kg of phytase had improved growth performance (P < 0.05) in comparison with broilers fed diets containing 0 or 500 FTU/kg of phytase. The addition of 500 FTU/kg of phytase in diets fed to broilers did not affect ileal digestibility or growth performance (P > 0.05). Data obtained from these experiments demonstrated extra-phosphoric effects in broilers fed diets supplemented with 1,000 FTU/kg of phytase and diminishing returns with higher concentrations.


Simulations and measurements of 3-D ultrasonic fields radiated by phased-array transducers using the westervelt equation.
The purpose of this work is to validate, by comparing numerical and experimental results, the ability of the Westervelt equation to predict the behavior of ultrasound beams generated by phased-array transducers. To this end, the full Westervelt equation is solved numerically and the results obtained are compared with experimental measurements. The numerical implementation of the Westervelt equation is performed using the explicit finite-difference time-domain method on a three-dimensional Cartesian grid. The validation of the developed numerical code is first carried out by using experimental data obtained for two different focused circular transducers in the regimes of small-amplitude and finite-amplitude excitations. Then, the comparison of simulated and measured ultrasonic fields is extended to the case of a modified 32-element array transducer. It is shown that the developed code is capable of correctly predicting the behavior of the main lobe and the grating lobes in the cases of zero and nonzero steering angles for both the fundamental and the second-harmonic components.


Drug solubility: importance and enhancement techniques.
Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.


Optic neuropathy secondary to cat scratch disease: distinguishing MR imaging features from other types of optic neuropathies.
MR imaging characteristics of optic neuropathy caused by cat scratch disease have not yet been described; this lack of information may result in incorrect diagnosis and may contribute to initiation of inappropriate therapy. Our study was based on the hypothesis that cat scratch disease-related optic neuropathy has distinct MR imaging features compared with those of other types of optic neuropathies. Eighty-two patients with various causes of optic neuropathy and available MR imaging examinations were included in this study. Two readers blinded to the diagnosis reviewed the MR images independently in regard to presence, location, and extent of optic nerve enhancement. The MR imaging findings were correlated with the final diagnosis. Eleven percent (9/82) of the patients received a final diagnosis of cat scratch disease. Optic nerve enhancement in patients with cat scratch disease (5/37) was localized to a 3- to 4-mm segment at the optic nerve-globe junction. All other patients with optic neuropathy (31/37) with one exception showed enhancement away from the optic nerve-globe junction or a long-segment enhancement when the optic nerve-globe junction was also involved. Four patients with cat scratch disease did not show any optic nerve MR abnormalities. Unilateral, short-segment enhancement localized to the optic nerve-globe junction is highly specific for cat scratch disease as the underlying cause of optic neuropathy and may help in establishing the diagnosis of this condition.


Emboli from an extraluminal blood flow hollow fiber oxygenator with and without an arterial filter during cardiopulmonary bypass in a pig model.
The effect of an arterial filter on visceral emboli was quantified with autologous indium-111 labeled platelets (INPLT) during cardiopulmonary bypass (CPB) in Yorkshire pigs. Biodistribution of INPLT was determined in 12 control pigs (30-35 kg, unoperated control [n = 6] and sham operated control [n = 6]). CPB was carried out with (n = 6) and without (n = 6) an arterial filter in 12 pigs at a flow rate of 2.5-3.5 L/min. Platelets labeled with In-111 tropolone (650-780 microCi) were injected intravenously 24 hr before CPB. All pigs were systemically heparinized (activated coagulation time > 400 sec); CPB was instituted with a roller pump, an extraluminal blood flow oxygenator (Bentley Univox, 1.8 m2), and an arterial filter (0.25 m2) and continued for 3 hr. Platelet kinetics, pooling, and counts were monitored by a Geiger probe and a Coulter counter. The thrombi in the oxygenator and arterial filter and emboli in viscera and brain were imaged with a gamma camera and measured with an ion chamber and gamma counter. Percentage of INPLT (mean +/- SD) in organs, tissues, and components of the circuit in four groups of pigs was calculated. Flow cytometry with antibodies to CD61 (GPIIIa) and CD62P (GMP-140: control) of porcine platelets was carried out with blood samples taken before, during, and after CPB for estimation of circulating platelet aggregates and platelet microparticles. Pulmonary, renal, cardiac, and cerebral emboli in pigs undergoing CPB with and without a filter were similar (p < 0.1). The amount of filter adherent thrombi was small (0.04 +/- 0.01%); oxygenator adherent thrombus in both groups was similar (p < 0.1). Emboli were found in the cerebral medulla, hippocampus, and posterior cerebral cortex in both groups. During CPB, the arterial filter functioned minimally as a trap for platelet thrombi detached from the oxygenator and circulating emboli. Flow cytometry of blood demonstrated the shift of equilibria from single platelets to platelet aggregates and microparticles during CPB and their gradual reversal to single platelets after CPB; the loosely adherent emboli disaggregated and further shifted these equilibria to single platelets and smaller aggregates, probably through the action of endogenous nitric oxide and prostacyclin. The emboli were trapped in organs and tissues and microparticles were sequestered by the reticuloendothelial system.


Optimization and validation of a modified radial-arm water maze protocol using a murine model of mild closed head traumatic brain injury.
Cognitive impairments can be a significant problem after a traumatic brain injury (TBI), which affects millions worldwide each year. There is a need for establish reproducible cognitive assays in rodents to better understand disease mechanisms and to develop therapeutic interventions towards treating TBI-induced impairments. Our goal was to validate and standardize the radial arm water maze (RAWM) test as an assay to screen for cognitive impairments caused by TBI. RAWM is a visuo-spatial learning test, originally designed for use with rats, and later adapted for mice. The present study investigates whether test procedures, such us the presence of extra-maze cues influences learning and memory performance. C57BL/6 mice were tested in an 8-arm RAWM using a four-day protocol. We demonstrated that two days of training, exposing the mice to extra-maze cues and a visible platform, influenced learning and memory performance. Mice that did not receive training performed poorer compared to mice trained. To further validate our RAWM protocol, we used scopolamine. We, also, demonstrated that a single mild closed head injury (CHI) caused deficits in this task at two weeks post-CHI. Our data supported the use of 7 trials per day and a spaced training protocol as key factor to unmask memory impairment following CHI. Here, we provide a detailed standard operating procedure for RAWM test, which can be applied to a variety of mouse models including neurodegenerative diseases and pathology, as well as when pharmacological approaches are used.


Matcha-silver nanoparticles reduce gamma radiation-induced oxidative and inflammatory responses by activating SIRT1 and NLRP-3 signaling pathways in the Wistar rat spleen.
The biogenic synthesis of nanoparticles has drawn significant attention. The spleen is the largest lymphatic organ that is adversely impacted during irradiation. The current study was designated to evaluate the possible anti-inflammatory effect of matcha-silver nanoparticles (M-AgNPs) to reduce inflammation associated with γ-radiation induced-oxidative stress and inflammation in rats' spleen. Silver nanoparticles (AgNPs) were synthesized by biogenic synthesis using a green sonochemical method from matcha (M) green tea. The obtained M-AgNPs were extensively characterized by dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, and Fourier-transform infrared spectroscopy. Using zetasizer analysis, the surface charge, particle size, and radical scavenging DPPH assay of M-AgNPs were also examined. Biocompatibility and cytotoxicity were analyzed by MTT assay, and the IC50 was calculated. Four groups of 24 Wistar rats each had an equal number of animals. The next step involved measuring the levels of oxidative stress markers in the rat splenic tissue. Additionally, the amounts of inflammatory protein expression were evaluated using the ELISA analysis. The results indicated the formation of spherical nanoparticles of pure Ag° coated with matcha polyphenols at the nanoscale, as well as uniform monodisperse particles suited for cellular absorption. Results revealed that M-AgNPs improved all biochemical parameters. Furthermore, M-AgNPs relieve inflammation by reducing the expression of NOD-like receptor family pyrin domain-containing 3 (NLRP3), interleukin-1β (IL-1β), and enhancing the levels of ileSnt information regulator 1 (SIRT1). Histopathological examinations demonstrated the ability of M-AgNPs to overcome the damage consequent to irradiation and recover the spleen's cellular structure. These results confirmed that matcha is a potential biomaterial for synthesizing AgNPs, which can be exploited for their anti-inflammatory activity.


Artificial light at night decreases plant diversity and performance in experimental grassland communities.
Artificial light at night (ALAN) affects many areas of the world and is increasing globally. To date, there has been limited and inconsistent evidence regarding the consequences of ALAN for plant communities, as well as for the fitness of their constituent species. ALAN could be beneficial for plants as they need light as energy source, but they also need darkness for regeneration and growth. We created model communities composed of 16 plant species sown, exposed to a gradient of ALAN ranging from 'moonlight only' to conditions like situations typically found directly underneath a streetlamp. We measured plant community composition and its production (biomass), as well as functional traits of three plant species from different functional groups (grasses, herbs, legumes) in two separate harvests. We found that biomass was reduced by 33% in the highest ALAN treatment compared to the control, Shannon diversity decreased by 43% and evenness by 34% in the first harvest. Some species failed to establish in the second harvest. Specific leaf area, leaf dry matter content and leaf hairiness responded to ALAN. These responses suggest that plant communities will be sensitive to increasing ALAN, and they flag a need for plant conservation activities that consider impending ALAN scenarios. This article is part of the theme issue 'Light pollution in complex ecological systems'.


Structure of 2C-methyl-D-erythritol 2,4- cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development.
The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5'-diphosphate and Mn(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmevalonate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a beta prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn(2+) with tetrahedral coordination. A Mn(2+), with octahedral geometry, is positioned between the alpha and beta phosphates acting in concert with the Zn(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria.


Capillary-to-fiber surface ratio in rat fast-twitch hindlimb muscles after chronic electrical stimulation.
We examined the relative plasticity of capillaries and fiber mitochondria in rat fast-twitch hindlimb muscles in response to chronic electrical stimulation. Specifically we addressed whether the size of the capillary-fiber interface increases in proportion to fiber mitochondrial volume, inasmuch as fiber aerobic capacity increases severalfold with chronic stimulation. Tibialis anterior and extensor digitorum longus muscles of six rats [367 +/- 17 (SD) g body wt] were stimulated (10 Hz, 8 h/day, 7 days/wk) for 28 consecutive days. Subsequently they were perfusion fixed in situ and stimulated, and contralateral control samples from the midbelly were processed for electron microscopy and morphometry. Capillary length density, capillary-to-fiber ratio, and fiber mitochondrial volume density increased two- to threefold in stimulated muscles, with no change in fiber or capillary diameter. Capillary-to-fiber surface area ratio per fiber unit mitochondrial volume was unchanged in stimulated muscles compared with contralateral controls, indicating a proportional increase in the size of the capillary-fiber interface and fiber mitochondrial volume in the muscles after chronic electrical stimulation.


Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomised feasibility trial.
In 2020 Globocan reported nearly 1.4 million new cases of gynaecology cancer worldwide. Cancer related fatigue has been identified as a symptom that can be present for gynaecology cancer patients many years after treatment. The current evidence around the management of this symptom suggests that exercise has the most positive outcome. However, some ambiguity remains around the evidence and whether it can address all areas of fatigue effectively. More recently, other interventions such as mindfulness have begun to show a favourable response to the management of symptoms for cancer patients. To date there has been little research that explores the feasibility of using both these interventions together in a gynaecology cancer population. This study aims to explore the feasibility of delivering an intervention that involves mindfulness and mindfulness and exercise and will explore the effect of this on fatigue, sleep, mood and quality of life. This randomised control trial will assess the interventions outcomes using a pre and post design and will also include a qualitative process evaluation. Participants will be randomised into one of 2 groups. One group will undertake mindfulness only and the other group will complete exercise and mindfulness. Both groups will use a mobile application to complete these interventions over 8 weeks. The mobile app will be tailored to reflect the group the participants have drawn during randomisation. Self-reported questionnaire data will be assessed at baseline prior to commencing intervention and at post intervention. Feasibility will be assessed through recruitment, adherence, retention and attrition. Acceptability and participant perspective of participation (process evaluation), will be explored using focus groups. This trial will hope to evidence and demonstrate that combination of two interventions such as mindfulness and exercise will further improve outcomes of fatigue and wellbeing in gynaecology cancer. The results of this study will be used to assess (i) the feasibility to deliver this type of intervention to this population of cancer patients using a digital platform; (ii) assist this group of women diagnosed with cancer to manage fatigue and other symptoms of sleep, mood and impact their quality of life. NCT05561413.


Identification of novel diagnostic biomarkers for asthma and chronic obstructive pulmonary disease.
Proteomics may identify a useful panel of biomarkers for identification of asthma and chronic obstructive pulmonary disease (COPD). To conduct an unsupervised analysis of peripheral blood proteins in well-characterized subjects with asthma and COPD, and identify and validate a biomarker panel for disease discrimination. Two-dimensional difference gel electrophoresis was used to separate plasma proteins from healthy control subjects, stable patients with asthma, and individuals with COPD. Candidate protein markers were identified by matrix assisted laser desorption ionization time of flight mass spectrometry and subsequently validated in two populations via immunoassay. A panel of four biomarkers was selected and their ability to distinguish between groups was assessed in isolation and in combination in two separate validation populations. Seventy-two protein spots displayed significantly different expression levels between the three subject groupings (P < 0.05). Fifty-eight were positively identified, representing 20 unique proteins. A panel of four biomarkers (α(2)-macroglobulin, haptoglobin, ceruloplasmin, and hemopexin) was able to discriminate with statistical significance between the clinical groups of patients with asthma, patients with COPD, and control subjects, and these results were confirmed in a second clinical population of older adults with airflow obstruction. Proteomics has identified novel biomarkers for asthma and COPD, and shown that the iron metabolism pathways and acute-phase response may be involved in the pathogenesis of airway disease. The panel of peripheral blood biomarkers has the potential to become an extremely useful addition to the clinical diagnosis and management of respiratory disease.


Arylaminobenzoate block of the cardiac cyclic AMP-dependent chloride current.
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel has been identified in the cardiac muscle of a number of mammalian species, including humans. The goal of this study was to begin quantifying the structural requirements necessary for arylaminobenzoate block of the CFTR channel. The cardiac cAMP-dependent Cl- current (ICl) was measured using the whole-cell arrangement of the patch-clamp technique in guinea pig ventricular myocytes during stimulation of protein kinase A with forskolin. At drug concentrations below the IC50 value for channel block, reduction of ICl by the arylaminobenzoates occurred in a strongly voltage-dependent manner with preferential inhibition of the inward currents. At higher drug concentrations, block of both the inward and outward ICl was observed. Increasing the length of the carbon chain between the benzoate and phenyl rings of the arylaminobenzoates resulted in a marked increase in drug block of the channel, with IC50 values of 47, 17, and 4 microM for 2-benzylamino-5-nitro-benzoic acid, 5-nitro-2-(2-phenylethylamino)-benzoic acid, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), respectively. Increasing the carbon chain length further with the compound 5-nitro-2-(4-phenylbutylamino)-benzoic acid, caused no additional increase in the potency of drug block (IC50 = 4 microM). Inhibition of ICl by the arylaminobenzoates was modulated by the pH of the external solution; increasing the pH from 7.4 to 10.0 greatly weakened NPPB block, whereas decreasing the pH to 6.4 enhanced block. In addition, block of ICl was observed during intracellular dialysis of NPPB, and this action was not affected by raising the external pH.


Validity and reliability of two brief physical activity questionnaires among Spanish-speaking individuals of Mexican descent.
Mexican Americans are the largest minority group in the US and suffer disproportionate rates of diseases related to the lack of physical activity (PA). Since many of these Mexican Americans are Spanish-speaking, it is important to validate a Spanish language physical activity assessment tool that can be used in epidemiology as well as clinical practice. This study explored the utility of two Spanish translated physical activity questionnaires, the Stanford Brief Activity Survey (SBAS) and the Rapid Assessment of Physical Activity (RAPA), for use among Spanish-speaking Mexican Americans. Thirty-four participants (13 M, 21 F; 37.6 ± 9.5 y) completed each of the two PA surveys twice, one week apart. During that week 31 participants also wore an ActiGraph GT1M accelerometer for 7 days to objectively measure PA. Minutes of moderate and vigorous PA (MVPA) were determined from the accelerometer data using Freedson and Matthews cut points. Validity, determined by Spearman correlation coefficients between questionnaire scores and minutes of ActiGraph measured MVPA were 0.38 and 0.45 for the SBAS and RAPA, respectively. Test-retest reliability was 0.61 for the SBAS and 0.65 for the RAPA. Sensitivity and specificity were 0.60 and 0.47 for the SBAS, and 0.73 and 0.75 for the RAPA. Participants who were classified as meeting the 2008 National Physical Activity Guidelines by the RAPA engaged in significantly (p < 0.05) more minutes of MVPA than those who were not, while there were no significant differences in minutes of MVPA classified by the SBAS. The SBAS and the RAPA are both reasonably valid measures for quickly assessing PA and determining compliance to the PA guidelines in Spanish-speaking Mexican Americans. Although the two questionnaires had comparable reliability, the RAPA was better able to distinguish between those who met and did not meet National PA Guidelines.


Procoagulants and osteonecrosis.
To study the relationship between hypofibrinolysis, thrombophilia, and osteonecrosis. We evaluated the frequency of abnormal concentrations of 9 coagulation factors in patients diagnosed with osteonecrosis. Blood samples were drawn from 45 patients diagnosed with osteonecrosis. Etiologic associations included systemic lupus erythematosus (n = 9), inflammatory bowel disease (n = 1), corticosteroid therapy (n = 20), or history of heavy alcohol (n = 4) or tobacco (n = 3) use. No associated risk factors were identified in 5 patients; these individuals were labeled "idiopathic." The patient cohort was matched to a similarly studied cohort of 40 healthy individuals without documented osteonecrosis. The following factors were analyzed: plasminogen activator inhibitor (PAI-Fx), stimulated tissue plasminogen activator, lipoprotein (a), resistance to activated protein C, anticardiolipin antibodies (aCL IgG, IgM), protein C, protein S (free), and homocysteine. Thirty-seven of the 45 patients (82.2%) with osteonecrosis were found to have at least one coagulopathy, versus 30% of controls (p < 0.0001). Twenty-one patients (46.7%) were identified with 2 or more abnormal test results versus 2.5% of controls (p < 0.0001). Patients were more likely than controls to have high levels of the hypofibrinolytic plasminogen activator inhibitor activity (42% vs 3%; p < 0.0001), and high anticardiolipin antibody IgG (34% vs 10%; p = 0.008). At least one coagulation factor abnormality was detected in all 5 idiopathic patients; elevated aCL IgG and PAI-Fx were evident in 4 patients. This study revealed a high incidence of thrombophilic and hypofibrinolytic coagulation abnormalities in patients with osteonecrosis. These findings have major implications for the diagnosis as well as the treatment of this disease. Since some of these abnormalities may be the result of autosomal dominant disorders, it may be possible to detect individuals at risk for development of this disease.


Pathogenicity of Ichthyophonus hoferi for laboratory-reared Pacific herring Clupea pallasi and its early appearance in wild Puget Sound herring.
Laboratory-reared pathogen-free Pacific herring were exposed to pure cultures of Ichthyophonus hoferi, and reproduced the disease seen in naturally infected fish--thus fulfilling Koch's Postulates. Pathogen-free herring used in this study were reared from artificially spawned eggs incubated in filtered, UV-sterilized seawater, eliminating the variables associated with multiple infections, which are common in wild herring. Wild free-ranging herring were captured monthly from June through October by dip net from 'herring balls' located in the northern Puget Sound. I. hoferi infections were identified in these fish soon after metamorphoses, about 4 mo post-hatch. The prevalence increased from 5 to 6% in 0-yr fish to 24% in 1-yr-old fish to 50 to 70% in fish over 2 yr old, with no associated increase in mortality. The route of natural transmission to wild herring was not determined, but carnivorous fish became infected and died when they were experimentally fed tissues infected with the organism. In vitro culture of tissues was the most sensitive method for identifying both clinical and subclinical infections.


"Plug and play" full-dimensional ab initio potential energy and dipole moment surfaces and anharmonic vibrational analysis for CH4-H2O.
The potential energy surface of the methane-water dimer is represented as the sum of a new intrinsic two-body potential energy surface and pre-existing intramolecular potentials for the monomers. Different fits of the CH4-H2O intrinsic two-body energy are reported. All these fits are based on 30 467 ab initio interaction energies computed at CCSD(T)-F12b/haTZ (aug-cc-pVTZ for C and O, cc-pVTZ for H) level of theory. The benchmark fit is a full-dimensional, permutationally-invariant analytical representation with root-mean-square (rms) fitting error of 3.5 cm(-1). Two other computationally more efficient two-body potentials are also reported, albeit with larger rms fitting errors. Of these a compact permutationally invariant fit is shown to be the best one in combining precision and speed of evaluation. An intrinsic two-body dipole moment surface is also obtained, based on MP2/haTZ expectation values, with an rms fitting error of 0.002 au. As with the potential, this dipole moment surface is combined with existing monomer ones to obtain the full surface. The vibrational ground state of the dimer and dissociation energy, D0, are determined by diffusion Monte Carlo calculations, and MULTIMODE calculations are performed for the IR spectrum of the intramolecular modes. The relative accuracy of the different intrinsic two-body potentials is analyzed by comparing the energetics and the harmonic frequencies of the global minimum well, and the maximum impact parameter employed in a sample methane-water scattering calculation.


Prediction of paravalvular leakage after transcatheter aortic valve implantation.
Significant paravalvular leakage (PVL) after transcatheter aortic valve implantation (TAVI) is related to patient mortality. Predicting the development of PVL has focused on computed tomography (CT) derived variables but literature targeting CoreValve devices is limited, controversial, and did not make use of standardized echocardiographic methods. The study included 164 consecutive patients with severe aortic stenosis that underwent TAVI with a Medtronic CoreValve system©, with available pre-TAVI CT and pre-discharge transthoracic echocardiography. The predictive value for significant PVL of the CT-derived Agatston score, aortic annulus size and eccentricity, and "cover index" was assessed, according to both echocardiographic Valve Academic Research Consortium (VARC) criteria and angiographic Sellers criteria. Univariate predictors for more than mild PVL were the maximal diameter of the aortic annulus size (for both angiographic and echocardiographic assessment of PVL), cover index (for echocardiographic assessment of PVL only), and Agatston score (for both angiographic and echocardiographic assessment of PVL). The aortic annulus eccentricity index was not predicting PVL. At multivariate analysis, Agatston score was the only independent predictor for both angiographic and echocardiographic assessment of PVL. Agatston score is the only independent predictor of PVL regardless of the used imaging technique for the definition of PVL.


Narrow band imaging with magnifying endoscopy for Peyer's patches in patients with inflammatory bowel disease.
Peyer's patches (PPs) play a major role in mucosal immunity, but little is known about their alterations in patients with inflammatory bowel disease (IBD). We aimed to evaluate endoscopic changes of PPs in IBD patients using narrow band imaging with magnifying endoscopy (NBI-ME). Images of PPs using NBI-ME by ileocolonoscopy were consecutively collected. Existence of branch-like structures and the vessel occupancy in the dome lesions of PPs were analyzed. Appearance of the surrounding villi of the domes in PPs was evaluated using a 'villi index' consisting of irregular formation, hyperemia, and altered vascular network pattern. Vascularity of PPs was immunohistologically analyzed by anti-CD34 antibody. 17 patients with Crohn's disease (CD), 43 with ulcerative colitis (UC), and 23 healthy control subjects (HC) were analyzed. Both CD and UC patients had a high prevalence of having branch-like structures and significantly higher vascularity in the dome lesions than HC. The villi indices and vascular widths in the villi were significantly larger in CD and UC patients than in HC. Precise examination with NBI-ME characterized alteration of vascular structure in the dome and surrounding villi lesions of PPs not only in CD but also in UC patients.


Pathways for phosphatidylcholine biosynthesis in bacteria.
Phosphatidylcholine (PC) is the major membrane-forming phospholipid in eukaryotes with important structural and signalling functions. Although many prokaryotes lack PC, it can be found in significant amounts in membranes of rather diverse bacteria. Two pathways for PC biosynthesis are known in bacteria, the methylation pathway and the phosphatidylcholine synthase (PCS) pathway. In the methylation pathway, phosphatidylethanolamine is methylated three times to yield PC, in reactions catalysed by one or several phospholipid N-methyltransferases (PMTs). In the PCS pathway, choline is condensed directly with CDP-diacylglyceride to form PC in a reaction catalysed by PCS. Using cell-free extracts, it was demonstrated that Sinorhizobium meliloti, Agrobacterium tumefaciens, Rhizobium leguminosarum, Bradyrhizobium japonicum, Mesorhizobium loti and Legionella pneumophila have both PMT and PCS activities. In addition, Rhodobacter sphaeroides has PMT activity and Brucella melitensis, Pseudomonas aeruginosa and Borrelia burgdorferi have PCS activities. Genes from M. loti and L. pneumophila encoding a Pmt or a Pcs activity and the genes from P. aeruginosa and Borrelia burgdorferi responsible for Pcs activity have been identified. Based on these functional assignments and on genomic data, one might predict that if bacteria contain PC as a membrane lipid, they usually possess both bacterial pathways for PC biosynthesis. However, important pathogens such as Brucella melitensis, P. aeruginosa and Borrelia burgdorferi seem to be exceptional as they possess only the PCS pathway for PC formation.


Time-dependent relevance of steroid receptors in breast cancer.
To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation. We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered. ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased. The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.


Recent Genetic Changes Affecting Enterohemorrhagic Escherichia coli Causing Recurrent Outbreaks.
Enterohemorrhagic E. coli (EHEC) is responsible for significant human illness, death, and economic loss. The main reservoir for EHEC is cattle, but plant-based foods are common vectors for human infection. Several outbreaks have been attributed to lettuce and leafy green vegetables grown in the Salinas and Santa Maria regions of California. Bacteria causing different outbreaks are mostly not close relatives, but one group of closely-related O157:H7 has caused several of them. This unusual pattern of recurrence may have some genetic basis. Here I use whole-genome sequences to reconstruct the genetic changes that occurred in the recent ancestry of this EHEC. In a short period of time corresponding to little genetic change, there were several changes to adhesion-related sequences, mainly adhesins. These changes may have greatly altered the adhesive properties of the bacteria. Possible consequences include increased persistence of cattle infections, more bacteria shed in cattle feces, and greater virulence in humans. Similar constellations of genetic change, which are detectable by current sequencing-based surveillance, may identify other bacteria that are particular threats to human health. In addition, the Santa Maria subclade carries a nonsense mutation affecting ArsR, a repressor of genes that confer resistance to arsenic and antimony. This suggests that the persistent source of Santa Maria contamination is located in an area with arsenic-contaminated groundwater, a problem in many parts of California. This inference may aid identification of the reservoir of EHEC, which would greatly aid mitigation efforts. IMPORTANCE Food-borne bacterial infections cause substantial illness and death. Understanding how bacteria contaminate food and cause disease is important for combating the problem. Closely-related E. coli, likely originating in cattle, have repeatedly caused outbreaks spread by vegetables grown in California. Such recurrence is atypical, and might have a genetic basis. The genetic changes that occurred in the recent ancestry of these E. coli can be reconstructed from their DNA sequences. Several mutations affect genes involved in bacterial adhesion. These might affect persistence of infection in cattle, quantity of bacteria in their feces, and human disease. They also suggest a way of detecting dangerous bacteria from their genome sequences. Furthermore, a subgroup carries a mutation affecting the regulation of genes conferring arsenic resistance. This suggests that the reservoir for contamination utilizes groundwater contaminated with arsenic, a problem in parts of California. This observation may be an aid to locating the persistent reservoir of contamination.


The "CHEOPS" bundle for the management of Left Ventricular Diastolic Dysfunction in critically ill patients: an experts' opinion.
The impact of left ventricular (LV) diastolic dysfunction (DD) on the outcome of patients with heart failure was established over three decades ago. Nevertheless, the relevance of LVDD for critically ill patients admitted to the intensive care unit has seen growing interest recently, and LVDD is associated with poor prognosis. Whilst an assessment of LV diastolic function is desirable in critically ill patients, treatment options for LVDD are very limited, and pharmacological possibilities to rapidly optimize diastolic function have not been found yet. Hence, a proactive approach might have a substantial role in improving the outcomes of these patients. Recalling historical Egyptian parallelism suggesting that Doppler echocardiography has been the "Rosetta stone" to decipher the study of LV diastolic function, we developed a potentially useful acronym for physicians at the bedside to optimize the management of critically ill patients with LVDD with the application of the bundle. We summarized the bundle under the acronym of the famous ancient Egyptian pharaoh CHEOPS: Chest Ultrasound, combining information from echocardiography and lung ultrasound; HEmodynamics assessment, with careful evaluation of heart rate and rhythm, as well as afterload and vasoactive drugs; OPtimization of mechanical ventilation and pulmonary circulation, considering the effects of positive end-expiratory pressure on both right and left heart function; Stabilization, with cautious fluid administration and prompt fluid removal whenever judged safe and valuable. Notably, the CHEOPS bundle represents experts' opinion and are not targeted at the initial resuscitation phase but rather for the optimization and subsequent period of critical illness.


Prevalence of HIV and syphilis infection among men who have sex with men in China: a meta-analysis.
To figure out the most current prevalence of HIV and syphilis in MSM in China. A meta-analysis was conducted on the studies searched through PubMed, CNKI, and Wanfang published between 1 January 2009 and 11 April 2013. Eighty-four eligible studies, either in Chinese or in English, were included in this review. The pooled prevalence of HIV and syphilis infection in MSM in China was 6.5% and 11.2%, respectively. The subgroup analyses indicated that the prevalence of HIV infection was higher in the economically less developed cities than that in the developed cities (7.5% versus 6.1%, P<0.05). In contrast, the prevalence of syphilis infection was lower in less developed cities than in developed cities (8.6% versus 15.1%). Studies with a sample size smaller than 500 had a lower prevalence of HIV and syphilis infection than those with a sample size greater than 500 (5.9% versus 7.2% for HIV; 11.0% versus 11.5% for syphilis, respectively). HIV and syphilis infection are prevalent in MSM in China. The different prevalence of HIV and syphilis infection between developing and developed cities underscores the need to target prevention strategies based on economic conditions.


Association of the interferon-gamma receptor variant (Val14Met) with systemic lupus erythematosus.
Genetic factors seem to play a significant role in susceptibility to systemic lupus erythematosus (SLE). The purpose of this study was to investigate whether the amino acid polymorphism (Val14Met) found within the IFN-gamma receptor gene (IFNGR1) plays a prominent role in susceptibility to SLE. We found Val14Met located at the COOH terminal of the signal peptide of the IFN-gamma receptor. There was a significant difference in this polymorphism frequency between SLE patients and healthy populations. To clarify whether this amino acid substitution resulted in the alteration of the receptor function, we evaluated the induction of HLA-DR antigen expression on B cells by IFN-gamma stimulation. There was also a significant difference in the induction of HLA-DR by IFN-gamma stimulation between B cells. Furthermore, an intracellular cytokine assay indicated that the Th1/Th2 balance of Th cells bearing the variant receptor shifted to Th2. The genetic polymorphism found within the IFN-gamma receptor gene (Val14Met) may result in a shift to Th2, and this shift may increase susceptibility to SLE.


Major genetic marker of nidoviruses encodes a replicative endoribonuclease.
Coronaviruses are important pathogens that cause acute respiratory diseases in humans. Replication of the approximately 30-kb positive-strand RNA genome of coronaviruses and discontinuous synthesis of an extensive set of subgenome-length RNAs (transcription) are mediated by the replicase-transcriptase, a barely characterized protein complex that comprises several cellular proteins and up to 16 viral subunits. The coronavirus replicase-transcriptase was recently predicted to contain RNA-processing enzymes that are extremely rare or absent in other RNA viruses. Here, we established and characterized the activity of one of these enzymes, replicative nidoviral uridylate-specific endoribonuclease (NendoU). It is considered a major genetic marker that discriminates nidoviruses (Coronaviridae, Arteriviridae, and Roniviridae) from all other RNA virus families. Bacterially expressed forms of NendoU of severe acute respiratory syndrome coronavirus and human coronavirus 229E were revealed to cleave single-stranded and double-stranded RNA in a Mn(2+)-dependent manner. Single-stranded RNA was cleaved less specifically and effectively, suggesting that double-stranded RNA is the biologically relevant NendoU substrate. Double-stranded RNA substrates were cleaved upstream and downstream of uridylates at GUU or GU sequences to produce molecules with 2'-3' cyclic phosphate ends. 2'-O-ribose-methylated RNA substrates proved to be resistant to cleavage by NendoU, indicating a functional link with the 2'-O-ribose methyltransferase located adjacent to NendoU in the coronavirus replicative polyprotein. A mutagenesis study verified potential active-site residues and allowed us to inactivate NendoU in the full-length human coronavirus 229E clone. Substitution of D6408 by Ala was shown to abolish viral RNA synthesis, demonstrating that NendoU has critical functions in viral replication and transcription.


Abiotic and biotic influences on the dispersal behavior of metamorph cane toads (Bufo marinus) in tropical Australia.
A mechanistic understanding of factors influencing the dispersal behavior of metamorph cane toads (Bufo marinus) has direct conservation relevance in Australia. These invasive anurans are toxic to native predators, and if we can predict their distribution across the landscape, we can also predict (and perhaps, manage) the scale of their impact. We propose that the major drivers of metamorph distribution are the risk of dehydration (restricting the young toads to moist substrates near pond margins) and biotic advantages to dispersal away from the pond (especially, less risk of cannibalism). To test this model, we investigated the influence of abiotic and biotic cues on the behavior of individual toads in the laboratory. Substrate moisture levels strongly influenced metamorph activity levels and habitat selection: dry substrates induced most metamorphs to remain near water. The only biotic cue to influence metamorph dispersal was proximity of a larger (cannibalistic) conspecific; a cannibal's presence at the pond margin caused most metamorphs to spend less time there, and as a consequence, to dehydrate more rapidly. Our results suggest that the spatial and temporal distribution of metamorph cane toads reflects a trade-off between competing risks: the danger of desiccation tends to keep young toads close to the pond margin in dry conditions, whereas the danger of cannibalism stimulates dispersal.


A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors.
Oligodendrocyte development is controlled by a number of survival and migratory factors. The present study shows that signaling of CXCR4 receptor by the chemokine CXCL12 regulates survival and migration of neural precursors (NP) as well as oligodendrocyte progenitors (OP). CXCR4 is expressed by E14 striatal NP and OP generated by neurospheres. In CXCR4-defective mice, the number of NP in neurosphere outgrowth was twofold less than in wild-type (WT) mice; NP radial cell migration was also decreased. In contrast, the addition of CXCL12 to WT NP increased radial migration from the sphere in a dose-dependent manner with a maximal response at 200 nM. When oligodendrocytes differentiated in neurosphere outgrowth, CXCR4 was downregulated. OP isolated from newborn brain coexpressed CXCR4 with platelet-derived growth factor receptor-alpha (PDGFR alpha) or chondroitin sulfate proteoglycan; receptor expression also decreased during differentiation in vitro. Neonatal OP showed a peak migratory response to 20 nM of CXCL12 in chemotactic chambers, a migration inhibited by a CXCR4 antagonist and anti-CXCL12 antibody. In the embryonic spinal cord, the number of OP-expressing PDGFR alpha was reduced more than twofold in CXCR4-defective mice compared with WT and the ratio of ventral to dorsal OP was significantly increased. This indicates a defect in OP survival and their dorsal migration from the ventral cord region, probably because CXCR4(-/-) OP are unable to respond to CXCL12 made by vascular endothelia and the pia mater. We propose that CXCR4 signaling regulate survival and outward chemotactic migration of OP during embryonic and postnatal CNS development.


[Transposition of the tendon of M. tibialis posterior an effective treatment of drop foot; retrospective study with follow-up in 12 patients].
To evaluate the results of transposition of the tendon of the M. tibialis posterior in patients with a drop foot. Descriptive, retrospective and follow-up investigation. Surgical treatment was carried out in 12 patients with a drop foot (9 women and 3 men, with an average age of 37 years) in the period 1986-1998. The aetiology of the drop foot was a traumatic or iatrogenic lesion of the peroneal nerve or sciatic nerve in 9 patients and in 3 patients spina bifida occulta, leprosy and a herniation of a lumbar disc respectively. None of the patients had important comorbidity. Treatment consisted of lengthening the Achilles tendon according to Huckstep, transposition of the tibial posterior tendon in two tails to the dorsomedial and dorsolateral side of the foot, and six weeks of immobilisation in plaster of Paris. The postoperative period was without complications. The treatment improved the heel-toe steppage gait in all patients. None of the 10 patients who had used an orthosis preoperatively still used it at the time of the follow up. Fifty per cent of the patients acquired a dorsiflexion of the foot of more than 0 degree. The results were in accordance with those in the literature. Transposition of the tibial posterior tendon is a worthwhile alternative for those patients with a drop foot (and without important comorbidity) who cannot walk satisfactorily with an ankle-foot orthosis.


Towards in vivo monitoring of neutron distributions for quality control of BNCT.
Dose delivery in boron neutron capture therapy (BNCT) is complex because several components contribute to the dose absorbed in tissue. This dose is largely determined by local boron concentration, thermal neutron distribution and patient positioning. In vivo measurements of these factors would considerably improve quality control and safety. During therapy, a y-ray telescope measures the y-rays emitted following neutron capture by hydrogen and boron in a small volume of the head of a patient. Scans of hydrogen y-ray emissions could be used to verify the actual distribution of thermal neutrons during neutron irradiation. The method was first tested on different phantoms. These measurements showed good agreement with calculations based on thermal neutron distributions derived from a treatment planning program and from Monte Carlo N-particle (MCNP) simulations. Next, the feasibility of telescope scans during patient irradiation therapy was demonstrated. Measurements were reproducible between irradiation fractions. In theory, this method can be used to verify the positioning of the patient in vivo and the delivery of thermal neutrons in tissue. However, differences between measurements and calculations based on a routine treatment planning program were observed. These differences could be used to refine the treatment planning. Further developments will be necessary for this method to become a standard quality control system.


Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals.
Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.


A Clinical Role of PET-MRI in Prostate Cancer?
PET/MRI is a relevant application field for prostate cancer management, offering advantages in early diagnosis, staging, and therapy planning. Despite drawbacks such as higher costs, longer acquisition time, and the need for skilled personnel, the technical integration of PET and MRI provides valuable information for detecting primary tumors, identifying metastases, and characterizing the disease, leading to more accurate staging and personalized treatment strategies. However, PET/MRI adoption has been slow, but ongoing technological advancements and AI integration might overcome challenges and improve clinical utility. As precision medicine gains importance in oncology, PET/MRI's multiparametric data can tailor treatment plans to individual patients, providing a comprehensive assessment of tumor biology and aggressiveness for more effective therapeutic strategies.