Molecular shuttles by the protecting group approach
Two new [2]rotaxane-based molecular shuttles, in which a mechanically bound dibenzo[24]crown-8 (DB24C8) macroring shunts back and forth between two dialkylammonium recognition sites situated on a chemical dumbbell, have been constructed by a novel synthetic strategy that relies upon the use of the tert-butoxycarbonyl (Boc) protecting group. During the syntheses of both molecular shuttles, this protecting group masks a dialkylammonium recognition center which is liberated only after the [2]rotaxane constitution is established. In both cases, the molecular shuttles' other dialkylammonium center is essential for the rotaxane-forming reactions and it ensures that DB24C8 is interpenetrated by threadlike precursors, as a result of noncovalent bonding interactions, to produce [2]pseudorotaxanes which are stoppered subsequently through 1,3-dipolar cycloadditions between azides and bulky acetylenedicarboxylates. The new molecular shuttles have been examined by means of dynamic 1H NMR spectroscopy, which reveals that the movements of the DB24C8 macroring are very highly dependent both on solvent properties and on the nature of the spacer unit linking the two dialkylammonium centers. Thus, DB24C8 shunts facilely between the dialkylammonium centers when the shuttles are dissolved in solvents that readily donate their nonbonding electrons into noncovalent bonds, e.g., DMF, and when spacer units that do not offer much steric resistance to shuttling, e.g., hexamethylene, are used. On the other hand, shuttling is difficult in solvents that are less inclined to donate their electrons into noncovalent bonds, e.g., (CDCl2)2, and when relatively bulky benzenoid spacer units, e.g., p-xylylene, link the two dialkylammonium centers. It has been proposed that the DB24C8 might act as a "ferry" which carries a proton between dialkylammonium and dialkylamine moieties in a singly protonated [2]rotaxane by means of ion-dipole interactions.


Microbial communities in contaminated sediments, associated with bioremediation of uranium to submicromolar levels.
Microbial enumeration, 16S rRNA gene clone libraries, and chemical analysis were used to evaluate the in situ biological reduction and immobilization of uranium(VI) in a long-term experiment (more than 2 years) conducted at a highly uranium-contaminated site (up to 60 mg/liter and 800 mg/kg solids) of the U.S. Department of Energy in Oak Ridge, TN. Bioreduction was achieved by conditioning groundwater above ground and then stimulating growth of denitrifying, Fe(III)-reducing, and sulfate-reducing bacteria in situ through weekly injection of ethanol into the subsurface. After nearly 2 years of intermittent injection of ethanol, aqueous U levels fell below the U.S. Environmental Protection Agency maximum contaminant level for drinking water and groundwater (<30 microg/liter or 0.126 microM). Sediment microbial communities from the treatment zone were compared with those from a control well without biostimulation. Most-probable-number estimations indicated that microorganisms implicated in bioremediation accumulated in the sediments of the treatment zone but were either absent or in very low numbers in an untreated control area. Organisms belonging to genera known to include U(VI) reducers were detected, including Desulfovibrio, Geobacter, Anaeromyxobacter, Desulfosporosinus, and Acidovorax spp. The predominant sulfate-reducing bacterial species were Desulfovibrio spp., while the iron reducers were represented by Ferribacterium spp. and Geothrix spp. Diversity-based clustering revealed differences between treated and untreated zones and also within samples of the treated area. Spatial differences in community structure within the treatment zone were likely related to the hydraulic pathway and to electron donor metabolism during biostimulation.


Laser-induced breakdown spectroscopy analysis of energetic materials.
A number of energetic materials and explosives have been studied by laser-induced breakdown spectroscopy (LIBS). They include black powder, neat explosives such as TNT, PETN, HMX, and RDX (in various forms), propellants such as M43 and JA2, and military explosives such as C4 and LX-14. Each of these materials gives a unique spectrum, and generally the spectra are reproducible shot to shot. We observed that the laser-produced microplasma did not initiate any of the energetic materials studied. Extensive studies of black powder and its ingredients by use of a reference spectral library have demonstrated excellent accuracy for unknown identification. Finally, we observed that these nitrogen- and oxygen-rich materials yield LIBS spectra in air that have correspondingly different O:N peak ratios compared with air. This difference can help in the detection and identification of such energetic materials.


Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal.
Cerebral ischemia stimulates increased activity of polyamine oxidase, a ubiquitous enzyme that catabolizes polyamines to produce 3-aminopropanal. 3-Aminopropanal is a reactive aldehyde that mediates progressive neuronal necrosis and glial apoptosis. Here we report that increased levels of 3-aminopropanal-modified protein levels in humans after aneurysmal subarachnoid hemorrhage correlate with the degree of cerebral injury as measured by admission Hunt/Hess grade. In vitro screening of clinically approved drugs reveals that N-2-mercaptopropionyl glycine (N-2-MPG), an agent clinically approved for prevention of renal stones in patients with cysteinuria, significantly inhibits the cytotoxicity of 3-aminopropanal. N-2-MPG reacts with 3-aminopropanal to yield a nontoxic thioacetal adduct, as confirmed by electrospray ionization mass spectroscopy. Administration of N-2-MPG in clinically relevant doses to rats significantly reduces cerebral 3-aminopropanal-modified protein immunoreactivity and infarct volume in a standardized model of middle cerebral artery occlusion, even when the agent is administered after the onset of ischemia. These results implicate 3-aminopropanal as a therapeutic target for cerebral ischemia.


Functional diversification of CLAVATA3-related CLE proteins in meristem maintenance in rice.
Postembryonic development in plants depends on the activity of the shoot apical meristem (SAM) and root apical meristem (RAM). In Arabidopsis thaliana, CLAVATA signaling negatively regulates the size of the stem cell population in the SAM by repressing WUSCHEL. In other plants, however, studies of factors involved in stem cell maintenance are insufficient. Here, we report that two proteins closely related to CLAVATA3, FLORAL ORGAN NUMBER2 (FON2) and FON2-LIKE CLE PROTEIN1 (FCP1/Os CLE402), have functionally diversified to regulate the different types of meristem in rice (Oryza sativa). Unlike FON2, which regulates the maintenance of flower and inflorescence meristems, FCP1 appears to regulate the maintenance of the vegetative SAM and RAM. Constitutive expression of FCP1 results in consumption of the SAM in the vegetative phase, and application of an FCP1 CLE peptide in vitro disturbs root development by misspecification of cell fates in the RAM. FON1, a putative receptor of FON2, is likely to be unnecessary for these FCP1 functions. Furthermore, we identify a key amino acid residue that discriminates between the actions of FCP1 and FON2. Our results suggest that, although the basic framework of meristem maintenance is conserved in the angiosperms, the functions of the individual factors have diversified during evolution.


[Efficiency of medication nebulizers in the treatment of dust obstructive bronchitis].
The clinical and functional study was aimed to evaluate efficiency of nebulized 2-agonists in miners suffering from moderate dust obstructive bronchitis. The nebulizers were used if conventional therapy appeared ineffective. The authors proved Berodual and Atrovent in nebulizers to be effective against dust obstructive bronchitis. Nebulizers enable to successfully cope with bronchial obstruction and occur to positively influence minor circulation hemodynamics.


PCV2-DNA in formalin-fixed and paraffin embedded lymph nodes of wild boar (Sus scrofa ssp. scrofa): one sampling approach for two laboratory techniques.
Superficial inguinal lymph nodes from 72 wild boars examined in a previous immunohistochemical (IHC) study on porcine circovirus type 2 (PCV2) were selected for a PCV2 polymerase chain reaction (PCR) analysis. Four of these lymph nodes were PCV2-IHC strongly positive with PMWS histological lesions (outcome 1), 6 weak to mild PCV2-IHC positive without PMWS histological lesions (outcome 2) and 62 PCV2-IHC negative. Considering IHC the gold standard for diagnosis, the aims of the study were to evaluate the suitability of the PCV2-DNA extraction from formalin-fixed and paraffin-embedded (FFPE) tissue and the sensitivity and specificity of PCR under two IHC interpretations criteria: (A) the sample was considered positive if the result was outcome 1; (B) the sample was considered positive if the result was outcome 1 or 2. Under (A) criteria, sensitivity and specificity of PCR were 100% and 89.7%, respectively; the Cohen's Kappa coefficient was 0.49. Under (B) criteria, sensitivity and specificity of PCR were 80.0% and 95.2%, respectively; the Cohen's Kappa coefficient was 0.72. The high Cohen's Kappa coefficient under the (B) interpretative criteria indicates good agreement between the two methods. In conclusion, 1) DNA extracted from FFPE specimens of wild boar is suitable for PCR and further represents a screening test for PCV2/PCVD (PCV2 Diseases) investigations in wild boar as well; 2) routine histological sampling can also be useful for PCV2 virological studies in wild boar.


The Emergence of Employees' Change Readiness for Energy-Conservation Behavior During Guided Group Discussions.
Studies of energy conservation efforts to reduce CO2 emissions in the residential sector are abundant; however similar efforts in organizations have not received as much attention as they deserve. In this study, we focus on methods for increasing employees' readiness to change their behaviors in favor of energy conservation, specifically examining the use of guided group discussions (GGDs). We use observational research methods to examine the micro-level of behavioral dynamics and understand the emergence of change readiness. We describe how facilitators ("change agents") can conduct GGDs and foster employees' change readiness using the established communication approach of Motivational Interviewing (MI). We also explore how employees can increase each other's change readiness regarding energy conservation behavior. Based on our sample of eight videotaped GGDs (5430 behavioral events), interaction analysis reveals that solution-focused communication elicits change readiness in employees, whereas problem-focused communication prompts resistance to change. We further show that employees can motivate their co-workers to express "green" intentions: when employees verbalized statements in favor of energy saving, this increased other employees' change readiness, while verbalized statements against energy saving had the opposite effect. This demonstrates that GGD participants are active individuals who can spark behavior change in their co-workers. Finally, based on our findings we propose several communication guidelines for working with groups and discuss the importance of solution-focused energy management practices to facilitate change readiness for energy saving in the workplace.


Cyclic AMP modulation of a specific ion channel in an identified nerve cell: possible role for protein phosphorylation.
Multidisciplinary studies of the role of cAMP in synaptic transmission have been made possible by the favorable properties of the molluscan nervous system, and there is now evidence from several laboratories implicating cAMP in physiological responses in various Aplysia nerve and muscle cells (9,10,15,18,21). The results we have obtained satisfy all the criteria (8) necessary to establish that cAMP mediates the response to a neurotransmitter: a) the response is mimicked by intra- or extracellular application of cAMP derivatives, and by activation of adenylate cyclase within R15; b) a phosphodiesterase inhibitor enhances the response to low concentrations of serotonin; c) serotonin causes cAMP to accumulate within R15, and stimulates adenylate cyclase activity in membranes prepared from R15 cell bodies; and d) the serotonin receptors mediating adenylate cyclase stimulation and R15 hyperpolarization are pharmacologically very similar. This is the first time all these criteria have been satisfied in a neuronal system, and thus we conclude that the serotonin-induced increase in potassium conductance in neuron R15 is mediated by cAMP.


Global profiling of prolactin-modulated transcripts in breast cancer in vivo.
Prolactin (PRL) is essential for normal mammary gland development. PRL promotes mammary tumor formation in rodents and elevated serum prolactin is associated with increased risk of estrogen-receptor positive breast cancer in women. On the other hand, PRL may also exert pro-differentiation effects and act to suppress invasive features of established breast cancer. Previously published limited global transcript profiling analyses of prolactin-regulated gene expression in human breast cancer cells have exclusively been performed in vitro. The present study aimed to shed new light on how PRL modulates estrogen receptor (ER)-positive breast cancer through global transcript profiling of a human breast cancer xenograft model in vivo. The prolactin-responsive human T47D breast cancer cell line was xenotransplanted into nude mice and global transcript profiling was carried out following treatment with or without human PRL for 48 h. A subset of PRL-modulated transcripts was further validated using qRT-PCR and immunohistochemistry. The in vivo analyses identified 130 PRL-modulated transcripts, 75 upregulated and 55 downregulated, based on fold change >1.6 and P-value <0.05. From this initial panel of transcripts, a subset of 18 transcripts with established breast cancer-relevance were selected and validated by qRT-PCR. Some but not all of the transcripts were also PRL-modulated in vitro. The selected PRL-modulated transcripts were tested for dependence on Stat5, Jak1 or Jak2 activation, and for co-regulation by 17β-estradiol (E2). The protein encoded by one of the PRL-regulated transcripts, PTHrP, was examined in a panel of 92 human breast cancers and found by in situ quantitative immunofluorescence analysis to be highly positively correlated with nuclear localized and tyrosine phosphorylated Stat5. Gene Ontology analysis revealed that PRL-upregulated genes were enriched in pathways involved in differentiation. Finally, a gene signature based on PRL-upregulated genes was associated with prolonged relapse-free and metastasis-free survival in breast cancer patients. This global analysis identified and validated a panel of PRL-modulated transcripts in an ER-positive human breast cancer xenotransplant model, which may have value as markers of relapse-free and metastasis-free survival. Gene products identified in the present study may facilitate ongoing deciphering of the pleiotropic effects of PRL on human breast cancer.


Electro-acupuncture Suppresses AXL Expression in Dorsal Root Ganglion Neurons and Enhances Analgesic Effect of AXL Inhibitor in Spinal Nerve Ligation Induced-Neuropathic Pain Rats.
Electro-acupuncture (EA) has been used for clinic analgesia for many years. However, its mechanisms are not fully understood. We recently reported that AXL, a tyrosine kinase receptor, contributes to the peripheral mechanism of neuropathic pain. We here aim to figure out the significance of EA on neuropathic pain mediated by AXL in dorsal root ganglion (DRG). Spinal nerve ligation (SNL) was used as a neuropathic pain model. EA was applied at ''Huantiao'' (GB-30) and ''Yanglingquan'' (GB-34) acupoints for 30 min daily from day 7 to day 10 after SNL. EA not only gradually attenuated SNL-induced mechanical allodynia, but also suppressed the expression of phosphorylated AXL (p-AXL) and AXL in injured DRGs of SNL rats examined by western blotting and immunofluorescence. Moreover, intrathecal injection of the subthreshold dose of AXL inhibitor TP0903, significantly prolonged the analgesic time of single EA treatment and enhanced the analgesic effect of repeated EA treatments, suggesting a synergic effect of EA and AXL inhibitor. These results indicate that AXL signaling underlies EA analgesia and combination of AXL inhibitor and EA might be a new strategy for clinic analgesia on neuropathic pain.


Synthesis, stability, and antimicrobial studies of electronically tuned silver acetate N-heterocyclic carbenes.
A series of methylated imidazolium salts with varying substituents on the 4 and 5 positions of the imidazole ring were synthesized. These salts were reacted with silver acetate to afford their corresponding silver N-heterocyclic carbene (NHC) complexes. These complexes were then evaluated for their stability in water as well as for their antimicrobial efficacy against a variety of bacterial strains associated with cystic fibrosis and chronic lung infections.


Chlamydia pneumoniae infection related atherosclerotic clinical variables on carotid stenosis.
Research results showed that Chlamydia pneumoniae infection is related to atherosclerosis. C. pneumoniae infection may exacerbate atherogenesis. We investigated the presence of this microorganism for patients who underwent carotid endarterectomy and evaluated clinical values of C. pneumoniae infection on carotid stenosis. Twenty patients with carotid stenosis were enrolled in this prospective study between 1997 and 1999. The patients were observed on whether they were positive or negative in four C. pneumoniae measures, namely; IgA titers, IgG titers, presence of electron microscopy, and immunocytochemistry in the endarterectomy specimens. Possible clinical findings for atherosclerosis were also observed of Chlamydial measures such as the percentage of carotid stenosis, cholesterol and triglyceride levels, smoking status, symptomatic or non-transient ischaemic attack or stroke, previous ischaemic event, calcification at surgery, ulceration on angiographies, ulceration at surgery and hypertension were included in this evaluation. Specific C. pneumoniae IgG were detected as positive in 9 (45%) of 20 patient samples. These patients were regarded as having chronic Chlamydia pneumoniae infection. None of the patients were positive for IgA antibody. This result demonstrated no evidence of reinfection. Immunocytochemistry and electron microscopy were positive in 7 (35%) of the 20 patients and correlated with positive serological results. The proportion of previous ischaemic events, calcification at surgery, ulceration on angiography, and ulceration at surgery were found significantly higher ( p < 0.05 ) for patients who are positive for chlamydial measures than those who are negative. The results of this study demonstrated an association between C. pneumoniae to atherosclerosis. The proportion of patients who are positive for Chlamydia measures (IgG titers, electron microscopy, and immunocytochemistry) is significantly higher for those who were positive for each of these clinical variables (PIE, CALCI, U1, and U2) than who were negative. We emphasise, the higher incidence in clinical variables of PIE, CALCI, U1, and U2 in Chlamydia measures positive group may support the association of C. pneumoniae with atherosclerotic events.


Pyeloureteral Anastomosis as a Reconstructive Technique for Post-Renal Transplant Ureteral Stenosis.
Ureteral stenosis in renal transplant patients is a frequent urological complication that involves significant morbidity and may compromise graft function. Despite the common use of minimally invasive techniques, surgery continues to be the definitive treatment for ureteral stenosis, and pyeloureteral anastomosis is an infrequent but effective technique in the management of this pathology and has been described as a safe treatment with a low percentage of complications. This is a retrospective study of patients in whom surgical intervention via pyeloureteral anastomosis was carried out in our center in the last 12 years. A descriptive analysis of perioperative management, complications, and functional results is provided. A comparison of renal function at diagnosis and after surgery was made to evaluate the effectiveness of the procedure. Thirteen patients underwent surgery within the described time frame. Time to diagnosis of stenosis was 60 days [interquartile range (IQR) 31-368]. Creatinine at diagnosis was 2.2 mg/dL [IQR 1.9-3] with a glomerular filtration rate, estimated by the modification of diet in renal disease equation, of 29 mL/min/1.73 m2 [IQR 22.6-34.5]. Of these patients, 92.3% underwent percutaneous nephrostomy, and 38.5% also had a ureteral catheter. The mean duration of surgery was 265 minutes [IQR 240-300], and hospital stay was 9 days [IQR 7.5-16]. A double J was placed in all cases, which was maintained for 36 days [IQR 30-49]. Postoperative complications occurred in 15.4% of patients. Serum creatinine 1 year after surgery was 1.6 ± 0.4 mg/dL. Among the patients, 76.9% had no new pyelocalyceal dilatation on follow-up Doppler ultrasound scans at a mean follow-up time of 12 months. The restenosis rate was 23.1%, and all were successfully treated by endoscopic approach. There was an improvement in renal function figures at 1, 3, 6, and 12 months compared to renal function at diagnosis, both in terms of serum creatinine and glomerular filtration rate, with statistically significant results. Pyeloureteral anastomosis as a reconstructive technique of the urinary tract in renal transplant patients is an effective and reproducible technique with good long-term results.


Vibration attenuates spasm-like activity in humans with spinal cord injury.
Cutaneous reflexes were tested to examine the neuronal mechanisms contributing to muscle spasms in humans with chronic spinal cord injury (SCI). Specifically, we tested the effect of Achilles and tibialis anterior tendon vibration on the early and late components of the cutaneous reflex and reciprocal Ia inhibition in the soleus and tibialis anterior muscles in humans with chronic SCI. We found that tendon vibration reduced the amplitude of later but not earlier cutaneous reflex in the antagonist but not in the agonist muscle relative to the location of the vibration. In addition, reciprocal Ia inhibition between antagonist ankle muscles increased with tendon vibration and participants with a larger suppression of the later component of the cutaneous reflex had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration attenuates late cutaneous spasm-like reflex activity, likely via reciprocal inhibitory mechanisms, and may represent a method, when properly targeted, for controlling spasms in humans with SCI. The neuronal mechanisms contributing to the generation of involuntary muscle contractions (spasms) in humans with spinal cord injury (SCI) remain poorly understood. To address this question, we examined the effect of Achilles and tibialis anterior tendon vibration at 20, 40, 80 and 120 Hz on the amplitude of the long-polysynaptic (LPR, from reflex onset to 500 ms) and long-lasting (LLR, from 500 ms to reflex offset) cutaneous reflex evoked by medial plantar nerve stimulation in the soleus and tibialis anterior, and reciprocal Ia inhibition between these muscles, in 25 individuals with chronic SCI. We found that Achilles tendon vibration at 40 and 80 Hz, but not other frequencies, reduced the amplitude of the LLR in the tibialis anterior, but not the soleus muscle, without affecting the amplitude of the LPR. Vibratory effects were stronger at 80 than 40 Hz. Similar results were found in the soleus muscle when the tibialis anterior tendon was vibrated. Notably, tendon vibration at 80 Hz increased reciprocal Ia inhibition between antagonistic ankle muscles and vibratory-induced increases in reciprocal Ia inhibition were correlated with decreases in the LLR, suggesting that participants with a larger suppression of later cutaneous reflex activity had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration suppresses late spasm-like activity in antagonist but not agonist muscles, likely via reciprocal inhibitory mechanisms, in humans with chronic SCI. We argue that targeted vibration of antagonistic tendons might help to control spasms after SCI.


The prevalence and predictors of loneliness in caregivers of people with dementia: findings from the IDEAL programme.
To establish the prevalence of loneliness among family caregivers of people with dementia and to identify potential risk factors for loneliness. Using data from the baseline wave of the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study, we examined loneliness in 1283 family caregivers of people with mild-to-moderate dementia living in Great Britain. Multinomial regression was used to examine the relative influence of a series of risk factors for caregiver loneliness. Almost half, 43.7%, of caregivers reported moderate loneliness and 17.7% reported severe loneliness. Greater social isolation and increased caregiving stress were linked with both moderate and severe loneliness. Better quality of relationship with the person with dementia along with increased levels of well-being and life satisfaction were associated with a lower relative risk of reporting both moderate and severe loneliness. This study examines the prevalence and predictors of loneliness in a large sample of family caregivers of people with dementia. Notably over two-thirds of caregivers in our sample reported feeling lonely. Interventions aimed at reducing caregiving stress and supporting meaningful relationships may go some way towards helping to reduce loneliness.


A review of the issues and challenges involved in using participant-produced photographs in nursing research.
To discuss the issues and challenges that may occur when using participant-produced photographs in nursing research. The place of visual representation in society is increasingly being recognized and there is a growing discussion on the advantages of implementing visual methods, such as photography, in health and illness research. Integrating photographs has much potential for both nurse researchers and participants but it remains a novel method of gathering qualitative data and many aspects have had little consideration in the nursing and medical literature. This paper presents a discussion of some of the issues that may arise when using photographs as data. It draws on examples of the insights and experiences we had when we asked study participants to produce photographs to complement their interviews designed to explore their experience of living after cancer. Discussion paper This paper is based on our own experiences and supported by literature and theory. Disseminating this research has prompted much interest from nurses and clinical staff. This paper should highlight some of the factors that may need to be addressed before employing such a novel method, thus ensuring the research process is positive and the outcome relevant for all parties. Examples are used here to illustrate practical, ethical and philosophical issues around the research plan, creating and interpreting photographic data, confidentiality and copyright and analysing and disseminating photographs produced for research.


Conservative management of a transverse fracture of the distal phalanx in a Quarter Horse.
A 7-year-old Quarter Horse gelding was evaluated because of sudden onset of severe left forelimb lameness of 4 days' duration. Clinical evaluation and diagnostic perineural analgesia localized the lameness to the distal portion of the left forelimb. Radiography revealed a transverse fracture of the distal phalanx of the left forelimb. The horse was treated conservatively with stall rest and stabilization of the hoof with fiberglass cast material and an elevated heel support. These treatments improved the lameness considerably. Over the following 4 months, the horse was exercised at an increasing level; external coaptation of the hoof was removed, and the horse was gradually shod in a flat shoe. At 6 months after injury, the horse had no signs of lameness when working at its previous performance level, but it was euthanized for reasons unrelated to orthopedic disease. Radiographically, the fracture was unapparent; however, results of magnetic resonance imaging and histologic examination of the cadaveric limb confirmed the presence of tissue changes consistent with a healing fracture. Conservative management of transverse fractures of the distal phalanx of a forelimb may be effective and enable affected horses to be returned to their intended use.


[The noninvasive estimation of right atrial pressure improves the Doppler evaluation of the pulmonary systolic pressure].
The right ventricular systolic pressure can be evaluated with the Doppler method through the right ventricular-atrial gradient (RV-RA gradient) and the right atrial pressure. The former is expressed by the transtricuspid velocity of flow, the latter is generally assumed. In 50 patients with elevated pulmonary pressure we tested whether ultrasounds may be utilized for the evaluation of the right atrial pressure, and whether the derived values contribute to improve the accuracy of the method. We estimated the right ventricular systolic pressure with method A: RV-RA gradient + 10; and method B: RV-RA gradient x 1.1 + 14, where 10 and 14 are the assumed right atrial pressure (mmHg). Through the collapsibility index of the inferior vena cava, taken as an ultrasound-derived index of right atrial pressure, we were able to identify 3 groups of patients with normal (Group 1, 14 cases), elevated (Group 2, 21 cases) and moderately elevated (Group 3, 15 cases) right atrial pressure, respectively. In them the right ventricular systolic pressures obtained with both method A and method B were compared to those derived with catheter. In Group 1 the non-invasive values were significantly closer to the invasive ones when calculated with method A; the same was true of method B in Group 2. In Group 3 the accuracy of the 2 methods was similar. We conclude that ultrasound assists in the non-invasive approximation of the right atrial pressure as well as in the choice of the appropriate formula, so that Doppler estimation of the right ventricular systolic pressure is improved.


Decisional Capacity in Amyotrophic Lateral Sclerosis.
The cognitive and behavioral changes that can be observed in the neurodegenerative terminal disease amyotrophic lateral sclerosis (ALS), once characterized as purely a motor neuron disease, have become increasingly recognized over the past century. Detecting cognitive deficits earlier and identifying continued changes at regular intervals can lead to improved care, proactive treatments, and earlier discussions about end-of-life wishes. Although medical decisional capacity is required for every treatment decision made, its importance becomes paramount when making decisions on complex medical treatments that will invariably and significantly affect quality of life or life itself. In this review, we conducted a critical analysis of the evidence-based literature on the cognitive and behavioral impairments in ALS that can compromise medical decisional capacity. We review specific ALS-related clinical scenarios in which decisional capacity is of utmost importance and discuss a practical framework for cognitive and behavioral assessment that can be routinely and efficiently used, while being mindful of the confounding factors associated with ALS. Finally, we review models for preserving patient choices that can be used in patients with ALS to help safeguard autonomy and retain dignity toward the end of life.


Congenital diaphragmatic hernia and the management of persistent foetal circulation.
Twenty-two cases of diaphragmatic hernia, presenting from 1978 to 1982, were reviewed. Sixteen patients presented before 24 hours of life, of whom nine survived (56%). Six were late presenters who all did well. Seven babies had ten documented episodes of persistent foetal circulation (PFC) occurring as early as three hours postoperatively, although three babies had episodes in their second week. Hyperventilation, with hand bagging, was successful in treating five out of six episodes of PFC (83%), without complication. Tolazoline caused improvement in two out of four episodes of PFC but was associated with significant complications. We recommend early and sometimes persistent use of hyperventilation by hand bagging as a means of managing PFC in diaphragmatic hernia.


Interaction of Pseudomonas aeruginosa Exotoxin A with the human Sec61 complex suppresses passive calcium efflux from the endoplasmic reticulum.
According to live-cell calcium-imaging experiments, the Sec61 complex is a passive calcium-leak channel in the human endoplasmic reticulum (ER) membrane that is regulated by ER luminal immunoglobulin heavy chain binding protein (BiP) and cytosolic Ca(2+)-calmodulin. In single channel measurements, the open Sec61 complex is Ca(2+) permeable. It can be closed not only by interaction with BiP or Ca(2+)-calmodulin, but also with Pseudomonas aeruginosa Exotoxin A which can enter human cells by retrograde transport. Exotoxin A has been shown to interact with the Sec61 complex and, thereby, inhibit ER export of immunogenic peptides into the cytosol. Here, we show that Exotoxin A also inhibits passive Ca(2+) leakage from the ER in human cells, and we characterized the N-terminus of the Sec61 α-subunit as the relevant binding site for Exotoxin A.


Determinants of pulse wave velocity trajectories from youth to young adulthood: the Georgia Stress and Heart Study.
Increased arterial stiffness measured by pulse wave velocity (PWV) has been shown to be an important parameter of cardiovascular risk. Longitudinal development of PWV from youth to early adulthood and its possible sociodemographic, anthropometric, hemodynamic and behavioral moderators will be illustrated. Individual growth curves of carotid-distal PWV across age were created for 559 African American and European American men and women with a maximum of five assessments over an average of 7-year follow-up (mean age at participants' first assessment, 22.3 ± 3.4). African Americans and men had significantly higher PWV than did European Americans and women (Ps < 0.01), respectively. A three-way interaction (P < 0.001) between age, sex and ethnicity was observed with African American men displaying a larger rate of increase in PWV with age than the other three ethnic and sex groups. The ethnicity and sex effects on PWV persisted when controlling for other moderators. Waist circumference was the strongest anthropometric predictor but its effect on PWV was only significant in women. Mean arterial pressure was the strongest hemodynamic predictor, marital status of parents was the strongest socioeconomic predictor and marijuana use was the strongest behavioral predictor of PWV. The best-fitting full model explained in total 59.4% of the between-subject variance in PWV with ethnicity, sex and age explaining 25.6%. We observed significant ethnic and sex differences in longitudinal trajectories of PWV in youth and young adults. In addition, individual differences in PWV growth can largely be explained by mean arterial pressure, waist, marital status of parents and marijuana use.


Factor structure, reliability, and validity of the Pain Catastrophizing Scale.
The Pain Catastrophizing Scale (PCS; Sullivan et al., Psychol. Assess. 7, 524-532, 1995) has recently been developed to assess three components of catastrophizing: rumination, magnification, and helplessness. We conducted three studies to evaluate the factor structure, reliability, and validity of the PCS. In Study I, we conducted principal-components analysis with oblique rotation to replicate the three factors of the PCS. Gender differences on the original PCS subscales were also analyzed. In Study II, we conducted confirmatory factor analyses to evaluate the adequacy of fit of four alternative models. We also evaluated evidence for concurrent and discriminant validity. In Study III, we evaluated the ability of the PCS and subscales to differentiate between the responses of clinic (students seeking treatment) and nonclinic undergraduate samples. Also, in the clinic sample, we evaluated evidence of concurrent and predictive validity for the PCS. The internal consistency reliability indices for the total PCS and subscales were examined in all three studies. Limitations and future directions are discussed.


Correlates of serum IGF-1 in young children with moderate acute malnutrition: a cross-sectional study in Burkina Faso.
Serum insulin-like growth factor 1 (sIGF-1) is an important growth factor in childhood. However, studies on sIGF-1 among children from low-income countries are few, and the role of body composition is unknown. To assess the associations of anthropometry, body composition, inflammation, and breastfeeding with sIGF-1 among children with moderate acute malnutrition (MAM). A cross-sectional study based on admission data from 6- to 23-mo-old children with MAM participating in a nutrition intervention trial (Treatfood) in Burkina Faso. Linear regression analysis was used to identify correlates of sIGF-1. Among 1546 children, the median (IQR) sIGF-1 was 12 (8.2-18.3) ng/mL. sIGF-1 was highest at 6 mo, with a nadir ∼10-11 mo, and higher in girls than boys. Length-for-age z score (LAZ), weight-for-length z score (WLZ), and midupper arm circumference were positively associated with sIGF-1 (P ≤ 0.001). Fat-free mass (FFM) was also positively associated, as sIGF-1 increased 1.5 (95% CI: 0.5, 2.5) ng/mL for each 1-kg increase in FFM. However, the association disappeared after adjustment for height. Elevated serum C-reactive protein and α1-acid glycoprotein were negatively associated with sIGF-1 (P ≤ 0.001), as was fever (P < 0.001) but not a positive malaria test per se (P = 0.15). Children never breastfed had lower sIGF-1 (-5.1; 95% CI: -9.8, -0.3). LAZ and WLZ were positively and inflammation negatively associated with sIGF-1. As all children were moderately malnourished and many had inflammation, this probably explains the very low median sIGF-1. The association of FFM with sIGF-1 was fully explained by height. There was a marked age pattern, with a nadir in late infancy, confirming findings from smaller studies from well-nourished populations. There is a need for prospective studies to disentangle the role of sIGF-1 in growth and health. This trial was registered at https://www.isrctn.com as ISRCTN42569496.


An in vivo comparison of two frequency-based electronic apex locators.
The purpose of this study was to compare the accuracy of a two-frequency (Root ZX) and a five-frequency (Endo Analyzer Model 8005) electronic apex locator under clinical conditions. Thirty-two teeth planned for extraction were used. The coronal portion of each canal was flared using Gates Glidden drills and Orifice Shapers. The canals were irrigated with 2.6% sodium hypochlorite. A K-type file was used to determine a separate working length in each canal using the electronic apex locators. The teeth were extracted and the apical 4 mm of each root canal was exposed along the long axis of the tooth. Photographic slides of each canal were projected and the file position in relation to the minor diameter was determined by two investigators. The mean distance between the electronic apex locator working length and minor diameter was 1.03 mm for the Endo Analyzer and 0.19 mm for the Root ZX. A paired sample t test showed that the Endo Analyzer had significantly longer readings beyond the minor diameter than the Root ZX (p < 0.0001). The ability to locate the minor diameter (+/- 0.5 mm) was 90.7% for the Root ZX and 34.4% for the Endo Analyzer Model 8005.


Associations of financial strain and income with depressive and anxiety disorders.
Previous research has shown socioeconomic inequality in prevalence and onset of depressive disorders. It is not yet clear whether perceived financial strain is associated with depressive and/or anxiety disorders in addition to an objective indicator, such as income. This study examines whether financial strain is associated with the prevalence and onset/recurrence of depressive and/or anxiety disorders, above income. Data are from the Netherlands Study of Depression and Anxiety. Associations between financial strain, income and presence of depressive and/or anxiety disorder at baseline were assessed among 2937 participants (18-65 years). Impact of financial strain and income on 4-year onset/recurrence of depressive and/or anxiety disorders were examined among 1250 participants without a depressive or anxiety disorder at baseline. Depressive and anxiety disorders were determined with the Composite-International-Diagnostic-Interview. Financial strain and income were assessed in an interview. Participants with mild or severe financial strain had higher odds of being depressed (OR=1.68, 95% CI 1.35 to 2.09; OR=3.88, 95% CI 2.58 to 5.81) or remitted (OR=1.56, 95% CI 1.24 to 1.96; OR=1.99, 95% CI 1.27 to 3.11) at baseline compared with healthy controls, after adjusting for income. Mild or severe financial strain was not associated with onset/recurrence of depressive and/or anxiety disorders during follow-up (OR=1.08, 95% CI 0.83 to 1.42; OR=1.05, 95% CI 0.64 to 1.73). Financial strain was associated with having a depressive and/or anxiety disorder, above the effect of income. Healthcare and social services should be alert to this association, even for higher income households. However, financial strain and income were not related with 4-year onset/recurrence of depressive and/or anxiety disorders.


The maternal nucleolus is essential for early embryonic development in mammals.
With fertilization, the paternal and maternal contributions to the zygote are not equal. The oocyte and spermatozoon are equipped with complementary arsenals of cellular structures and molecules necessary for the creation of a developmentally competent embryo. We show that the nucleolus is exclusively of maternal origin. The maternal nucleolus is not necessary for oocyte maturation; however, it is necessary for the formation of pronuclear nucleoli after fertilization or parthenogenetic activation and is essential for further embryonic development. In addition, the nucleolus in the embryo produced by somatic cell nuclear transfer originates from the oocyte, demonstrating that the maternal nucleolus supports successful embryonic development.


Using rare earth elements to control phosphorus and track manure in runoff.
Concern over the enrichment of agricultural runoff with phosphorus (P) from land applied livestock manures has prompted the development of manure amendments that minimize P solubility. In this study, we amended poultry, dairy, and swine manures with two rare earth chlorides, lanthanum chloride (LaCl(3).7H(2)O) and ytterbium chloride (YbCl(3).6H(2)O), to evaluate their effects on P solubility in the manure following incubation in the laboratory as well as on the fate of P and rare earth elements (REEs) when manures were surface-applied to packed soil boxes and subjected to simulated rainfall. In terms of manure P solubility, La:water-extractable P (WEP) ratios close to 1:1 resulted in maximum WEP reduction of 95% in dairy manure and 98% in dry poultry litter. Results from the runoff study showed that REE applications to dry manures such as poultry litter were less effective in reducing dissolved reactive phosphorus (DRP) in runoff than in liquid manures and slurries, which was likely due to mixing limitations. The most effective reductions of DRP in runoff by REEs were observed in the alkaline pH soil, although reductions of DRP in runoff from the acidic soil were still >50%. Particulate REEs were strongly associated with particulate P in runoff, suggesting a potentially useful role in tracking the fate of P and other manure constituents from manure-amended soils. Finally, REEs that remained in soil following runoff had a tendency to precipitate WEP, especially in soils receiving manure amendments. The findings have valuable applications in water quality protection and the evaluation of P site assessment indices.


Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1.
Malignant glioma belong to the most aggressive neoplasms in humans with no successful treatment available. Patients suffering from glioblastoma multiforme (GBM), the highest-grade glioma, have an average survival time of only around one year after diagnosis. Both microglia and peripheral macrophages/monocytes accumulate within and around glioma, but fail to exert effective anti-tumor activity and even support tumor growth. Here we use microarray analysis to compare the expression profiles of glioma-associated microglia/macrophages and naive control cells. Samples were generated from CD11b+ MACS-isolated cells from naïve and GL261-implanted C57BL/6 mouse brains. Around 1000 genes were more than 2-fold up- or downregulated in glioma-associated microglia/macrophages when compared to control cells. A comparison with published data sets of M1, M2a,b,c-polarized macrophages revealed a gene expression pattern that has only partial overlap with any of the M1 or M2 gene expression patterns. Samples for the qRT-PCR validation of selected M1 and M2a,b,c-specific genes were generated from two different glioma mouse models and isolated by flow cytometry to distinguish between resident microglia and invading macrophages. We confirmed in both models the unique glioma-associated microglia/macrophage phenotype including a mixture of M1 and M2a,b,c-specific genes. To validate the expression of these genes in human we MACS-isolated CD11b+ microglia/macrophages from GBM, lower grade brain tumors and control specimens. Apart from the M1/M2 gene analysis, we demonstrate that the expression of Gpnmb and Spp1 is highly upregulated in both murine and human glioma-associated microglia/macrophages. High expression of these genes has been associated with poor prognosis in human GBM, as indicated by patient survival data linked to gene expression data. We also show that microglia/macrophages are the predominant source of these transcripts in murine and human GBM. Our findings provide new potential targets for future anti-glioma therapy.


Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis.
Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis. Cancer Res; 77(13); 3467-78. ©2017 AACR.


Transformation of Arabidopsis thaliana with the codA gene for choline oxidase; accumulation of glycinebetaine and enhanced tolerance to salt and cold stress.
Glycinebetaine is one of the compatible solutes that accumulate in the chloroplasts of contain halotolerant plants when these plants are exposed to salt or cold stress. The codA gene for choline oxidase, the enzyme that converts choline into glycinebetaine, has previously been cloned from a soil bacterium, Arthrobacter globiformis. Transformation of Arabidopsis thaliana with the cloned codA gene under the control of the 35S promoter of cauliflower mosaic virus enabled the plant to accumulate glycinebetaine and enhanced its tolerance to salt and cold stress. At 300 mM NaCl, considerable proportions of seeds of transformed plants germinated well, whereas seeds of wild-type plants failed to germinate. At 100 mM NaCl, transformed plants grew well whereas wild-type plants did not do so. The transformed plants tolerated 200 mM NaCl, which was lethal to wild-type plants. After plants had been incubated with 400 mM NaCl for two days, the photosystem II activity of wild-type plants had almost completely disappeared, whereas that of transformed plants remained at more than 50% of the original level. When exposed to a low temperature in the light, leaves of wild-type plants exhibited symptoms of chlorosis, whereas those of transformed plants did not. These observations demonstrate that the genetic modification of Arabidopsis thaliana that allowed it to accumulate glycinebetaine enhanced its ability to tolerate salt and cold stress.


[Prognostication of the course of stable ischemic heart disease by exercise stress echocardiography].
We analyzed data from 549 patients (450 with high and 99 -- low pretest probability of ischemic events). Duration of observation was 12-42 (mean 20.1+/-11.6) months. End points were death, nonfatal myocardial infarction, and revascularization. Cox proportional hazards model was used for assessment of relationship between clinical-instrumental data and events. One year risk of cardiac death and nonfatal myocardial infarction was 3 and 15%, event free survival -- 95 and 66% for patients with negative and positive result of stress echocardiography, respectively. Besides local contractility disturbances total test duration less than 6 min was significantly related to prognosis of main events while left ventricular hypertrophy, amount of METs, development of angina during stress test, and hypertensive disease were predictors of combined end point (death, nonfatal myocardial infarction, or revascularization). Thus results of exercise stress echocardiography had high prognostic power in patients with ischemic heart disease.


Reporting methods of blinding in randomized trials assessing nonpharmacological treatments.
Blinding is a cornerstone of treatment evaluation. Blinding is more difficult to obtain in trials assessing nonpharmacological treatment and frequently relies on "creative" (nonstandard) methods. The purpose of this study was to systematically describe the strategies used to obtain blinding in a sample of randomized controlled trials of nonpharmacological treatment. We systematically searched in Medline and the Cochrane Methodology Register for randomized controlled trials (RCTs) assessing nonpharmacological treatment with blinding, published during 2004 in high-impact-factor journals. Data were extracted using a standardized extraction form. We identified 145 articles, with the method of blinding described in 123 of the reports. Methods of blinding of participants and/or health care providers and/or other caregivers concerned mainly use of sham procedures such as simulation of surgical procedures, similar attention-control interventions, or a placebo with a different mode of administration for rehabilitation or psychotherapy. Trials assessing devices reported various placebo interventions such as use of sham prosthesis, identical apparatus (e.g., identical but inactivated machine or use of activated machine with a barrier to block the treatment), or simulation of using a device. Blinding participants to the study hypothesis was also an important method of blinding. The methods reported for blinding outcome assessors relied mainly on centralized assessment of paraclinical examinations, clinical examinations (i.e., use of video, audiotape, photography), or adjudications of clinical events. This study classifies blinding methods and provides a detailed description of methods that could overcome some barriers of blinding in clinical trials assessing nonpharmacological treatment, and provides information for readers assessing the quality of results of such trials.


Sensitivity of environmental microorganisms to antimicrobial agents.
The sensitivity of different microorganisms, considered as typical representatives of the microflora of soil and water, was established to evaluate the influence of the nonmedical use of antimicrobial agents on bacterial ecology. Only seven strains, six chemoorganotrophs and one chemolithotroph, could be considered as relatively sensitive to the 21 antimicrobial compounds tested. The other 29 microorganisms may be regarded as resistant to most antimicrobial agents. Streptomyces were sensitive to high concentrations of active substances. Broad-spectrum antibiotics showed an effect on environmental bacteria similar to that on human pathogens. Cephalothin stimulated the growth of a Chlorella sp. From these experiments, it appears that spilled antimicrobial agents have little chance of causing an alteration in the microbial ecology.


Hypoperfusion Symptoms Poorly Predict Hemodynamic Compromise and Stroke Risk in Vertebrobasilar Disease.
Background and Purpose- Cerebral hypoperfusion symptoms (defined as symptoms related to change in position, effort or exertion, or recent change in antihypertensive medication) have been used in stroke studies as a surrogate for detecting hemodynamic compromise. However, the validity of these symptoms in identifying flow compromise in patients has not been well established. We examined whether hypoperfusion symptoms correlated with quantitative measurements of flow compromise in the prospective, observational VERiTAS study (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke). Methods- VERiTAS enrolled patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis or occlusion in vertebral or basilar arteries. Hemodynamic status using vertebrobasilar large vessel flow was measured using quantitative magnetic resonance angiography, and patients were designated as low, borderline, or normal flow based on distal territory regional flow, incorporating collateral capacity. The presence of qualifying event hypoperfusion symptoms was assessed relative to the quantitatively determined flow status (normal versus borderline/low) and also examined as a predictor of subsequent stroke risk. Results- Of the 72 enrolled subjects, 66 had data on hypoperfusion symptoms available. On initial quantitative magnetic resonance angiography designation, 43 subjects were designated as normal flow versus 23 subjects designated as low flow (n=16) or borderline flow (n=7). Of these, 5 (11.6%) normal flow and 3 (13.0%) low/borderline flow subjects reported at least one qualifying event hypoperfusion symptom ( P=0.99, Fisher exact test). Hypoperfusion symptoms had a positive predictive value of 37.5% and negative predictive value of 65.5% for low/borderline flow status. Compared with flow status, which strongly predicted subsequent stroke risk, hypoperfusion symptoms were not associated with stroke outcome ( P=0.87, log-rank test). Conclusions- These results suggest that hypoperfusion symptoms alone correlate poorly with actual hemodynamic compromise as assessed by quantitative magnetic resonance angiography and subsequent stroke risk in vertebrobasilar disease, and are not a reliable surrogate for flow measurement. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00590980.


[Ki-67 and p53 expression in gastric dysplasias and cancer].
The authors analyzed the heterogenicity of a cell population in dysplasia of varying degrees and gastric cancer from the expression of the proliferation marker Ki-67 and apoptosis activator p53 gene. Twenty-four stomachs (surgically removed for cancer) and biopsy materials (4 cases of moderate dysplasia, 4 cases of severe dysplasia) were studied. Four samples from clinically healthy individuals served as a control. The labeling index of Ki-67 in third-degree dysplasia was 37.9 +/- 2.5% and that in cancer 61.6 +/- 3.8%. There was no expression of the p53 gene in the controls. In three-degree dysplasia and cancer, the expression was 17.7 +/- 5.7% and as high as 69%, respectively. The densitometric characteristics of the labeled cells were of great diagnostic importance. Gastric cancer was represented mainly by 2 cell populations: (1) a stem cell line located in G1 with a low labeling index and a low optical density of Ki-67 and p53 and (2) an aggressive cell clone located in the S and G2 phase with marker hyperexpression.


[Menorrhagia during oral anticoagulant therapy].
Menorrhagia is a common complication to oral anticoagulant therapy in premenopausal women. Clinical management of menorrhagia poses a clinical dilemma with the need of weighting bleeding risk against the risk of recurrent thrombosis. In this review, we describe the risk of menorrhagia during oral anticoagulant therapy, with emphasis on the differences between the specific anticoagulant drugs. We critically assess the treatment options for anticoagulant-associated menorrhagia, and we provide a treatment algorithm for the management of anticoagulant-associated menorrhagia.


Evidence in support of a role for plant-mediated proteolysis in the rumens of grazing animals.
The present work aimed to differentiate between proteolytic activities of plants and micro-organisms during the incubation of grass in cattle rumens. Freshly cut ryegrass was placed in bags of varying permeability and incubated for 16 h in the rumens of dairy cows that had previously grazed a ryegrass sward, supplemented with 4 kg dairy concentrate daily. Woven polyester bags (50 microm pore size) permitted direct access of the micro-organisms and rumen fluid enzymes to the plant material. The polythene was impermeable even to small molecules such as NH(3). Dialysis tubing excluded micro-organisms and rumen enzymes/metabolites larger than 10 kDa. DM loss was 46.3 % in polyester, 36.2 % in polythene and 38.1 % in dialysis treatments. It is possible that the DM loss within polythene bags occurred due to a solubilisation of plant constituents (e.g. water-soluble carbohydrates) rather than microbial attachment/degradation processes. The final protein content of the herbage residues was not significantly different between treatments. Regardless of bag permeability, over 97 % of the initial protein content was lost during incubations in situ. Electrophoretic separation showed that Rubisco was extensively degraded in herbage residues whereas the membrane-associated, light-harvesting protein remained relatively undegraded. Protease activity was detected in herbage residues and bathing liquids after all incubation in situ treatments. Although rumen fluid contains proteases (possibly of plant and microbial origin), our results suggest that, owing to cell compartmentation, their activity against the proteins of intact plant cells is limited, supporting the view that plant proteases are involved in the degradation of proteins in freshly ingested herbage.


Identification of a Novel Long Non-Coding RNA G8110 That Modulates Porcine Adipogenic Differentiation and Inflammatory Responses.
Long non-coding RNAs (lncRNAs) have been extensively studied, and their crucial roles in adipogenesis, lipid metabolism, and gene expression have been revealed. However, the exact regulatory or other mechanisms by which lncRNAs influence the functioning of mesenteric adipose tissue (MAT) remain largely unknown. In this paper, we report the identification of a new lncRNA, named G8110, from the MAT of Bama pigs. The coordinated expression levels of lncRNA G8110 and NFE2L1 were significantly decreased in the MAT of obese Bama pigs compared with those in the MAT of lean pigs. Using a bone mesenchymal stem cell adipogenic differentiation model, we found that lncRNA G8110 played a role in adipocyte differentiation by positively regulating NFE2L1. We also found that lncRNA G8110 inhibited the formation of intracellular lipid synthesis, promoted lipid metabolism, and inhibited the expression of inflammatory cytokines. Our findings regarding lipid synthesis may further promote the role of lncRNAs in driving adipose tissue remodeling and maintaining metabolic health.


Advanced practice nurses in ESRD: varied roles and a cost analysis.
The predicted shortage of nephrologists to care for end-stage renal disease (ESRD) patients has prompted examination of the potential roles for physician extenders, such as physician assistants and nurse practitioners or advanced practice nurses (APNs) in the care of these patients. Although the case management model is ideally suited for the care of ESRD patients, little is known about incorporating APNs within this model in either dialysis or transplant programs. Furthermore, the cost-effectiveness of APNs working in dialysis units has been unexplored. We report our experience with APNs working in our dialysis and transplant programs, providing a description of their varied roles in the outpatient and inpatient settings that emphasizes the flexibility of the case management model in the care of ESRD patients. A time log survey completed by dialysis APNs outlines a mode for job responsibilities and shows that 93% of their time is spent in direct patient care. The dialysis cost analysis reveals that employment of a nurse practitioner is cost effective if the dialysis program includes at least 85 chronic dialysis patients. Additional studies of the impact of APNs in ESRD programs is needed.


Bimetallic Doped RuO2 with Manganese and Iron as Electrocatalysts for Favorable Oxygen Evolution Reaction Performance.
Synthesizing oxygen evolution reaction (OER) catalysts with enhanced activity by codoping has been proven to be a feasible approach for the efficient use of noble metals via renewing their basic intrinsic properties. In continuation of the research in codoping, we prepare a ruthenium-based bimetallic doped catalyst Mn x Fe y Ru1-x-y O2 with an outstanding OER activity as compared to pure RuO2, one of the state-of-the-art OER catalysts. The synthesized codoped RuO2 with a Mn/Fe molar ratio of 1 reflected a Tafel slope of only 41 mV dec-1, which is appreciably lower than 64 mV dec-1 for pure RuO2. The X-ray photoelectron spectroscopy (XPS) performed reveals that oxygen vacancy and manganese valency are the key factors of the OER activity for codoped catalysts.


Extracellular vesicles and their microRNA cargo in ischaemic stroke.
Acute ischaemic stroke (AIS) is a leading cause of death and disability. MicroRNAs (miRNAs) are short non-coding RNAs which hold the potential to act as a novel biomarker in AIS. The majority of circulating miRNAs are actively encapsulated by extracellular vesicles (EVs) produced by many cells and organs endogenously. EVs released by mesenchymal stem cells (MSCs) have been extensively studied for their therapeutic potential. In health and disease, EVs are vital for intercellular communication, as the cargo within EVs can be exchanged between neighbouring cells or transported to distant sites. It is clear here from both current preclinical and clinical studies that AIS is associated with specific EV-derived miRNAs, including those transported via MSC-derived EVs. In addition, current studies provide evidence to show that modulating levels of specific EV-derived miRNAs in AIS provides a novel therapeutic potential of miRNAs in the treatment of stroke. Commonalities exist in altered miRNAs across preclinical and clinical studies. Of those EV-packaged miRNAs, miRNA-124 was described both as an EV-packaged biomarker and as a potential EV-loaded therapeutic in experimental models. Alterations of miRNA-17 family and miRNA-17-92 cluster were identified in preclinical, clinical and MSC-EV-mediated neuroprotection in experimental stroke. Finally, miRNA-30d and -30a were found to mediate therapeutic effect when overexpressed from MSC and implicated as a biomarker clinically. Combined, EV-derived miRNAs will further our understanding of the neuropathological processes triggered by AIS. In addition, this work will help determine the true clinical value of circulating EV-packaged miRNAs as biomarkers of AIS or as novel therapeutics in this setting.


Arteriographic comparison of amaurosis fugax and hemispheric transient ischaemic attacks.
The results of carotid angiography were compared in 53 patients with amaurosis fugax and 92 with hemispheric transient ischaemic attacks (TIAs). Evidence of extracranial disease was found in 71% of those with retinal ischaemia and these patients rarely had evidence of intracranial disease (11%) or normal angiograms (15%). By contrast patients with hemispheric symptoms less frequently showed disease of the cervical carotid artery (36%) and more often had intracranial disease (27%) or normal angiograms (35%). It is suggested that amaurosis fugax is usually due to emboli originating in the internal carotid artery but that the pathogenesis of cerebral TIAs in the carotid territory is more heterogeneous. These conclusions have implications for the design and interpretation of both medical and surgical trials.


A black-hole mass measurement from molecular gas kinematics in NGC4526.
The masses of the supermassive black holes found in galaxy bulges are correlated with a multitude of galaxy properties, leading to suggestions that galaxies and black holes may evolve together. The number of reliably measured black-hole masses is small, and the number of methods for measuring them is limited, holding back attempts to understand this co-evolution. Directly measuring black-hole masses is currently possible with stellar kinematics (in early-type galaxies), ionized-gas kinematics (in some spiral and early-type galaxies) and in rare objects that have central maser emission. Here we report that by modelling the effect of a black hole on the kinematics of molecular gas it is possible to fit interferometric observations of CO emission and thereby accurately estimate black-hole masses. We study the dynamics of the gas in the early-type galaxy NGC 4526, and obtain a best fit that requires the presence of a central dark object of 4.5(+4.2)(-3.1) × 10(8) solar masses (3σ confidence limit). With the next-generation millimetre-wavelength interferometers these observations could be reproduced in galaxies out to 75 megaparsecs in less than 5 hours of observing time. The use of molecular gas as a kinematic tracer should thus allow one to estimate black-hole masses in hundreds of galaxies in the local Universe, many more than are accessible with current techniques.


Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells.
Micronuclei (MN) and other nuclear anomalies such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are biomarkers of genotoxic events and chromosomal instability. These genome damage events can be measured simultaneously in the cytokinesis-block micronucleus cytome (CBMNcyt) assay. The molecular mechanisms leading to these events have been investigated over the past two decades using molecular probes and genetically engineered cells. In this brief review, we summarise the wealth of knowledge currently available that best explains the formation of these important nuclear anomalies that are commonly seen in cancer and are indicative of genome damage events that could increase the risk of developmental and degenerative diseases. MN can originate during anaphase from lagging acentric chromosome or chromatid fragments caused by misrepair of DNA breaks or unrepaired DNA breaks. Malsegregation of whole chromosomes at anaphase may also lead to MN formation as a result of hypomethylation of repeat sequences in centromeric and pericentromeric DNA, defects in kinetochore proteins or assembly, dysfunctional spindle and defective anaphase checkpoint genes. NPB originate from dicentric chromosomes, which may occur due to misrepair of DNA breaks, telomere end fusions, and could also be observed when defective separation of sister chromatids at anaphase occurs due to failure of decatenation. NBUD represent the process of elimination of amplified DNA, DNA repair complexes and possibly excess chromosomes from aneuploid cells.


COMP is selectively up-regulated in degenerating acinar cells in chronic pancreatitis and in chronic-pancreatitis-like lesions in pancreatic cancer.
Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized histomorphologically by progressive development of fibrosis and atrophy of the pancreatic parenchyma. Cartilage oligomeric matrix protein (COMP) is a member of the thrombospondin (TSP) family of extracellular glycoproteins that is expressed in CP tissues. In the present study, we characterized COMP mRNA and protein expression in the normal pancreas, chronic pancreatitis, and pancreatic cancer tissues. 15 normal pancreatic tissues, 14 CP tissues and 14 pancreatic cancer tissues were analyzed by Northern blotting, Western blotting, in situ hybridization and immunohistochemistry. COMP mRNA and protein were detected at moderate to high levels in chronic pancreatitis tissues, at moderate levels in pancreatic cancer tissues, but at low levels in normal pancreatic tissues and in four pancreatic cancer cell lines. COMP mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells in CP tissues as well as in CP-like lesions in pancreatic cancer tissues. COMP protein was also present in the fibrotic tissue in CP. In contrast, COMP expression was weak to absent in the cytoplasm of cancer cells in pancreatic cancer tissues, and in ductal cells and islet cells in normal pancreatic tissues. COMP is preferentially expressed in degenerating acinar cells in CP and in CP-like areas in pancreatic cancer, suggesting a potential role of this gene in the course of acinar cell degeneration and dedifferentiation. COMP might thus serve as a marker for tissue destruction and disease activity in CP.


Aromatic oligoamide β-sheet foldamers.
A rational approach for the construction of multi-stranded artificial β-sheets based not on hydrogen bonding, but rather on π-π aromatic stacking, is presented. Using 4,6-dinitro-1,3-phenylenediamine units, rigid turns were designed that allow face-to-face π-π interactions between appended linear aromatic segments to be strong enough for folding in an organic solvent, but weak enough to prevent aggregation and precipitation. Solution and solid-state studies on a series of turn units showed that the desired degree of rigidity, resulting from hindered bond rotation, could be fine-tuned by the inclusion of additional methyl substituents on the aromatic rings. The high degree of preorganization afforded by these qualities further allowed the facile preparation of macrocyclic sheet structures from their noncyclic precursors. These macrocycles were shown to have slow internal dynamics and defined conformational preferences. Using this background, three- and five-stranded artificial β-sheets were synthesized and their folded conformations extensively characterized in solution by NMR. The solid-state structures of the three- and five-stranded sheets were also elucidated in the solid state by X-ray crystallography and confirmed intramolecular π-π aromatic stacking.


Clinical Implication of Sarcopenia in Patients with Inflammatory Bowel Disease.
Recent studies have shown that inflammatory bowel disease (IBD) patients are affected by altered body composition, especially low muscle mass or sarcopenia. Detection of sarcopenia is important, as it can independently predict osteopenia, sarcopenic obesity, and poor disease outcomes during IBD progress. The challenges are needed to identify diagnostic and managing strategies for sarcopenia in IBD to improve disease outcomes and increase the quality of life in patients with IBD.


Maternal interventions to decrease stillbirths and neonatal mortality in Tanzania: evidence from the 2017-18 cross-sectional Tanzania verbal and social autopsy study.
Reduction of Tanzania's neonatal mortality rate has lagged behind that for all under-fives, and perinatal mortality has remained stagnant over the past two decades. We conducted a national verbal and social autopsy (VASA) study to estimate the causes and social determinants of stillbirths and neonatal deaths with the aim of identifying relevant health care and social interventions. A VASA interview was conducted of all stillbirths and neonatal deaths in the prior 5 years identified by the 2015-16 Tanzania Demographic and Health Survey. We evaluated associations of maternal complications with antepartum and intrapartum stillbirth and leading causes of neonatal death; conducted descriptive analyses of antenatal (ANC) and delivery care and mothers' careseeking for complications; and developed logistic regression models to examine factors associated with delivery place and mode. There were 204 stillbirths, with 185 able to be classified as antepartum (88 [47.5%]) or intrapartum (97 [52.5%]), and 228 neonatal deaths. Women with an intrapartum stillbirth were 6.5% (adjusted odds ratio (aOR) = 1.065, 95% confidence interval (CI) 1.002, 1.132) more likely to have a C-section for every additional hour before delivery after reaching the birth attendant. Antepartum hemorrhage (APH), maternal anemia, and premature rupture of membranes (PROM) were significantly positively associated with early neonatal mortality due to preterm delivery, intrapartum-related events and serious infection, respectively. While half to two-thirds of mothers made four or more ANC visits (ANC4+), a third or fewer received quality ANC (Q-ANC). Women with a complication were more likely to deliver at hospital only if they received Q-ANC (neonates: aOR = 4.5, 95% CI 1.6, 12.3) or ANC4+ (stillbirths: aOR = 11.8, 95% CI 3.6, 38.0). Nevertheless, urban residence was the strongest predictor of hospital delivery. While Q-ANC and ANC4 + boosted hospital delivery among women with a complication, attendance was low and the quality of care is critical. Quality improvement efforts in urban and rural areas should focus on early detection and management of APH, maternal anemia, PROM, and prolonged labor, and on newborn resuscitation.


[Neurosarcoidosis: diagnosis and therapy].
Sarcoidosis is an inflammatory systemic disease with a prevalence of 20 to 50 of 100,000 inhabitants in West-Germany. Caused by an abnormal immune response to a hypothetic inhalative antigen, a granulomatous inflammation in mediastinal lymph nodes occurs, which frequently extends to the lung and sometimes to other tissues. The nervous system is clinically involved in 5% of the cases. The most frequent neurologic symptom is solitary or combined cranial nerve involvement. Cerebral manifestations are nodular or diffuse granulomatous infiltration of the brain and lymphocytic inflammation of the basal meninges. The rarer myelopathies and peripheral neuropathies often cause major neurological deficits. Muscular involvement, which is present in about half of the cases of sarcoidosis, normally causes clinically silent lesions. Chronic sarcoid myopathy or acute polymyositis are rare. Elements of the diagnostic procedure are X-ray of the lung, measurement of serum Angiotensin-Converting Enzyme (ACE)- and serum Lysozyme (LZM)-levels, Bronchoalveolar lavage, Gallium-67-scanning and Kveim-test. The diagnostic value of these investigations and the typical findings in CSF examination, computed tomography, nuclear magnetic resonance, myelography and electrophysiological investigation are presented. Suspected diagnosis of sarcoidosis should be confirmed by biopsy of non-caseating granulomatous lesions in involved tissues. An initially high dosage corticosteroid therapy for many months to several years is often effective. If this is not helpful in cerebral sarcoidosis whole brain irradiation with 1500 to 3000 rd administered in 10 single doses is indicated. Peripheral neuropathy refractory to therapy with orally administered cortisone should be treated with parenteral ultrahigh steroid therapy.


Spatio-Spectral Representation Learning for Electroencephalographic Gait-Pattern Classification.
The brain plays a pivotal role in locomotion by coordinating muscles through interconnections that get established by the peripheral nervous system. To date, many attempts have been made to reveal the underlying mechanisms of humans' gait. However, decoding cortical processes associated with different walking conditions using EEG signals for gait-pattern classification is a less-explored research area. In this paper, we design an EEG-based experiment with four walking conditions (i.e., free walking, and exoskeleton-assisted walking at zero, low, and high assistive forces by the use of a unilateral exoskeleton to right lower limb). We proposed spatio-spectral representation learning (SSRL), a deep neural network topology with shared weights to learn the spatial and spectral representations of multi-channel EEG signals during walking. Adoption of weight sharing reduces the number of free parameters, while learning spatial and spectral equivariant features. SSRL outperformed state-of-the-art methods in decoding gait patterns, achieving a classification accuracy of 77.8%. Moreover, the features extracted in the intermediate layer of SSRL were observed to be more discriminative than the hand-crafted features. When analyzing the weights of the proposed model, we found an intriguing spatial distribution that is consistent with the distribution found in well-known motor-activated cortical regions. Our results show that SSRL advances the ability to decode human locomotion and it could have important implications for exoskeleton design, rehabilitation processes, and clinical diagnosis.


Effects of baicalin on inflammatory reaction, oxidative stress and PKDl and NF-kB protein expressions in rats with severe acute pancreatitis1.
To investigate the effects of baicalin on inflammatory reaction, oxidative stress and protein kinase D1 (PKD1) and nuclear factor-kappa B (NF-κB) protein expressions in severe acute pancreatitis (SAP) rats. Sixty rats were divided into sham operation, model, and low-, medium- and high-dose baicalin group. SAP model was established in later 4 groups. The later 3 groups were injected with 0.1, 0.2 and 0.4 ml/100 g 5% baicalin injection, respectively. At 12 h, the serum SAP related indexes and inflammatory factors, peripheral blood CD3 and γδT cell percentages, wet/dry ratio and pancreas ascites volume, oxidative stress indexes and PKD1 and NF-κB protein expressions in pancreatic tissue were determined. Compared with model group, in high-dose baicalin group the wet/dry ratio and ascites volume, serum amylase level, phospholipase A2 activity, TNF-α, IL-1 and IL-6 levels, and pancreatic malondialdehyde level and PKD1 and NF-κB protein expression were significantly decreased (P < 0.05), and peripheral blood CD3 and γδT cell percentages and pancreatic superoxide dismutase and glutathione peroxidase levels were significantly increased (P < 0.05). Baicalin can resist the inflammatory reaction and oxidative stress, and down-regulate protein kinase D1 and nuclear factor-kappa B protein expressions, thus exerting the protective effects on severe acute pancreatitis in rats.


Computationally Designed Peptides for Zika Virus Detection: An Incremental Construction Approach.
Herein, and in contrast to current production of anti-Zika virus antibodies, we propose a semi-combinatorial virtual strategy to select short peptides as biomimetic antibodies/binding agents for the detection of intact Zika virus (ZIKV) particles. The virtual approach was based on generating different docking cycles of tetra, penta, hexa, and heptapeptide libraries by maximizing the discrimination between the amino acid motif in the ZIKV and dengue virus (DENV) envelope protein glycosylation site. Eight peptides, two for each length (tetra, penta, hexa, and heptapeptide) were then synthesized and tested vs. intact ZIKV particles by using a direct enzyme linked immunosorbent assay (ELISA). As a reference, we employed a well-established anti-ZIKV antibody, the antibody 4G2. Three peptide-based assays had good detection limits with dynamic range starting from 105 copies/mL of intact ZIKV particles; this was one order magnitude lower than the other peptides or antibodies. These three peptides showed slight cross-reactivity against the three serotypes of DENV (DENV-1, -2, and -3) at a concentration of 106 copies/mL of intact virus particles, but the discrimination between the DENV and ZIKV was lost when the coating concentration was increased to 107 copies/mL of the virus. The sensitivity of the peptides was tested in the presence of two biological matrices, serum and urine diluted 1:10 and 1:1, respectively. The detection limits decreased about one order of magnitude for ZIKV detection in serum or urine, albeit still having for two of the three peptides tested a distinct analytical signal starting from 106 copies/mL, the concentration of ZIKV in acute infection.


Psychological Distress and Physiological Reactivity During In Vivo Exposure in People With Aviophobia.
Exposure is regarded to be a crucial component of therapies for phobias. According to emotional processing theory, the success of exposure therapy is predicted by activation of subjective and physiological fear responses and their within-session habituation and between-session adaptation. This study tested this prediction for aviophobia. Seventy-nine participants following a highly standardized treatment program for aviophobia provided self-reported and physiological (heart rate, respiratory sinus arrhythmia and pre-ejection period) measurements of fear activation, within-session habituation, and between-session adaptation during exposure to flight-related stimuli, a flight simulator, and during two real flights. Multiple regression analyses were conducted to examine whether these measurements predicted therapy outcome up to 3 years after finishing therapy, including number of flights flown in this period. Both subjective and physiological arousal measurements indicated strong fear activation and large within-session habituation and between-session adaptation during exposure. Flight anxiety measures showed large improvements up to 3 years after treatment (η between 0.72 and 0.91). Lower self-reported anxiety during flight exposure was associated with lower flight anxiety after exposure (R = 0.15) and more flights flown (R = 0.14). Within-flight habituation or between-session adaptation of self-reported anxiety had no relationship with treatment outcome. Within-flight habituation of HR reactivity (R = 0.10) and respiratory sinus arrhythmia reactivity (R = 0.11) was associated with lower flight anxiety directly after the flight, but not on flight anxiety 3 years after finishing therapy or on long-term flying behavior. The results provide only weak support for emotional processing theory. Low self-reported anxiety during in vivo flight exposure was the best predictor of successful long-term therapy outcome.


CD44 Promotes intoxication by the clostridial iota-family toxins.
Various pathogenic clostridia produce binary protein toxins associated with enteric diseases of humans and animals. Separate binding/translocation (B) components bind to a protein receptor on the cell surface, assemble with enzymatic (A) component(s), and mediate endocytosis of the toxin complex. Ultimately there is translocation of A component(s) from acidified endosomes into the cytosol, leading to destruction of the actin cytoskeleton. Our results revealed that CD44, a multifunctional surface protein of mammalian cells, facilitates intoxication by the iota family of clostridial binary toxins. Specific antibody against CD44 inhibited cytotoxicity of the prototypical Clostridium perfringens iota toxin. Versus CD44(+) melanoma cells, those lacking CD44 bound less toxin and were dose-dependently resistant to C. perfringens iota, as well as Clostridium difficile and Clostridium spiroforme iota-like, toxins. Purified CD44 specifically interacted in vitro with iota and iota-like, but not related Clostridium botulinum C2, toxins. Furthermore, CD44 knockout mice were resistant to iota toxin lethality. Collective data reveal an important role for CD44 during intoxication by a family of clostridial binary toxins.


A multifactorial evaluation of illness risk factors in athletes preparing for the Summer Olympic Games.
Illness can disrupt training and competition performance of athletes. Few studies have quantified the relative contribution of the known medical, behavioural and lifestyle risk factors. Cross-sectional. Olympic athletes from 11 sports (n=221) were invited to complete questionnaires administered nine months before the Rio 2016 Olympic Games. These included the Depression, Anxiety and Stress Questionnaire (DASS-21), Perceived Stress Scale (PSS), Dispositional Resilience Scale (DRS), Recovery-Stress Questionnaire (REST-Q-52 item), Low Energy in Females Questionnaire (LEAF-Q), a modified Personal and Household Hygiene questionnaire, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and custom-made questionnaires on probiotic usage and travel. An illness (case) was defined as an event which limited training or competition for greater hours in the prior month. Odds ratios and attributable fractions in the population (AFP) were utilised for categorical variables with independent t-tests or Wilcoxon rank-sum for continuous variables. Eighty-one athletes responded (male, n=26; female, n=55). There were 16 illness cases and 65 controls. Female athletes were at higher odds of illness (OR=9.4, 95%CI 1.3-410, p=0.01, AFP=0.84). Low energy availability (LEAF-Q score ≥8: OR=7.4, 95%CI 0.78-352, p=0.04, AFP=0.76), depression symptoms (DASS-21: depression score >4, OR=8.4, 95%CI 1.1-59, p<0.01; AFP=0.39) and higher perceived stress (PSS: 10-item, p=0.04) were significantly associated with illness. Female sex, low energy availability, and mental health are associated with sports incapacity (time loss) due to illness. Low energy availability had high attributable fractions in the population and stands out as a primary association with illness.


Efficient neuroplasticity induction in chronic stroke patients by an associative brain-computer interface.
Brain-computer interfaces (BCIs) have the potential to improve functionality in chronic stoke patients when applied over a large number of sessions. Here we evaluated the effect and the underlying mechanisms of three BCI training sessions in a double-blind sham-controlled design. The applied BCI is based on Hebbian principles of associativity that hypothesize that neural assemblies activated in a correlated manner will strengthen synaptic connections. Twenty-two chronic stroke patients were divided into two training groups. Movement-related cortical potentials (MRCPs) were detected by electroencephalography during repetitions of foot dorsiflexion. Detection triggered a single electrical stimulation of the common peroneal nerve timed so that the resulting afferent volley arrived at the peak negative phase of the MRCP (BCIassociative group) or randomly (BCInonassociative group). Fugl-Meyer motor assessment (FM), 10-m walking speed, foot and hand tapping frequency, diffusion tensor imaging (DTI) data, and the excitability of the corticospinal tract to the target muscle [tibialis anterior (TA)] were quantified. The TA motor evoked potential (MEP) increased significantly after the BCIassociative intervention, but not for the BCInonassociative group. FM scores (0.8 ± 0.46 point difference, P = 0.01), foot (but not finger) tapping frequency, and 10-m walking speed improved significantly for the BCIassociative group, indicating clinically relevant improvements. Corticospinal tract integrity on DTI did not correlate with clinical or physiological changes. For the BCI as applied here, the precise coupling between the brain command and the afferent signal was imperative for the behavioral, clinical, and neurophysiological changes reported. This association may become the driving principle for the design of BCI rehabilitation in the future. Indeed, no available BCIs can match this degree of functional improvement with such a short intervention.


Predictors of emotional wellbeing in osteopathic medical students in a COVID-19 world.
In March 2020, the World Health Organization declared the novel coronavirus disease 2019 (COVID-19) outbreak a pandemic. Due to the rapid spread, strong contagion, high incidence of lethality in severe cases, and the lack of a pharmaceutical prevention or cure, COVID-19 has posed a serious threat to human life and health. It has also had a tremendous impact on mental health, including fear and worry, difficulty sleeping or concentrating, and increased use of poor coping mechanisms. Osteopathic medical students have had additional concerns regarding the interruption of their studies, closing of clinical rotations, and postponed licensing exams. To date, few reports have focused on osteopathic medical students and their reactions to the outbreak. To assess resilience, coping, health behaviors, and emotional wellbeing of osteopathic medical students during the onset of the COVID-19 pandemic. In this cross-sectional study, we distributed an anonymous online survey to all medical students enrolled at Nova Southeastern University in May 2020 (n=1,310) via an e-mail invitation using the institution's student listservs. Our major study variables were based on published reports and anecdotal evidence; we subsequently developed the Emotional Wellbeing in Healthcare Professions Students Questionnaire (EWB-Q). This EWB-Q contained validated scales to assess the contribution of levels of coping strategies used, personal resilience, and health behaviors on the emotional wellbeing of osteopathic medical students. Multiple linear regression and other statistical analyses were conducted using SPSS v0.26. Of the 1,310 students invited to participate, 335 (25.5%) surveys were returned. Of those, 133 had more than 33% of the necessary data missing and were removed, resulting in 202 (15.4%) completed questionnaires. The mean age of the participants was 26.7 years. About half (n=92; 45.5%) were in the clinical phase (years 3 and 4) of their medical school training (in rotations). A significant regression equation was found (F[4,171]=17.481, p<0.000, R2 =0.290, R2adjusted=0.274), indicating that levels of coping, personal resilience, and health behaviors (i.e., not sleeping more than usual, not exercising less than usual) accounted for a significant amount of the variance in emotional wellbeing scores in osteopathic medical students. Higher levels of resilience, greater use of coping strategies, not sleeping more than usual, and not exercising less than usual were predictors of emotional wellbeing. Cultivating positive mental health should be a high priority for medical educators as they develop and implement curriculum-based initiatives to help medical students bolster their personal resilience and to encourage healthy coping behaviors during times of crisis and beyond. A proactive position that assists with building personal resilience and developing stress management habits is paramount in assisting students who are grappling not only with the challenges of rigorous medical training, but also with the uncertainty and stress that exists during any major global health or socioeconomic crisis.


Camptothecins and lung cancer: improved delivery systems by aerosol.
Lung cancer is the largest and the most common cause of cancer-related deaths worldwide. The cure rate for lung cancer remains lowest among all malignancies. The discovery of new chemical agents with activity in first onset and recurrent disease is crucial for advancing treatment of patients with pulmonary tumors. Camptothecins are known as inhibitors of topoisomerase I, one of the key enzymes for DNA replication and subsequent cell proliferation. Preclinical and clinical studies had shown that the camptothecins are active against lung cancer and other solid malignancies. In this paper, we review the status of camptothecin and derivatives for treatment of pulmonary cancers, including the development of new formulations and, particularly, novel aerosol routes of drug administration, and their application in combination therapy.


Characterization of a rat liver cyclic GMP-activated phosphodiesterase by chromatography on hexyl-agarose. Inhibition of phosphodiesterase activity by hexyl-agarose.
Chromatography on hexyl-agarose resolved a partially purified cyclic GMP-activated phosphodiesterase from rat liver into two peaks of activity: the first was eluted with 0.5 M-KCl and was cyclic AMP-specific. The second was tightly bound to hexyl-agarose and was not eluted with KCl (0--2.0 M), which enhanced the hydrophobic interactions of this form with the matrix. It was eluted with 0.5 M-Tris, hydrolysed cyclic AMP and cyclic GMP and was specifically activated by cyclic GMP. The cyclic GMP-activated phosphodiesterase was immobilized on hexyl-agarose. Enzyme activity, quantitatively bound to hexyl-agarose, was not released from the hydrophobic matrix in the presence of cyclic AMP or cyclic GMP, under our assay conditions. The immobilized form of the enzyme retained catalytic activity, was inhibited by 0.1 mM-cyclic AMP and was activated by micromolar concentrations of cyclic GMP to a lesser extent (7-fold) than the control, i.e. the enzyme mixed with unsubstituted agarose (15-fold). When the enzyme was immobilized, inhibition of cyclic AMP phosphodiesterase activity was only observed in the presence of cyclic GMP (at 3 microM); in its absence, activity remained unchanged. The kinetic behaviour of the immobilized enzyme is consistent with the hypothesis of a binding site distinct from the hydrolytic and activating sites.


Induction of allograft tolerance in the absence of Fas-mediated apoptosis.
Using certain immunosuppressive regimens, IL-2 knockout (KO) mice, in contrast to wild-type (wt) controls, are resistant to the induction of allograft tolerance. The mechanism by which IL-2 regulates allograft tolerance is uncertain. As IL-2 KO mice have a profound defect in Fas-mediated apoptosis, we hypothesized that Fas-mediated apoptosis of alloreactive T cells may be critical in the acquisition of allograft tolerance. To definitively study the role of Fas in the induction of transplantation tolerance, we used Fas mutant B6.MRL-lpr mice as allograft recipients of islet and vascularized cardiac transplants. Alloantigen-stimulated proliferation and apoptosis of Fas-deficient cells were also studied in vivo. Fas mutant B6.MRL-lpr (H-2b) mice rapidly rejected fully MHC-mismatched DBA/2 (H-2d) islet allografts and vascularized cardiac allografts with a tempo that is comparable to wt control mice. Both wt and B6.MRL-lpr mice transplanted with fully MHC-mismatched islet allografts or cardiac allografts can be readily tolerized by either rapamycin or combined costimulation blockade (CTLA-4Ig plus anti-CD40L mAb). Despite the profound defect of Fas-mediated apoptosis, Fas-deficient T cells can still undergo apoptotic cell death in vivo in response to alloantigen stimulation. Our study suggests that: 1) Fas is not necessarily essential for allograft tolerance, and 2) Fas-mediated apoptosis is not central to the IL-2-dependent mechanism governing the acquisition of allograft tolerance.


Seasonal mixing and catastrophic degassing in tropical lakes, cameroon, west Africa.
Lethal gas releases from Lakes Nyos and Monoun in Cameroon seem to be more lacustrine than volcanic in origin. Both of these events occurred in August and were only 2 years apart. Data show that the period of deepest mixing and lake turnover also occurs during late summer in this region of tropical Africa. In addition, recent trends of decreases in both air temperatures and effective insolation relative to long-term means suggest that weakening of stratification, coupled with a predictable seasonal interval of reduced stability in August, may be responsible for the timing of these events.


Stroke characterization in Sun Saharan Africa: Congolese population.
Stroke is the second cause of death worldwide and over than 80% of deaths occurs in developing countries. However, its characteristics in the Democratic Republic of Congo (DRC) are poorly defined. This study aimed to describe the key features of stroke in a hospital population of Kinshasa in DRC and to assess the frequency of cardiovascular risk factors and their impact on target organs. A descriptive study was carried out from three hospitals in Kinshasa between January and April 2013. Cardiovascular risk factors, clinical and biological data were collected during the study period. The study involved 166 patients aged 18years and over. The mean age of patients was 59.6±12.3years, the sex ratio for male of 1.9. Stroke was ischemic in 66% of cases. Hypertension was the most frequent cardiovascular risk factor (84.3%), followed by high blood cholesterol (45.2%).The etiologies of ischemic stroke (TOAST classification) were dominated by lacunas (38.5%) and embolic heart diseases (12.8%). The origin was unknown in 45.9% of cases. Coma was observed in 37% of patients on admission and was the main independent prognostic factor of mortality, which was 19.3%. Left ventricular hypertrophy and renal failure were found respectively in 64.7% and 34% of patients. This study found a growing increase of ischemic stroke in a society where hemorrhagic type used to be the most common, a high rate of hypertension, hypercholesterolemia and diabetes, indicative of a fast epidemiological transition.