Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT.
Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.


Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin.
Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7-36.7) and 153 (138-175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h-1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1-1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.


Simple clinical indicators for early psoriatic arthritis detection.
Diagnosis of psoriatic arthritis (PsA), in a period of 12 months from the onset of the first articular episode, permits of identifying the early form defined as "early PsA". The recognition of the disease in this phase leads to better outcome. The aim of this study was to identify peculiar clinical and/or laboratory findings that could be useful for the diagnosis of "early PsA". Thirty-five patients with early onset of arthritis were observed. The following data were collected for each patient: family and personal history, physical examination, tender and swollen joint counts (TJC, SJC), tender entheseal count, presence of dactylitis and low back pain (LBP), and laboratory tests. Among the 35 total patients, 24 showed skin and/or nail psoriasis or a family history of psoriasis. The remaining 11 patients showed absence of concomitant or previous psoriasis and/or familiarity for psoriasis. The comparison between the two groups showed that patients with psoriasis had a significant presence of LBP, dactylitis and enthesitis than patients with psoriasis. The study confirms that the distinctive clinical findings of PsA is psoriasis, but also LBP, dactylitis and enthesitis have a relevant role in early identification. A low number of SJC and TJC are frequently observed in early phases of PsA than in other forms of early arthritis. These aspects could be mostly helpful when psoriasis is not detected or can follow arthritis in absence of familiar positivity, making difficult PsA diagnosis. In conclusion, careful medical history, clinical examination and first-level laboratory investigations are useful to characterize early phases of PsA.


The effectiveness of omeprazole, clarithromycin and tinidazole in eradicating Helicobacter pylori in a community screen and treat programme. Leeds Help Study Group.
Helicobacter pylori screening and treatment has been proposed as a cost-effective method of preventing gastric cancer. To assess, in a randomized controlled trial, the efficacy of therapy in eradicating H. pylori as part of a screening programme, and to report the adverse events associated with this strategy. Subjects between the ages of 40-49 years were randomly selected from the lists of 36 primary care centres. Participants attended their local practice and H. pylori status was determined by 13C-urea breath test. Infected subjects were randomized to receive omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and tinidazole 500 mg b.d. for 7 days (OCT) or identical placebos. Eradication was determined by a 13C-urea breath test 6 months and 2 years after the first visit. Successful eradication was defined as two negative 13C-urea breath tests or one negative and one missing test. Adverse events and compliance were assessed at the 6-month visit. A total of 32 929 subjects were invited to attend, 8407 were evaluable, and 2329 (28%) of these were H. pylori-positive. A total of 1161 subjects were randomized to OCT and 1163 to placebo; over 80% returned for a repeat 13C-urea breath test on at least one occasion. The eradication rates in those allocated to OCT were as follows: intention-to-treat, 710 out of 1161 (61%; 95% confidence interval: 58-64%); evaluable 710 out of 967 (73%; 95% CI: 71-76%); took all medication 645 out of 769 (84%; 95% CI: 81-87%). Adverse events occurred in 45% of the treatment group and in 18% of the placebo group (relative risk 2.5; 95% CI: 2.1-2.9). Compliance, male gender, no antibiotic prescription in the subsequent 2 years and experiencing a bitter taste with the medication were independently associated with treatment success. The OCT regimen has an eradication rate of 61% in intention-to-treat analysis and is therefore less successful in treating H. pylori as part of a screening programme compared with hospital studies in dyspeptic patients.


Urinary tract infection as a preventable cause of pregnancy complications: opportunities, challenges, and a global call to action.
The urinary tract is a common site of infection in humans. During pregnancy, urinary tract infection (UTI) is associated with increased risks of maternal and neonatal morbidity and mortality, even when the infection is asymptomatic. By mapping available rates of UTI in pregnancy across different populations, we emphasize this as a problem of global significance. Many countries with high rates of preterm birth and neonatal mortality also have rates of UTI in pregnancy that exceed rates seen in more developed countries. A global analysis of the etiologies of UTI revealed familiar culprits as well as emerging threats. Screening and treatment of UTI have improved birth outcomes in several more developed countries and would likely improve maternal and neonatal health worldwide. However, challenges of implementation in resource-poor settings must be overcome. We review the nature of the barriers occurring at each step of the screening and treatment pipeline and highlight steps necessary to overcome these obstacles. It is our hope that the information compiled here will increase awareness of the global significance of UTI in maternal and neonatal health and embolden governments, nongovernmental organizations, and researchers to do their part to make urine screening and UTI treatment a reality for all pregnant women.


Contrapuntal networks of gene expression during Arabidopsis seed filling.
We have used cDNA microarrays to examine changes in gene expression during Arabidopsis seed development and to compare wild-type and mutant wrinkled1 (wri1) seeds that have an 80% reduction in oil. Between 5 and 13 days after flowering, a period preceding and including the major accumulation of storage oils and proteins, approximately 35% of the genes represented on the array changed at least twofold, but a larger fraction (65%) showed little or no change in expression. Genes whose expression changed most tended to be expressed more in seeds than in other tissues. Genes related to the biosynthesis of storage components showed several distinct temporal expression patterns. For example, a number of genes encoding core fatty acid synthesis enzymes displayed a bell-shaped pattern of expression between 5 and 13 days after flowering. By contrast, the expression of storage proteins, oleosins, and other known abscisic acid-regulated genes increased later and remained high. Genes for photosynthetic proteins followed a pattern very similar to that of fatty acid synthesis proteins, implicating a role in CO(2) refixation and the supply of cofactors for oil synthesis. Expression profiles of key carbon transporters and glycolytic enzymes reflected shifts in flux from cytosolic to plastid metabolism. Despite major changes in metabolism between wri1 and wild-type seeds, <1% of genes differed by more than twofold, and most of these were involved in central lipid and carbohydrate metabolism. Thus, these data define in part the downstream responses to disruption of the WRI1 gene.


Non-invasive stimulation therapies for the treatment of refractory pain.
Drug-refractory pain is an indication for neurostimulation therapy, which can be either non-invasive [mainly transcutaneous electrical nerve stimulation (TENS), repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial direct current stimulation (tDCS)] or invasive which requires the intervention of a surgeon to implant electrodes and a pulse generator [peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS)]. In this review, the respective mechanisms of action and efficacy of TENS, rTMS, and tDCS are discussed. The advantages of TENS include non-invasiveness and ease to use, so that the technique can be operated by the patient. TENS can be indicated as a first-line treatment in patients suffering from peripheral neuropathic pain if the painful area is limited and the sensory deficit moderate. The current best indications are chronic radiculopathies, mononeuropathies, and postherpetic pain. Test sessions allow to select suitable patients and to determine the site, frequency, and optimal intensity of stimulation. Three to four 30- to 60-minute sessions per day are usually recommended. With regard to rTMS, published randomized controlled studies in chronic neuropathic and non-neuropathic pain (fibromyalgia) reached a sufficient level of evidence to recommend this technique for the indication of implanted motor cortex stimulation for the treatment of refractory neuropathic pain or as a long-term treatment for pain syndromes, in which surgery is not indicated, such as fibromyalgia. Other indications, concerning either chronic or acute pain syndromes, such as postoperative pain, should be developed in parallel with the optimization of stimulation parameters. This also includes the availability of new coils and magnetic field waveforms and progress in neuronavigation techniques, especially by the integration of functional imaging and high-resolution EEG data.


Identifying non-traditional stakeholders with whom to engage, when mitigating antimicrobial resistance in foodborne pathogens (Canada).
Antimicrobial resistance (AMR) is a critical public health issue that involves interrelationships between people, animals, and the environment. Traditionally, interdisciplinary efforts to mitigate AMR in the food chain have involved public health, human and veterinary medicine, and agriculture stakeholders. Our objective was to identify a more diverse range of stakeholders, beyond those traditionally engaged in AMR mitigation efforts, via diagramming both proximal and distal factors impacting, or impacted by, use and resistance along the Canadian food chain. We identified multiple stakeholders that are not traditionally engaged by public health when working to mitigate AMR in the food chain, including those working broadly in the area of food (e.g., nutrition, food security, international market economists) and health (e.g., health communication, program evaluation), as well as in domains as diverse as law, politics, demography, education, and social innovation. These findings can help researchers and policymakers who work on issues related to AMR in the food chain to move beyond engaging the 'traditional' agri-food stakeholders (e.g., veterinarians, farmers), to also engage those from the wider domains identified here, as potential stakeholders in their AMR mitigation efforts.


Postheparin serum lipolytic activity in psoriatic males.
As numerous papers have presented many disturbances of blood lipid composition and changes in lipolytic enzyme activity, it was considered appropriate to investigate the postheparin lipolytic activity in serum of psoriatic males. The course of serum lipolytic process provoked by intravenous application of heparin was observed by measuring the concentration of the major substrates and products: triglycerides (TG), free fatty acids (FFA) and glycerol (G) before intravenous bolus of heparin 10 units per 1 kg b.w. and after 30 minutes. The study group consisted of 30 psoriatic males with mean age 29.7 +/- 9.6 and mean BMI 24.2 +/- 3.3 and was compared with 35 healthy males with corresponding mean age and mean BMI. The release of glycerol and FFA and the reduction of TG concentrations following intravenous heparin were observed. Psoriatic sera demonstrated higher concentrations of triglycerides, glycerol and free fatty acids before and after the lipolysis compared with the controls. The course of postheparin lipolysis in psoriatic males seems to be changed as compared with the control group.


Risk of intravascular cardiac device infections in patients with bacteraemia: impact on device removal.
The risk of intravascular cardiac device infection (ICDI) has increased significantly over the last decade and is rising faster than the corresponding increase in device implantations. ICDIs may consist of pocket infections, wire infections, wire infections complicated by endocarditis, or combinations of these. In this review, we examine the microbiology of ICDIs, focusing on the risk of developing ICDI following bloodstream infections with key pathogens such as Staphylococcus aureus, coagulase-negative staphylococci, enterococci, etc., as well as the pathophysiology of these infections.


A B12-dependent radical SAM enzyme involved in oxetanocin A biosynthesis.
Oxetanocin A (OXT-A) is a potent antitumour, antiviral and antibacterial compound. Biosynthesis of OXT-A has been linked to a plasmid-borne Bacillus megaterium gene cluster that contains four genes: oxsA, oxsB, oxrA and oxrB. Here we show that both the oxsA and oxsB genes are required for the production of OXT-A. Biochemical analysis of the encoded proteins, a cobalamin (Cbl)-dependent S-adenosylmethionine (AdoMet) radical enzyme, OxsB, and an HD-domain phosphohydrolase, OxsA, reveals that OXT-A is derived from a 2'-deoxyadenosine phosphate in an OxsB-catalysed ring contraction reaction initiated by hydrogen atom abstraction from C2'. Hence, OxsB represents the first biochemically characterized non-methylating Cbl-dependent AdoMet radical enzyme. X-ray analysis of OxsB reveals the fold of a Cbl-dependent AdoMet radical enzyme, a family of enzymes with an estimated 7,000 members. Overall, this work provides a framework for understanding the interplay of AdoMet and Cbl cofactors and expands the catalytic repertoire of Cbl-dependent AdoMet radical enzymes.


Bisphosphonate anticancer activity in prostate cancer and other genitourinary cancers.
Anticancer therapies have traditionally been targeted directly against cancer cell growth. However, newer treatment strategies also target the microenvironment that supports metastatic cancer cell growth. Bisphosphonates are the standard of care for maintaining bone health in patients with bone metastases from solid tumors and bone lesions from multiple myeloma, and emerging evidence supports potential anticancer activity of bisphosphonates. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is currently advised for reducing the risk of skeletal morbidity in patients with bone metastases from prostate cancer and other genitourinary cancers, such as renal cell carcinoma and bladder cancer. Clinical studies indicate that ZOL can normalize bone marker levels (a potential measure of skeletal disease burden), which may improve survival in patients with aggressive bone disease from prostate and other genitourinary cancers, supporting a broader therapeutic role for ZOL in genitourinary malignancies. This review examines the rationale and emerging evidence supporting the anticancer activity of bisphosphonates, especially ZOL, against prostate and other genitourinary cancers.


Investigation of refractive index sensing based on Fano resonance in fiber Bragg grating ring resonators.
In this paper we theoretically investigate a ring resonant cavity obtained by closing on itself a π-shifted fiber Bragg grating, to be used for refractive index sensing applications. Differently from a conventional π-shifted fiber Bragg grating, the spectral structure of this cavity is characterized by an asymmetric splitting doublet composed by a right side resonance having an asymmetric Fano profile and a left side resonance having a symmetric Lorentzian profile. The right side resonance shows a narrower and sharper peak than all the other kinds of resonance achievable with both conventional ring resonators and π-shifted fiber Bragg gratings. A reduction of the resonant linewidth with respect to a conventional π-shifted Fiber Bragg grating and a fiber ring resonator, having the same physical parameters, is theoretically proved, achieving up to five orders of magnitude improvement with respect to the usual ring resonator. Due to these resonance features, the π-shifted Bragg grating ring resonator results suitable for RI sensing applications requiring extremely narrow resonances for high resolution measurements. In particular, by assuming a refractive index sensing to detect the presence of sugar in water, the sensor can show a theoretical resolution better than 10-9 RIU.


Intrinsic topological magnons in arrays of magnetic dipoles.
We study a simple magnetic system composed of periodically modulated magnetic dipoles with an easy axis. Upon adjusting the geometric modulation amplitude alone, chains and two-dimensional stacked chains exhibit a rich magnon spectrum where frequency gaps and magnon speeds are easily manipulable. The blend of anisotropy due to dipolar interactions between magnets and geometrical modulation induces a magnetic phase with fractional Zak number in infinite chains and end states in open one-dimensional systems. In two dimensions it gives rise to topological modes at the edges of stripes. Tuning the amplitude in two-dimensional lattices causes a band touching, which triggers the exchange of the Chern numbers of the volume bands and switches the sign of the thermal conductivity.


Extracellular Vesicles Carrying RUNX3 Promote Differentiation of Dental Pulp Stem Cells.
This study aims to clarify the mechanism underlying dental pulp cells-extracellular vesicles (DPC-EVs) carrying runt-related transcription factor 3 (RUNX3) in mediating odontogenic differentiation of dental pulp stem cells (DPSCs) with the involvement of miR-30a-5p-regulated NOTCH1. Extracellular vesicles (EVs) were isolated from human DPSCs, and identified using transmission electron microscopy, and nanoparticle tracking analysis. PBS, EVs, or EV inhibitor GW4869 was added to DPSCs for co-culture, whilst odontogenic differentiation was assessed in terms of ratio of mineralized nodules and expression odontoblast differentiation markers. Dual luciferase reporter gene assay and chromatin immunoprecipitation for binding relation among RUNX3, miR-30a-5p and NOTCH1were employed to evaluate their roles in odontogenic differentiation was determined. Animal experiment was established to confirm the effect of DPC-EVs-loaded RUNX3 on dental pulp. In vitro finding demonstrated that EVs delivered RUNX3 to DPSCs, thereby activated miR-30a-5p expression and inhibited NOTCH1 expression, which was reversed by addition of GW4869. RUNX3 upregulation promoted miR-30a-5p while miR-30a-5p targeted and inhibited NOTCH1. Silencing of RUNX3 in EVs decreased expression of those differentiation markers, downregulated miR-30a-5p and upregulated NOTCH1. DPSC-EVs can carry RUNX3 to the DPSCs, promote the transcription of miR-30a-5p, and then inhibit the expression of NOTCH1, and finally promote the odontogenic differentiation of DPSCs.


Isolated oropharyngeal abscess with hypopharyngeal extension recurring 12 years after initial surgical management: A case report and review of the literature.
Pharyngeal abscesses require urgent management as they have the propensity to cause severe and life-threatening complications. The introduction of antibiotics has led to a dramatic decline in the incidence of these infections. Regardless, abscess formation continues to be observed in the peritonsillar, parapharyngeal, and retropharyngeal spaces. Oropharyngeal and hypopharyngeal abscesses that cause airway obstruction are scarcely reported and tend to be secondary to other processes. Herein, we describe the case of an 83-year-old man presenting with an idiopathic, obstructive, oropharyngeal wall abscess, extending from the infratonsillar region to the hypopharynx, which recurred after initial surgical management 12 years prior for the same process. He required reintervention during both episodes for rapid reaccumulation. A detailed electronic literature search of PubMed and MedLine was performed for studies reporting on recurrent pharyngeal abscesses and their management. Results were limited to articles published in English from inception to August 2021. The timely management of pharyngeal infections acutely obstructing the airway is crucial. Physicians should adopt close and frequent monitoring and have a low threshold for reimaging should symptoms worsen or fail to improve after the initial surgical intervention.


Effect of clobazam as add-on antiepileptic drug in patients with epilepsy.
The use of clobazam in epilepsy has increased since its introduction in 1975. However, it has not been audited for its overall usefulness in Indian set up. The present study was aimed to evaluate usage pattern, retention rate, effectiveness and tolerability of clobazam during routine practice in an outpatient epilepsy clinic of a tertiary care hospital in New Delhi, India. This study was performed on the patients prescribed antiepileptic medication who had clobazam as last added drug in their treatment regimen during October 2010-March 2012. These patients were followed up for two OPD visits. The primary points evaluated were retention rate, percentage of seizure-free patients and reasons for discontinuing clobazam. Of the 417 consecutive patients, 132 (31.7%) were on clobazam treatment for more than four years (median 6 yr, range 4-15 yr). No seizure for previous 12 months was considered as seizure free and was observed in 151 (36.2%) patients. There was no improvement in seizure control in 32 (7.7%) patients. A decrease in seizure severity without any change in seizure frequency was observed in 76 (18.2%) patients. Clobazam was discontinued by 15 (3.6%) patients due to complaints like drowsiness (13), fatigue/tiredness (8), headache (6), poor memory (6), irritable behaviour (5), abdominal pain (3) and dizziness (3). Our results provide valuable information about the clinical use of clobazam as add-on antiepileptic drug therapy in the management of patients with epilepsy.


Biomarkers and surrogacy: relevance to chemoprevention.
Clinical cancer prevention trials that use disease as the end-point are of necessity large, lengthy and costly. While such trials will always remain the 'gold standard' for establishing efficacy, they are unwieldy and inefficient for the rapid translation of our accelerating understanding of the molecular basis of cancer into preventive strategies. The inclusion of biomarkers in the process of chemopreventive agent development is crucial for the advancement of the field. This overview highlights the types of approach that are being used in the development and application of biomarkers in chemoprevention studies. Biomarkers, which measure exposure, susceptibility or risk factors, can be used in selecting study cohorts, assessing participant compliance and/or determining agent efficacy. Key features of biomarkers include reliability, precision, accuracy and validity. Not all biomarkers are suitable for all purposes and are likely to be imperfect in any single setting. Judicious selection and matching of biomarkers with agents and study cohorts is required for their effective utilization. A critical but non-dichotomous element of risk biomarkers is their degree of surrogacy. A classification scheme is provided that relates the degree of surrogacy of risk biomarkers to their utility in preventive interventions.


Interatomic Potential for Hydrocarbons on the Basis of the Modified Embedded-Atom Method with Bond Order (MEAM-BO).
In this paper, we develop a new modified embedded atom method (MEAM) potential that includes the bond order (MEAM-BO) to describe the energetics of unsaturated hydrocarbons (double and triple carbon bonds) and also develop improved parameters for saturated hydrocarbons from those of our previous work. Such quantities like bond lengths, bond angles, and atomization energies at 0 K, dimer molecule interactions, rotational barriers, and the pressure-volume-temperature relationships of dense systems of small molecules give a comparable or more accurate property relative to experimental and first-principles data than the classical reactive force fields REBO and ReaxFF. Our extension of the MEAM potential for unsaturated hydrocarbons (MEAM-BO) is a step toward developing more reliable and accurate polymer simulations with their associated structure-property relationships, such as reactive multicomponent (organic/metal) systems, polymer-metal interfaces, and nanocomposites. When the constants for the BO are zero, MEAM-BO reduces to the original MEAM potential. As such, this MEAM-BO potential describing the interaction of organic materials with metals within the same MEAM formalism is a significant advancement for computational materials science.


Viruses Causing Hemorrhagic Fever. Safety Laboratory Procedures.
Viral hemorrhagic fevers are diseases caused by viruses which belong to different families, many of them causing severe diseases. These viruses may produce different symptomatology together with a severe multisystem syndrome, and the final result might be the production of hemorrhages in several sites of the body. The majority of them have no other treatment than supportive therapy, although some antiviral drugs can be used in some circumstances. Transmission of VHF has been demonstrated through contact with animal vectors or person-to-person through the contact with body fluids. No risk of transmission has been found during the incubation period, but when the viral load is high the risk of transmission is greatest. Both health care and clinical laboratory workers must safely handle patients and specimens by taking all required precautions during their management.


Diagnosing gestational diabetes mellitus: use of a glucose screen without administering the glucose tolerance test.
To determine if a 1-hour glucose screen value could be identified, above which gestational diabetes mellitus could be diagnosed without the 3-hour oral glucose tolerance test (GTT). Demographic, historic, obstetric, and neonatal data from 514 singleton pregnancies with glucose screen values at least 140 mg/dL followed by a GTT were reviewed (312 patients with normal GTTs and 202 with gestational diabetes mellitus). Statistical analyses used chi2, Fisher exact, Student t, and Mann-Whitney tests. After determining the optimal glucose screen cutoff point using receiver operating characteristic curve analyses, patients were regrouped according to this value and analyzed further. The optimal cutoff point for the upper limit of the glucose screen was determined to be 186 mg/dL (95.9% specificity, 98.2% negative predictive value, 36.1% sensitivity, and 19.6% positive predictive value). Comparison of patients with elevated screens and normal GTTs versus those with gestational diabetes revealed significant differences only regarding a history of gestational diabetes mellitus and neonatal hypoglycemia in the studied pregnancy. Those with screens greater than 185 mg/dL behaved like diabetic patients and, when compared with subjects with screens of 140-185 mg/dL, also had a significantly greater proportion of large for gestational age infants. Patients with 1-hour glucose screens greater than 185 mg/dL have a high probability of gestational diabetes mellitus and the diagnosis can be made without the GTT. Using this approach could allow prompt initiation of therapy without the inconvenience and discomfort of the GTT.


Protein Export into and across the Atypical Diderm Cell Envelope of Mycobacteria.
Mycobacteria, including the infamous pathogen Mycobacterium tuberculosis, are high-GC Gram-positive bacteria with a distinctive cell envelope. Although there is a typical inner membrane, the mycobacterial cell envelope is unusual in having its peptidoglycan layer connected to a polymer of arabinogalactan, which in turn is covalently attached to long-chain mycolic acids that help form a highly impermeable mycobacterial outer membrane. This complex double-membrane, or diderm, cell envelope imparts mycobacteria with unique requirements for protein export into and across the cell envelope for secretion into the extracellular environment. In this article, we review the four protein export pathways known to exist in mycobacteria: two conserved systems that exist in all types of bacteria (the Sec and Tat pathways) and two specialized systems that exist in mycobacteria, corynebacteria, and a subset of low-GC Gram-positive bacteria (the SecA2 and type VII secretion pathways). We describe the progress made over the past 15 years in understanding each of these mycobacterial export pathways, and we highlight the need for research to understand the specific steps of protein export across the mycobacterial outer membrane.


Regional decreases [corrected] in AMPA receptor density in mice infected with the LP-BM5 murine leukemia virus.
The status of alpha-amino-3-hydroxy-5-methyl-4-isoxizole (AMPA) receptors in several brain regions was investigated in a murine model of retrovirus-associated cognitive impairment, the LP-BM5 infected mouse. The Bmax of [3H]AMPA receptors in the cortex, striatum, hippocampus and cerebellum declined by 29-50% as early as 8 weeks post-inoculation. Immunohistochemistry revealed foci of decreased glutamate receptor (GluR)-2/3 protein expression by Purkinje neurons distributed throughout the cerebellum. Immunoblots indicated that cerebellar expression of only GluR-3 protein was reduced. This global decrease in AMPA receptors may constitute a compensatory response to elevated excitotoxin (glutamate) concentrations and are concurrent with the development of spatial learning deficits observed in these mice. Thus, the reduction in AMPA receptor density may contribute to the development of the cognitive abnormalities associated with infection by retroviruses such as HIV-1.


Depth estimation algorithm for light field data by epipolar image analysis and region interpolation.
In this paper, we propose an optimized algorithm to estimate the depth information in the 4D light field data. Our scheme has the advantage of conciseness compared to the traditional epipolar-plane image analysis method. First, we have analyzed the depth resolution properties of light field data not mentioned by the previous researchers. In the depth estimation process, epipolar analysis is confined in a small range to reduce the running time, combining with a regression test to reduce estimation error. Occlusion condition is especially dealt with by recognizing object margin. To test the accuracy of our algorithm, we use a benchmark dataset to evaluate the output depth result. We get a competitive result in the estimation error evaluation and prevailing runtime result compared to that of baseline algorithms. Owing to the high performance, this algorithm can be used in real-time depth recognition with the aid of parallel computing.


Diversity scaling of human vaginal microbial communities.
The composition and diversity of the human vaginal microbial community have been investigated intensively due to the diversity-stability relationship (DSR)-based hypothesis for bacterial vaginosis (BV) etiology, which was first proposed in the 1990s and has received renewed interest in recent years. Nevertheless, diversity changes (scaling) across individuals in a cohort or population have not yet been addressed, which is significant both theoretically and practically. Theoretically, biodiversity scaling is the core of biogeography, and practically, inter-subject heterogeneity is critical for understanding the etiology and epidemiology of human microbiome-associated diseases such as BV. Here we applied the diversity-area relationship (DAR), a recent extension to the classic species-area relationship (SAR), to study diversity scaling of the vaginal microbiome by reanalyzing reported data collected from 1 107 postpartum women. The model used here characterized the power-law (or its extension) relationships between accrued diversity and areas (numbers of individuals), upon which four biogeographic profiles were thus defined. Specifically, we established the DAR profile (relationship between diversity scaling parameter and so-termed diversity order (q)), similarly pair-wise diversity overlap (PDO) profile, maximal accrual diversity (MAD) profile, and ratio of individual-level to population-level diversity (RIP) profile. These four profiles offer valuable tools to assess and predict diversity scaling (changes) in the human vaginal microbiome across individuals, as well as to understand the dynamics of vaginal microbiomes in healthy women.


Relationship between sprint ability and loaded/unloaded jump tests in elite sprinters.
The neuromechanical determinants of sprint running performance have been investigated in team sports athletes and non-elite sprinters. The aim of this study was to quantify the relationships between kinetic and performance parameters, obtained in loaded and unloaded vertical and horizontal jumps, and sprinting in elite athletes. Twenty-two sprinters performed squat jumps, countermovement jumps, horizontal jumps, and jump squats with different loads on a force platform, in addition to a 50-m sprint. Results indicated that jumping height and distance in vertical and horizontal jumps are more strongly correlated (R ≈ 0.81) to sprinting speed than the respective peak forces (R ≈ 0.36). Furthermore, the optimum load generating the maximum power in the jump squat is also highly correlated to sprint performance (R ≈ 0.72). These results reveal that vertical and horizontal jump tests may be used by coaches for assessing and monitoring qualities related to sprinting performance in elite sprinters.


Comparison of four molecular typing methods for characterization of Corynebacterium diphtheriae and determination of transcontinental spread of C. diphtheriae based on BstEII rRNA gene profiles.
The diphtheria epidemic in the Russian Federation in the 1990s made diphtheria a focus of global concern once again. The development of rapid and reproducible typing methods for the molecular characterization of Corynebacterium diphtheriae has become a priority in order to be able to monitor the spread of this important pathogen on a global scale. We report on a comparison of four molecular typing methods (ribotyping, pulsed-field gel electrophoresis [PFGE], random amplification of polymorphic DNA [RAPD], and amplified fragment length polymorphism [AFLP]) for the characterization of C. diphtheriae strains. Initially, 755 isolates originating from 26 countries were analyzed by ribotyping. One strain of each ribotype was then randomly chosen and characterized by PFGE, RAPD, and AFLP. In order to ascertain whether the Eastern European epidemic ribotype could be further discriminated, 10 strains of ribotype D1 (the epidemic ribotype) from different geographical regions were randomly chosen and subjected to analysis by PFGE, RAPD, and AFLP. The results revealed that ribotyping is highly discriminatory and reproducible and is currently the method of choice for typing C. diphtheriae. PFGE and AFLP were less discriminatory than ribotyping and RAPD. An assessment of the transcontinental spread of the organism showed that several genotypes of C. diphtheriae circulated on different continents of the world and that each outbreak was caused by a distinct clone. The ribotypes seen in Europe appeared to be distinct from those seen elsewhere, and certain ribotypes appeared to be unique to particular countries.


Halorubrum luteum sp. nov., isolated from Lake Chagannor, Inner Mongolia, China.
A novel halophilic archaeon, strain CGSA15(T), was isolated from water of Lake Chagannor in China. The strain grew optimally at 33-37 degrees C, pH 9.5-10.0 and 4.0-4.3 M NaCl. The major polar lipids were phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester. The genomic DNA G+C content of strain CGSA15(T) was 60.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CGSA15(T) was a member of the genus Halorubrum and was related most closely to Halorubrum alkaliphilum AS 1.3528(T) (96.1 % similarity) and Halorubrum tibetense AS 1.3239(T) (96.9 %). Levels of DNA-DNA relatedness between strain CGSA15(T) and Hrr. alkaliphilum AS 1.3528(T) and Hrr. tibetense AS 1.3239(T) were 36.7 and 28.9 %, respectively. According to the phenotypic and genotypic data presented, strain CGSA15(T) is considered to represent a novel species of the genus Halorubrum, for which the name Halorubrum luteum sp. nov. is proposed. The type strain is CGSA15(T) (=CGMCC 1.6783(T) =CECT 7303(T)).


Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism.
Pitx2, a bicoid-related homeobox gene, is involved in Rieger's syndrome and the left-right (L-R) asymmetrical pattern formation in body plan. In order to define the genomic structure and roles of Pitx2, we analyzed the genomic structure and generated Pitx2-deficient mice with the lacZ gene in the homeobox-containing exon of Pitx2. We were able to show that among three isoforms of Pitx2, Pitx2c shows asymmetrical expression whereas Pitx2a, Pitx2b and Pitx2c show symmetrical expression. In Pitx2(-)(/)(-) embryos there was an increase in mesodermal cells in the distal end of the left lateral body wall and an amnion continuous with the lateral body wall thickened in its mesodermal layer. These changes resulted in a failure of ventral body wall closure. In lung and heart in which Pitx2 is expressed asymmetrically, right pulmonary isomerism, atrioventricular canals with prominent swelling, and juxtaposition of the atrium were detected. The hearts failed to develop tricuspid and mitral valves and a common atrioventricular valve forms. Further, dysgenesis of the Pitx2(-)(/)(-) extraocular muscle and thickening of the mesothelial layer of cornea were observed in the ocular system where Pitx2 is expressed symmetrically, and these resulted in enophthalmos. The present study shows that Pitx2 expressed in various sites participates in morphogenesis through three types of actions: the involvement of asymmetric Pitx2 expression in the entire morphogenetic process of L-R asymmetric organs; the involvement of asymmetric Pitx2 expression in the regional morphogenesis of asymmetric organs; and finally the involvement of symmetric Pitx2 expression in the regional morphogenesis of symmetric organs.


p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth.
The parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21(WAF1) (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-alpha (TGF-alpha), known to be elevated in hyperplastic and adenomatous human PT glands. The time course for dietary P regulation of PT expression of TGF-alpha and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperparathyroidism. In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT-TGF-alpha protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclear antigen (PCNA), an index of cell mitoses, correlated inversely with p21 and directly with TGF-alpha. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-alpha by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-alpha protein content. These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-alpha may function as an autocrine signal to stimulate growth further.


Evaluation of per-procedure equipment costs in an outpatient endoscopy center.
As disposable endoscopes become available, we need baseline costs associated with reusable instruments to make financially intelligent choices. Accordingly, we analyzed the per-use cost of several types of gastrointestinal endoscopes at our institution. Records of 44 gastrointestinal endoscopes were analyzed. Data defined included purchase price, repair and cleaning expense (labor and materials), and number of uses. The labor cost per-use associated with endoscope cleaning was estimated by taking an average time required to clean an endoscope multiplied by the technician's salary. The average number of years of endoscope use varied from 4.6 to 6.9 years contingent on the type of endoscope. For flexible sigmoidoscopes, the average total cost per use was $8.35, and for colonoscopes the cost was $21.81. For gastroscopes and diagnostic and therapeutic duodenoscopes, costs were $20.99, $49.15, and $45.16, respectively. (1) Excluding costs associated with the procedure itself (admit-recovery, drugs, disposable equipment, and procedural personnel), total peruse scope cost ranged from a low of $8.35 for the flexible sigmoidoscope to $49.15 for the diagnostic duodenoscope. (2) The most important variables associated with per-use endoscope cost included number of uses, initial purchase price, and repair costs. (3) Techniques such as the above can be used to define per-procedure costs for a particular practitioner or institution.


Regulation of intestinal Na+-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3.
In a study of the rat intestinal P(i) transport system, an activator protein for rat Na/P(i) co-transport system (PiUS) was isolated and characterized. We also investigated the effects of restriction of vitamin D and P(i) (two of the most important physiological and pathophysiological regulators of P(i) absorption in the small intestine) on intestinal P(i) transport activity and the expression of Na/P(i) co-transporters that are expressed in rat small intestine. Rat PiUS encodes a 424-residue protein with a calculated molecular mass of 51463 Da. The microinjection of rat PiUS into Xenopus oocytes markedly stimulated Na(+)-dependent P(i) co-transport activity. In rats fed with a low-P(i) diet, Na(+)-dependent P(i) co-transport activity was increased approx. 2-fold compared with that of rats fed a normal P(i) diet. Kinetic studies demonstrated that this increased activity was due to an elevation of V(max) but not K(m). The PiUS mRNA levels showed an approximate doubling in the rats fed with the low-P(i) diet compared with those fed with the normal P(i) diet. In addition, after the administration of 1, 25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] to vitamin D-deficient animals, the P(i) uptake was significantly increased in the Na(+)-dependent component in the brush border membrane vesicle (BBMV) at 24 and 48 h. In addition, we found a further high-affinity Na/P(i) co-transport system in the BBMV isolated from the vitamin D-replete animals. The levels of type III Na/P(i) co-transporter PiT-2 mRNA were increased 24 and 48 h after 1,25-(OH)(2)D(3) administration to vitamin D-deficient animals, whereas PiUS and the type IIb Na/P(i) co-transporter mRNA levels were unchanged. In conclusion, we first cloned a rat activator protein, PiUS, and then studied its role along with that of other type III Na/P(i) co-transporters. PiUS and PiT-2 might be important components in the regulation of the intestinal P(i) transport system by P(i) restriction and 1,25-(OH)(2)D(3).


Synthesis of the compatible solute proline by Bacillus subtilis: point mutations rendering the osmotically controlled proHJ promoter hyperactive.
The ProJ and ProH enzymes of Bacillus subtilis catalyse together with ProA (ProJ-ProA-ProH), osmostress-adaptive synthesis of the compatible solute proline. The proA-encoded gamma-glutamyl phosphate reductase is also used for anabolic proline synthesis (ProB-ProA-ProI). Transcription of the proHJ operon is osmotically inducible whereas that of the proBA operon is not. Targeted and quantitative proteome analysis revealed that the amount of ProA is not limiting for the interconnected anabolic and osmostress-responsive proline production routes. A key player for enhanced osmostress-adaptive proline production is the osmotically regulated proHJ promoter. We used site-directed mutagenesis to study the salient features of this stress-responsive promoter. Two important features were identified: (i) deviations of the proHJ promoter from the consensus sequence of SigA-type promoters serve to keep transcription low under non-inducing growth conditions, while still allowing a finely tuned induction of transcriptional activity when the external osmolarity is increased and (ii) a suboptimal spacer length for SigA-type promoters of either 16-bp (the natural proHJ promoter), or 18-bp (a synthetic promoter variant) is strictly required to allow regulation of promoter activity in proportion to the external salinity. Collectively, our data suggest that changes in the local DNA structure at the proHJ promoter are important determinants for osmostress-inducibility of transcription.


Gut microbiome signatures linked to HIV-1 reservoir size and viremia control.
The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridiales. Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption. Video abstract.


Long-term outcome after pancreas transplantation.
Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the very important risk factors for short-term survival of a pancreas transplant, there is not a lot of information available about factors that distinguish short-term from long-term graft function. The analysis of 18,159 pancreas transplants from the International Pancreas Transplant Registry, performed from 25 July 1978 to 31 December 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year and 20-year graft function for transplants with the appropriate follow-up time showed 80, 68 and 45%, respectively, for simultaneous pancreas/kidney transplants; 62, 46 and 16%, respectively, for pancreas after kidney; and 59, 39 and 12%, respectively, for pancreas transplants alone. Important factors influencing long-term function were factors that described the quality of the deceased donor. Pancreas transplants in younger or African-American recipients showed a higher risk of graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants. With a careful donor selection, not only short-term but also long-term pancreas graft function and, therefore, good metabolic control can be achieved for the diabetic patient.


Breathing lung transplantation with the Organ Care System (OCS) Lung: lessons learned and future implications.
Ex vivo lung perfusion (EVLP) represents a potentially important advancement in the preservation of donor lungs prior to transplantation. Portable EVLP or "Breathing Lung Transplantation" with the Organ Care System (OCS) Lung combines the fundamental components of EVLP with portability, thus reducing the total ischemic burden. The Food and Drug Administration (FDA) approved OCS for perfusion of standard donor lungs prior to transplant in 2018. The current review discusses the available literature on the clinical outcomes of OCS Lung as well as translational data.


Pitfalls in the evaluation and resuscitation of the trauma patient.
The management of the trauma patient presents the practitioner with a host of challenges, and the pace, variety of venues, and multidisciplinary nature of the field combine to create a system complexity that is laden with potential pitfalls. This review summarizes some of the general principles of medical errors and examines some of the more common pitfalls encountered in the initial resuscitation and evaluation of the major trauma patient.


[A lateralized reduction of NAA in a case of corticobasal degeneration (CBD): application of proton magnetic resonance spectroscopy (1H-MRS)].
We studied the application of proton magnetic resonance spectroscopy (1H-MRS) in a case of corticobasal degeneration. A 73-year-old woman was referred to our hospital for dysarthria and clumsiness in right arm movement. Intelligence was normal and neither ideational apraxia or ideomotor apraxia were observed. Her speech was slurred and extremely slow. Neurological findings showed a limitation of ocular upward gaze movement, impaired smooth pursuit in the horizontal gaze, rigidity, limb kinetic apraxia and cortical sensory disturbance in the right arm. Magnetic resonance imaging (MRI) showed diffuse brain atrophy, especially in the left fronto-parietal cortex around the central sulcus. A positron emission tomography (PET) study showed diffuse decrement of cerebral blood flow, dominantly in the left hemisphere. The decrease in the uptake of 18F-Fluoro-deoxyglucose also revealed glucose hypo-metabolism, especially in the left frontal and parietal lobe. 1H-MRS by the multivoxel method showed a decrease in N-acetylaspartate (NAA)/Creatine to 1.0 in the left basal ganglia and temporal lobe, compared to the values between 1.4 and 1.7 in the right basal ganglia. These findings indicated that 1H-MRS might detect neuronal loss or degeneration when MRI showed minimal cortical atrophy. This study, the first application of 1H-MRS in a case of corticobasal degeneration, showed that this method was useful for the evaluation of pathophysiological changes in corticobasal degeneration.


[Survival analysis for patients with hepatocellular carcinoma according to stage, liver function and treatment modalities].
Hepatocellular carcinoma (HCC) is 3rd leading cause of cancer in Korea and the prognosis for HCC patients is poor. For assessing the present treatment outcome, this study analyzed the three-year survival rate (3-YSR) and the prognostic factors for patients with HCC in Korea. Between November 2000 and December 2003, 905 patients with HCC who were diagnosed and treated at the National Cancer Center Korea were enrolled in this study. The clinical variables, tumor characteristics and survival periods were analyzed. The mean age of all patients was 56.2+/-10.3 years and 732 (80.9%) patients were male (M:F=4.2:1). 508 (56.1%) patients died and the median survival period was 15.3 months. The overall 3-YSR of the patients with modified UICC stage I, II, III, IVa and IVb were 67.4%, 65.2%, 30.7%, 9.0% and 5.0%, respectively. The modified UICC stage could not differentiate stage I from II, and stage IVa from IVb, on the 3-YSR. The 3-YSR of the Child-Pugh class A patients with modified UICC stage I or II was 85.4% by surgical resection and it was 69.6% by transcatheter chemoembolization (TACE), respectively (P= .461), and those values for patients with stage III were 49.2% and 36.8%, respectively (P=.081). As compared with systemic chemotherapy or conservative therapy, TACE increased the survival rate more for the Child-Pugh class A patients with stage IV. The independent prognostic factors were serum AFP, portal vein thrombosis, the Child-Pugh classification and the stage of HCC. This follow-up study will be helpful in assessing the results of treatments for HCC and it will provide data for the establishment of a more effective treatment strategy.


In vitro function of cyst epithelium from human polycystic kidney.
It is thought that cysts in polycystic kidneys originate from nephron segments and function in a manner similar to the segment or origin. The indirect evidence for this derives from studies of microanatomy and cyst fluid composition. Cysts with low Na+ have been classified as distal, whereas cysts with high Na+ have been classified as proximal. In order to directly determine the transport characteristics of cyst epithelium, cysts from a human polycystic kidney were studied in vitro using Ussing chamber techniques. Composition of cyst fluid was determined in parallel with these studies. Cysts with low Na+ (gradient cysts) demonstrate characteristics consistent with distal nephron origin including elevated potential difference (PD), short-circuit current (Isc), and low conductance. PD and Isc of gradient cysts were amiloride sensitive. Nongradient cysts, however, require additional characterization. At least two types of nongradient cysts were identified, one with characteristics consistent with proximal nephron origin and another apparently without function. These studies are the first direct evidence for active transport of cysts from human polycystic kidney and provide strong evidence to support the concept that cysts function in the same manner as the nephron segment of origin.


Flavor preference conditioning by oral self-administration of ethanol.
Oral self-administration and operant tasks have been used successfully to confirm ethanol's positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS-). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol's efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS- in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol's rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol's nutrient and pharmacological effects both contributed to the development of conditioned flavor preference.


Vibrational spectroscopic characterisation of salmeterol xinafoate polymorphs and a preliminary investigation of their transformation using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry.
Knowledge and control of the polymorphic phases of chemical compounds are important aspects of drug development in the pharmaceutical industry. Salmeterol xinafoate, a long acting beta-adrenergic receptor agonist, exists in two polymorphic Forms, I and II. Raman and near infrared spectra were obtained of these polymorphs at selected wavelengths in the range of 488-1064 nm; significant differences in the Raman and near-infrared spectra were apparent and key spectral marker bands have been identified for the vibrational spectroscopic characterisation of the individual polymorphs which were also characterised with X ray diffractometry. The solid-state transition of salmeterol xinafoate polymorphs was studied using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry isothermally between transitions. This method assisted in the unambiguous characterisation of the two polymorphic forms by providing a simultaneous probe of both the thermal and vibrational data. The study demonstrates the value of a rapid in situ analysis of a drug polymorph which can be of potential value for at-line in-process control.


[The interesting case--case no. 59].
Complications after endoscopic sinus surgery are rare and occur in about 0.5 % of all cases. However postoperative symptoms such as severe cephalgia and nasal discharge of clear fluids indicate a cerebrospinal fluid leakage. A 64 year-old-patient presented to our clinic four months after an endoscopic sinus surgery complaining of the two above mentioned symptoms for about 4 weeks. In a computed tomography study of the frontobasis there was no evidence of an osseous defect. An MRI of the head revealed a bilateral temporal fluid collection as seen in bilateral chronic subdural hematoma. Therefore the present illness was no consequence of the preceding surgery. Significant symptoms of severe postoperative complications after endoscopic sinus surgery can still be misleading. Therefore accurate diagnostic and imaging procedures are always crucial to support the initial diagnosis.


Using problem-based learning for occupational and environmental health nursing education: pesticide exposures among migrant agricultural workers.
Problem-based learning, which emphasizes group collaboration to solve real-world case scenarios, is an instructional approach that is well suited to occupational and environmental health nursing education. Learners actively work through case studies rather than passively receive information presented through lectures. Problem-based learning methods promote critical thinking skills and motivate learning, preparing learners for professional practice in complex, ever-changing environments. Despite these advantages, problem-based learning is under-utilized in nursing education compared to more traditional lecture methods. This article presents key concepts of problem-based learning, discusses problem-based learning in educating occupational and environmental health nurses, and describes the development of a problem-based learning case aimed at increasing occupational and environmental health nurses capacity to address pesticide exposure among migrant and seasonal agricultural workers.


Acquired and inherited disorders of cobalamin and folate in children.
Cobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. Most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions, both before and after birth.


Trajectories of Depression Symptoms among Older Youths Exiting Foster Care.
The purpose of this study was to determine the trajectories of depressive symptoms as older youths from the foster care system mature while also examining the correlates of these trajectories. Data came from a longitudinal study of 404 youths from the foster care system in Missouri, who were interviewed nine times between their 17th and 19th birthdays. Depression was assessed with the Depression Outcomes Module and the Diagnostic Interview Schedule for DSM-IV. Data best fit a model of three trajectory classes, describing young people (1) maintaining low levels of depressive symptoms (never depressed class, 78%), (2) with increasing symptoms (increasing class, 6%), and (3) with decreasing symptoms (decreasing class, 15%). The increasing depression group was mostly male youths who were working or in school; the decreasing class was mostly highly maltreated female youths exiting the foster care system from residential care, with low levels of employment, and in school. Implications for social work practice are discussed.


Trends in pediatric primary membranoproliferative glomerulonephritis costs and complications.
Data on pediatric membranoproliferative glomerulonephritis (MPGN) epidemiology, complications, and healthcare costs are critical to our understanding of MPGN's economic burden and of how best to direct clinical care and research efforts in the future. We analyzed 10-year trends in epidemiology, complications, and hospital charges for pediatric primary MPGN hospitalizations using the Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) for 1997-2006. We identified approximately 320 primary MPGN admissions per year, corresponding to approximately 4.3 % of all glomerular disease admissions. Older children were at higher risk for admission (odds ratios for ages 6-10, 11-15, and 16-18 years were 7.5, 9.3, and 4.7, respectively compared to 0-5 years; p < 0.0001). Gender, race, income, hospital location, and admission season were not significant risk factors. The incidence of MPGN admission-associated acute renal failure (ARF) increased to >147 % (from <3 to 7.4 %) over time, while admission-associated renal biopsy (approx. 34.8 %), renal replacement therapy (approx. 18.4 %), and transplantation (approx. 5 %) remained constant. Hospital length of stay (LOS) increased by 68 % (from 5.0 to 8.4 days), whereas mean total hospital charges increased by 213 % (from $13,718 to $42,891), concomitant with a strong trend from private toward public health insurance. We conclude that while the incidence of pediatric primary MPGN hospitalizations has remained stable over the last 10 years, they have been associated with marked increases in the frequency of ARF, as well as dramatically increased hospital LOS and charges.


Acetylcholinesterase inhibitors from plants and fungi.
This review describes 183 compounds obtained from plants and fungi which have been shown to inhibit acetylcholinesterase. The mechanism of action of cholinesterase, together with the binding sites, and, where this is known, the mode of action of inhibitors is described. The relative activities of the different compounds are recorded. The strongest inhibitors are generally alkaloids although some meroterpenoids from fungi have also been found to be active and display better selectivity.


Surface energies of elemental crystals.
The surface energy is a fundamental property of the different facets of a crystal that is crucial to the understanding of various phenomena like surface segregation, roughening, catalytic activity, and the crystal's equilibrium shape. Such surface phenomena are especially important at the nanoscale, where the large surface area to volume ratios lead to properties that are significantly different from the bulk. In this work, we present the largest database of calculated surface energies for elemental crystals to date. This database contains the surface energies of more than 100 polymorphs of about 70 elements, up to a maximum Miller index of two and three for non-cubic and cubic crystals, respectively. Well-known reconstruction schemes are also accounted for. The database is systematically improvable and has been rigorously validated against previous experimental and computational data where available. We will describe the methodology used in constructing the database, and how it can be accessed for further studies and design of materials.


Cohesion-driven mixing and segregation of dry granular media.
Granular segregation is a common, yet still puzzling, phenomenon encountered in many natural and engineering processes. Here, we experimentally investigate the effect of particles cohesion on segregation in dry monodisperse and bidisperse systems using a rotating drum mixer. Chemical silanization, glass surface functionalization via a Silane coupling agent, is used to produce cohesive dry glass particles. The cohesive force between the particles is controlled by varying the reaction duration of the silanization process, and is measured using an in-house device specifically designed for this study. The effects of the cohesive force on flow and segregation are then explored and discussed. For monosized particulate systems, while cohesionless particles perfectly mix when tumbled, highly cohesive particles segregate. For bidisperse mixtures of particles, an adequate cohesion-tuning reduces segregation and enhances mixing. Based on these results, a simple scheme is proposed to describe the system's mixing behaviour with important implications for the control of segregation or mixing in particulate industrial processes.


Developmental determinants of cortical plasticity.
A central problem in neuropsychology concerns the mechanisms by which functions are restored following injury to the brain. Functional recovery is particularly striking following damage to the cerebrum in early life and accordingly our studies deal with the effects of prefrontal cortical lesions performed on infant monkeys. We describe here two essentially different patterns of behavioral recovery following selective lesions of the dorsolateral and orbital prefrontal cortex. Following orbital lesions in infancy, the monkeys are impaired when tested initially between 12 and 18 months of age but give evidence of substantial recovery when they are retested at 24 months of age. In contrast, monkeys given dorsolateral resection early in life exhibit sparing of function during the initial period of testing but this impunity usually associated with dorsolateral injury in infancy gives way later to a picture of retarded development. We attribute these two patterns of recovery - progressive and regressive - to differential rates of development of the two prefrontal cortical regions involved. Our evidence suggests that while orbital cortex becomes functionally mature by 1 year of age and probably earlier, the elaboration of dorsolateral function is delayed well into the second year of life. We propose that the dorsolateral cortex, by virtue of its relative immaturity at the time of orbital excision, can come in time to subsume the functions of the orbital cortex but that the orbital cortex may be functionally "committed" too early in life to compensate reciprocally for injury sustained by the dorsolateral cortex.


Subcellular localization and activity of multidrug resistance proteins.
The multidrug resistance (MDR) phenotype is associated with the overexpression of members of the ATP-binding cassette family of proteins. These MDR transporters are expressed at the plasma membrane, where they are thought to reduce the cellular accumulation of toxins over time. Our data demonstrate that members of this family are also expressed in subcellular compartments where they actively sequester drugs away from their cellular targets. The multidrug resistance protein 1 (MRP1), P-glycoprotein, and the breast cancer resistance protein are each present in a perinuclear region positive for lysosomal markers. Fluorescence-activated cell sorting analysis suggests that these three drug transporters do little to reduce the cellular accumulation of the anthracycline doxorubicin. However, whereas doxorubicin enters cells expressing MDR transporters, this drug is sequestered away from the nucleus, its subcellular target, in vesicles expressing each of the three drug resistance proteins. Using a cell-impermeable inhibitor of MRP1 activity, we demonstrate that MRP1 activity on intracellular vesicles is sufficient to confer a drug resistance phenotype, whereas disruption of lysosomal pH is not. Intracellular localization and activity for MRP1 and other members of the MDR transporter family may suggest different strategies for chemotherapeutic regimens in a clinical setting.


Are there differences between macrocyclic gadolinium contrast agents for brain tumor imaging? Results of a multicenter intraindividual crossover comparison of gadobutrol with gadoteridol (the TRUTH study).
Gadobutrol (Gadavist) and gadoteridol (ProHance) have similar macrocyclic molecular structures, but gadobutrol is formulated at a 2-fold higher (1 mol/L versus 0.5 mol/L) concentration. We sought to determine whether this difference impacts morphologic contrast-enhanced MR imaging. Two hundred twenty-nine adult patients with suspected or known brain tumors underwent two 1.5T MR imaging examinations with gadoteridol or gadobutrol administered in randomized order at a dose of 0.1 mmol/kg of body weight. Imaging sequences and T1 postinjection timing were identical for both examinations. Three blinded readers evaluated images qualitatively and quantitatively for lesion detection and for accuracy in characterization of histologically confirmed brain tumors. Data were analyzed by using the Wilcoxon signed rank test, the McNemar test, and a mixed model. Two hundred nine patients successfully completed both examinations. No reader noted a significant qualitative or quantitative difference in lesion enhancement, extent, delineation, or internal morphology (P values = .69-1.00). One hundred thirty-nine patients had at least 1 histologically confirmed brain lesion. Two readers found no difference in the detection of patients with lesions (133/139 versus 135/139, P = .317; 137/139 versus 136/139, P = .564), while 1 reader found minimal differences in favor of gadoteridol (136/139 versus 132/139, P = .046). Similar findings were noted for the number of lesions detected and characterization of tumors (malignant/benign). Three-reader agreement for characterization was similar for gadobutrol (66.4% [κ = 0.43]) versus gadoteridol (70.3% [κ = 0.45]). There were no significant differences in the incidence of adverse events (P = .199). Gadoteridol and gadobutrol at 0.1 mmol/kg of body weight provide similar information for visualization and diagnosis of brain lesions. The 2-fold higher gadolinium concentration of gadobutrol provides no benefit for routine morphologic imaging.


Mycobacterium fortuitum as a cause of mastoiditis and wound infection.
Mycobacterium fortuitum is uncommonly pathogenic for man. When implicated, this organism usually infects soft-tissue structures. Therapy necessitates surgical excision and prolonged antimicrobial therapy. A patient had a mastoiditis and wound infection due to this organism. Her successful treatment included radical debridement and prolonged therapy with several antimicrobials. The necessity for including mycobacteria in the differential diagnosis of ear, nose, and throat diseases is emphasized by our experience. The complexities of management of these infections are reviewed.


In silico predictions of absorption of MDI substances after dermal or inhalation exposures to support a category based read-across assessment.
Methylenediphenyl diisocyanate (MDI) substances used polyurethane production can range from their simplest monomeric forms (e.g., 4,4'-MDI) to mixtures of the monomers with various homologues, homopolymer, and prepolymer derivatives. The relative dermal or inhalation absorption of 39 constituents of these substances in human were predicted using the GastroPlus® program. Predicted dermal uptake and absorption of the three MDI monomers from an acetone vehicle was 84-86% and 1.4-1.5%, respectively, with lower uptake and absorption predicted for the higher MW analogs. Lower absorption was predicted from exposures in a more lipophilic vehicle (1-octanol). Modeled inhalation exposures afforded the highest pulmonary absorption for the MDI monomers (38-54%), with 3-27% for the MW range of 381-751, and <0.1% for the remaining, higher MW derivatives. Predicted oral absorption, representing mucociliary transport, ranged from 5 to 10% for the MDI monomers, 10-25% for constituents of MW 381-751, and ≤3% for constituents with MW > 900. These in silico evaluations should be useful in category-based, worst-case, Read-Across assessments for MDI monomers and modified MDI substances for potential systemic effects. Predictions of appreciable mucociliary transport may also be useful to address data gaps in oral toxicity testing for this category of compounds.


[Value of probiotic in reducing frequency of infectious complications in premature infants].
Fifty five premature infants with very low body weight were observed as inpatients to assess effectiveness of the nursing. The standard program of the care included: adequate primary resuscitation, respiratory support (use of surfactant), thermal mode, early provision of nutrients with full or partial parenteral nutrition, antimicrobial therapy and if possible early enteral nutrition. The patients of the main group (n = 29) along with the standard therapy (the volume of the enteral nutrition of 5 ml or more) were treated orally with liquid probiotic based on E. faecium L3 in a dose of 0.5 ml (5 x 10(8) CFU) 3 times a day for 14 days. The control group (n = 26) was under the standard therapy. The effectiveness of the infants management was estimated by the frequency of disruption of the nutrition, the frequency of infectious complications, the changes in the hematologic indices, the dynamics of the composition of the intestinal microflora. The infectious complications were evident from perinatal viral infection, intraamniotic infection, necrotizing enterocolitis. In the main group patients there was recorded a significant decrease of the frequency of infectious complications: 20.7% against 53.9% in the control group patients. The use of probiotic strain E. faecium L3 in the preterm infants promoted conservation of the immunomodulatory function of the intestinal indigenic microflora and restricted the growth of the nosocomial flora.


Renal parenchymal area and risk of ESRD in boys with posterior urethral valves.
Approximately 20% of boys with posterior urethral valves develop ESRD; however, few factors associated with the risk of ESRD have been identified. The objective of this study was to determine if renal parenchymal area, defined as the area of the kidney minus the area of the pelvicaliceal system on first postnatal ultrasound, is associated with the risk of ESRD in infants with posterior urethral valves. A retrospective cohort of boys who were diagnosed with posterior urethral valves at less than 6 months of age between 1988 and 2011 and followed for at least 1 year at a free-standing children's hospital was assembled. Cox proportional hazard regression and Kaplan-Meier analysis were used to estimate the association between renal parenchymal area and time to ESRD. Cox models were adjusted for age at presentation, minimum creatinine 1 month after bladder decompression, and vesicoureteral reflux. Sixty patients were followed for 393 person-years. Eight patients developed ESRD. Median renal parenchymal area was 15.9 cm(2) (interquartile range=13.0-21.6 cm(2)). Each 1-cm(2) increase in renal parenchymal area was associated with a lower risk of ESRD (hazard ratio, 0.64; 95% confidence interval, 0.42 to 0.98). The rate of time to ESRD was 10 times higher in boys with renal parenchymal area<12.4 cm(2) than boys with renal parenchymal area≥12.4 cm(2) (P<0.001). Renal parenchymal area could best discriminate children at risk for ESRD when the minimum creatinine in the first 1 month after bladder decompression was between 0.8 and 1.1 mg/dl. In boys with posterior urethral valves presenting during the first 6 months of life, lower renal parenchymal area is associated with an increased risk of ESRD during childhood. The predictive ability of renal parenchymal area, which is available at time of diagnosis, should be validated in a larger, prospectively-enrolled cohort.


The risk of acute coronary syndrome in Ramadan.
Data on the effect of fasting on coronary disease are rare and controversial. The aim of our study was to investigate the influence of Ramadan on the prevalence of acute coronary syndrome among chest pain patients in the emergency department of Monastir. It was a prospective study, performed in the emergency department of Fattouma Bourguiba University Hospital of Monastir, during the 3 months before, during and after Ramadan from 2012 to 2014. We included all patients with non-traumatic chest pain during the study period. Data were collected using a standardized form. The uniformity chi 2 test, ANOVA test, Kruskal-Wallis test were performed at the 5% level. Binary logistic regression model was used for multivariate analysis. The SCA prevalence was 17% a month before Ramadan, 22% during Ramadan and 28% one month after Ramadan (p = 0.007). According to the results of the multivariate analysis, the period of Ramadan is not associated with increase of risk of SCA whereas the risk doubles after Ramadan in all group (p = 0.001). In subgroups analysis, the period of R was associated with an amplification of risk in men aged more than 55 years and women older than 65 years (OR: 2.1; p = 0.020) and among subjects with hypertension (OR: 2.4, p = 0.007). Ramadan and Shawwal were not associated with an increase of risk among subjects without CVX risk factor. We have demonstrated that the risk of SCA has increased in Ramadan only among the elderly and patient with hypertension. The increased risk in Shawwal can be explained by the lifting of dietary restriction.


Prevalence of illicit drug use in patients without controlled substance abuse in interventional pain management.
Drug abuse with illicit drugs and licit drugs has been increasing steadily over the past decade. A recent National Household Survey on Drug Abuse found statistically significant increases between 2000 and 2001 in the use of multiple drugs, including marijuana, cocaine, and non-medical use of pain relievers and tranquilizers. Prescription controlled substance abuse is a major issue in chronic pain management. Various means suggested to avoid or monitor abuse in patients in treatment include urine/serum drug screening whenever requested, along with other precautions including one prescribing physician and one designated pharmacy, etc. Based on the present evidence, physicians assume that patients adhering to controlled substance agreements and without obvious dependency behavior do not abuse either illicit or licit drugs. Thus, it is accepted that there is no necessity to perform routine urine/drug testing in this specific group of the patient population. One hundred patients undergoing interventional pain management and receiving controlled substances were randomly selected for evaluation of illicit drug abuse by urine drug testing. They were selected from a total of 250 patients who were identified as non-abusers of prescription drugs. Results showed that illicit drug abuse in patients without history of controlled substance abuse was seen in 16 patients. Thirteen of the 16 patients tested positive for marijuana and 3 patients tested positive for cocaine. Only one patient tested positive for a combined use of both marijuana and cocaine. This study showed that, in an interventional pain management setting, there is significant use of illicit drugs (16%) with 13% use of marijuana and 3% use of cocaine in patients who are considered as non-abusers of prescription controlled substances and those who are adherent to controlled substance agreements. However, if cocaine is considered as a hardcore drug in contrast to marijuana, abuse of hardcore illicit drugs is only 3%.


Arsenic trioxide inhibits cell growth and motility via up-regulation of let-7a in breast cancer cells.
Arsenic trioxide (ATO) has been reported to exert its anti-cancer activities in human cancers. However, the molecular mechanism of ATO-triggered anti-tumor activity has not been fully elucidated. Recently, multiple studies demonstrated that ATO could regulate miRNAs in human cancers. Therefore, in this study, we investigated whether ATO regulated let-7a in breast cancer cells. We found that ATO upregulated let-7a level in breast cancer cells. We also found that up-regulation of let-7a inhibited cell growth and induced apoptosis and retarded cell migration and invasion. We also observed that up-regulation of let-7a enhanced cell growth inhibition and invasion suppression induced by ATO treatment. Our findings suggest that ATO suppressed cell growth, stimulated apoptosis, and retarded cell invasion partly via upregulation of let-7a in breast cancer cells. Our study provides a new anti-tumor mechanism of ATO treatment in breast cancer.


Globalization and Christian love.
Globalization is having a very negative impact on the world's poorest people. Decisions made in the First World-decisions often based on a profit-oriented ethic-are degrading the quality of life of people in the Third World and taking away their voice. The church is called to act in solidarity to respond to people in need worldwide. It must take a radical stance to promote love, justice, development, and peace. Acting in solidarity with others expresses a commitment to the common good and recognizes that all people are interconnected-that "our" well-being depends on the well-being of others. It acknowledges that people exist within a community. The concept of solidarity-with its emphasis on relationships among people-runs counter to many of the structures that drive globalization. People of the church must undertake a personal assessment, examining their thoughts and feelings about acting in solidarity with people in need. Through change and personal action, these individuals can promote justice around the world.


Serum interferon-gamma (IFN-gamma) in chronic oral candidosis.
Serum IFN-gamma levels were studied in adult patients with chronic oral candidosis, associated with Candida albicans infection. In the group of patients, mean serum IFN-gamma levels (2.74+/-465 pg ml(-1)) were significantly lower than in healthy individuals (9.80+/-1.68 pg ml(-1)). In analysis of the C. albicans strains isolated from lesions in the patients, their ability was estimated to secrete proteinases. Serum IFN-gamma levels failed to correlate with infections induced by proteinase-producing C. albicans. The results allowed us to conclude that Candida infection may be associated with an insufficient IFN-gamma response of the host, which seems to result in chronic conversion of candidosis. Proteolytic activity of C. albicans strains in vitro is not related to virulence of the strains.


Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection.
We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection.


The powdery mildew resistance gene Pm8 derived from rye is suppressed by its wheat ortholog Pm3.
The powdery mildew resistance gene Pm8 derived from rye is located on a 1BL.1RS chromosome translocation in wheat. However, some wheat lines with this translocation do not show resistance to isolates of the wheat powdery mildew pathogen avirulent to Pm8 due to an unknown genetically dominant suppression mechanism. Here we show that lines with suppressed Pm8 activity contain an intact and expressed Pm8 gene. Therefore, the absence of Pm8 function in certain 1BL.1RS-containing wheat lines is not the result of gene loss or mutation but is based on suppression. The wheat gene Pm3, an ortholog of rye Pm8, suppressed Pm8-mediated powdery mildew resistance in lines containing Pm8 in a transient single-cell expression assay. This result was further confirmed in transgenic lines with combined Pm8 and Pm3 transgenes. Expression analysis revealed that suppression is not the result of gene silencing, either in wheat 1BL.1RS translocation lines carrying Pm8 or in transgenic genotypes with both Pm8 and Pm3 alleles. In addition, a similar abundance of the PM8 and PM3 proteins in single or double homozygous transgenic lines suggested that a post-translational mechanism is involved in suppression of Pm8. Co-expression of Pm8 and Pm3 genes in Nicotiana benthamiana leaves followed by co-immunoprecipitation analysis showed that the two proteins interact. Therefore, the formation of a heteromeric protein complex might result in inefficient or absent signal transmission for the defense reaction. These data provide a molecular explanation for the suppression of resistance genes in certain genetic backgrounds and suggest ways to circumvent it in future plant breeding.


Simultaneous speciation analysis of inorganic arsenic, chromium and selenium in environmental waters by 3-(2-aminoethylamino) propyltrimethoxysilane modified multi-wall carbon nanotubes packed microcolumn solid phase extraction and ICP-MS.
Speciation analysis of inorganic arsenic, chromium and selenium in environmental waters is of great significance for the monitoring of environmental pollution. In this work, 3-(2-aminoethylamino) propyltrimethoxysilane (AAPTS) functionalized multi-wall carbon nanotubes (MWCNTs) were synthesized and employed as the adsorbent for simultaneous speciation analysis of inorganic arsenic, chromium and selenium in environmental waters by microcolumn solid-phase extraction (SPE)-inductively coupled plasma mass spectrometry (ICP-MS). It was found that As(V), Cr(VI) and Se(VI) could be selectively adsorbed on the microcolumn packed with AAPTS-MWCNTs adsorbent at pH around 2.2, while As(III), Cr(III) and Se(IV) could not be retained at this pH and passed through the microcolumn directly. Total inorganic arsenic, chromium and selenium was determined after the oxidation of As(III), Cr(III) and Se(IV) to As(V), Cr(VI) and Se(VI) with 10.0 μmol L(-1) KMnO4. The assay of As(III), Cr(III) and Se(IV) was based on subtracting As(V), Cr(VI) and Se(VI) from the total As, Cr and Se, respectively. Under the optimized conditions, the detection limits of 15, 38 and 16 ng L(-1) with the relative standard deviations (RSDs) of 7.4, 2.4 and 6.2% (c=1 µg L(-1), n=7) were obtained for As(V), Cr(VI) and Se(VI), respectively. The developed method was validated by analyzing four Certified Reference Materials, rainwater, Yangtze River and East Lake waters.


Nonspecific phospholipase C NPC4 promotes responses to abscisic acid and tolerance to hyperosmotic stress in Arabidopsis.
Diacyglycerol (DAG) is an important class of cellular lipid messengers, but its function in plants remains elusive. Here, we show that knockout of the Arabidopsis thaliana nonspecific phospholipase C (NPC4) results in a decrease in DAG levels and compromises plant response to abscisic acid (ABA) and hyperosmotic stresses. NPC4 hydrolyzes various phospholipids in a calcium-independent manner, producing DAG and a phosphorylated head group. NPC4 knockout (KO) plants display decreased ABA sensitivity in seed germination, root elongation, and stomatal movement and had decreased tolerance to high salinity and water deficiency. Overexpression of NPC4 renders plants more sensitive to ABA and more tolerant to hyperosmotic stress than wild-type plants. Addition of a short-chain DAG or a short-chain phosphatidic acid (PA) restores the ABA response of NPC4-KO to that of the wild type, but the addition of DAG together with a DAG kinase inhibitor does not result in a wild-type phenotype. These data suggest that NPC4-produced DAG is converted to PA and that NPC4 and its derived lipids positively modulate ABA response and promote plant tolerance to drought and salt stresses.


Epidemiological characteristics and underlying risk factors for mortality during the autumn 2009 pandemic wave in Mexico.
Elucidating the role of the underlying risk factors for severe outcomes of the 2009 A/H1N1 influenza pandemic could be crucial to define priority risk groups in resource-limited settings in future pandemics. We use individual-level clinical data on a large series of ARI (acute respiratory infection) hospitalizations from a prospective surveillance system of the Mexican Social Security medical system to analyze clinical features at presentation, admission delays, selected comorbidities and receipt of seasonal vaccine on the risk of A/H1N1-related death. We considered ARI hospitalizations and inpatient-deaths, and recorded demographic, geographic, and medical information on individual patients during August-December, 2009. Seasonal influenza vaccination was associated with a reduced risk of death among A/H1N1 inpatients (OR = 0.43 (95% CI: 0.25, 0.74)) after adjustment for age, gender, geography, antiviral treatment, admission delays, comorbidities and medical conditions. However, this result should be interpreted with caution as it could have been affected by factors not directly measured in our study. Moreover, the effect of antiviral treatment against A/H1N1 inpatient death did not reach statistical significance (OR = 0.56 (95% CI: 0.29, 1.10)) probably because only 8.9% of A/H1N1 inpatients received antiviral treatment. Moreover, diabetes (OR = 1.6) and immune suppression (OR = 2.3) were statistically significant risk factors for death whereas asthmatic persons (OR = 0.3) or pregnant women (OR = 0.4) experienced a reduced fatality rate among A/H1N1 inpatients. We also observed an increased risk of death among A/H1N1 inpatients with admission delays >2 days after symptom onset (OR = 2.7). Similar associations were also observed for A/H1N1-negative inpatients. Geographical variation in identified medical risk factors including prevalence of diabetes and immune suppression may in part explain between-country differences in pandemic mortality burden. Furthermore, access to care including hospitalization without delay and antiviral treatment and are also important factors, as well as vaccination coverage with the 2008-09 trivalent inactivated influenza vaccine.


Conditional ambiguity of one-dimensional crystal structures determined from a minimum of diffraction intensity data.
When the number of intensities greatly exceeds the number of unknown atomic coordinates, the problem of obtaining a crystal structure from the intensities is overdetermined and, for a sufficiently small structure, a chemically meaningful solution can be found by direct methods. A difficulty in determining a structure has been historically attributed to the non-uniqueness of such a structure owing to multiple, or homometric, structures that yield the same set of intensities. The number of homometric structures has not been rigorously analyzed owing to the complexity of this problem. By using the method of elementary symmetric polynomials with a new origin definition, one-dimensional crystal structures of a small number of identical atoms (N < 5), determined from a minimum (N - 1) of the lowest-resolution intensities, are enumerated. It is demonstrated that such a structure is unique for N ≤ 3. Interestingly, for N = 4, the structure can be determined either uniquely or twofold ambiguously, depending on the intensity values. These results suggest that, even for larger structures, a minimum set of (or not many more) accurately measured intensities can yield a unique structure.