Current treatment of convulsive status epilepticus - a therapeutic protocol and review.
The management of status epilepticus (SE) has changed in recent years. Substantial differences exist regarding the definition and time frame of a seizure, which has been operationally defined as lasting for 5 min. Not only have many new intravenous drugs, such as levetiracetam and lacosamide been introduced but other routes of administration, such as intranasal or buccal administration for midazolam, are also being developed. Optimal and successful therapy initiated at the appropriate moment, adequately tailored to the clinical state of the patient, determines the first step in the normalisation of vital functions and leads to the restoration of the physiological homeostatic mechanisms of the organism. The aim of this review is to present the current treatment options for the management of convulsive status epilepticus (CSE) that have been widely confirmed as the most effective in clinical trials and approved by the international neurology authorities as the actual therapeutic standards. We also intend to indicate distinct and unequivocal differentiation and therapeutic indications for each phase of CSE, including the precise doses of the related medications, to present practical guidelines for clinicians. The treatment of patients with CSE requires emergency physicians, neurologists and specialists in intensive care to work together to provide optimal care that should be initiated as soon as possible and conducted as a unified procedure to improve neurocritical care in patients who are transferred from the ambulance service, through the emergency department and finally to the neurology department or ICU. Appropriate treatment also involves avoiding mistakes associated with inadequate doses of medications, overdosing a patient or choosing an inappropriate medication.


The development of heavy drinking and alcohol-related problems from ages 18 to 37 in a U.S. national sample.
The purpose of this study is to add to the understanding of the development of heavy alcohol use and alcohol-related problems by examining data from the National Longitudinal Survey of Youth (NLSY), a general population sample that contains information on alcohol use for the ages 18-37. A key question in this study is how background characteristics of the individual influence this development and whether the influence of these background characteristics changes over time. The data used in this study are a general population sample (N = 7,859) from the National Longitudinal Survey of Youth (NLSY). This study uses a multivariate outcome approach that focuses on individual variation in trajectories over age. The statistical analysis uses random coefficients in a latent variable framework. Across-age changes in the importance of the influence of background variables on the outcomes are modeled using varying centering points. A key finding is that dropping out of high school has no effect on alcohol-related problems for individuals in their mid-twenties, but is associated with significantly increased levels of alcohol-related problems for individuals in their mid-thirties. In contrast, going on to college is associated with lower levels of heavy drinking when individuals reach their late twenties and their thirties. Strong gender and ethnicity effects seen in the twenties diminish when individuals reach their thirties. The trajectory analysis expands the knowledge of problematic alcohol development for individuals in their late twenties and thirties. The increasing detrimental effect of dropping out of high school up to the age 37 endpoint of the study raises questions about the effects in later life of dropping out of high school.


Cell therapy for cystic fibrosis.
Currently there is no cure for cystic fibrosis (CF). Treatments are focused on addressing the disease symptoms, with varying degrees of success. Regenerative medicine holds the promise of regenerating dysfunctional or damaged tissues and to enhance the body's own endogenous repair mechanisms. The discovery of endogenous and exogenous stem cells has provided valuable tools for development of novel treatments for CF. The ability of stem cells to differentiate into functional pulmonary cells, modulate inflammatory responses and contribute to pulmonary function has provided researchers with multiple approaches to develop effective treatment strategies. Several approaches show promise to produce viable therapeutic treatments to treat the underlying cause of CF, reduce the symptoms and mitigate long-term damage, and generate functional replacement organs for end-stage transplantation. This review provides an overview of the rapidly progressing field of cell therapy for CF, focusing on the various cell types utilized and current strategies that show promise to improve life expectancy and quality of life for CF patients.


Spontaneous regression of focal nodular hyperplasia: a pathological report.
Focal nodular hyperplasia (FNH) is a benign tumour of the liver, occurring in 0.6-3% of the general population. Most lesions are diagnosed incidentally. With the increasing use and improvement of diagnostic imaging, FNH is being observed more often. It has been shown, using radiological approaches, that most FNH remain stable, or even regress, over a long follow-up period. In addition, it is extremely rare that FNH were discovered in elderly. However, to our knowledge, there is no pathological report illustrating the regression of FNH. We report here a case showing the pathological changes occurring during the regression phase of FNH, with dense fibrous tissue mixed with arteries replacing hepatocytes nodules.


Neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects.
Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m(2)), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = -0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = -0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.


Gastric cancer during pregnancy with placental involvement: case report and review of published works.
Gastric cancer involving the placenta during pregnancy is rare; however, we present 1 such case in this report. A 31-year-old Japanese woman was referred at 26 weeks of gestation for the evaluation of a swollen left supraclavicular lymph node. Biopsy revealed poorly differentiated adenocarcinoma, and esophagogastroduodenoscopy with biopsy of the stomach confirmed the diagnosis of gastric cancer. Her epigastric and back pain became more pronounced and her general status worsened, and we performed a cesarean delivery at 29 weeks. Microscopic examination of the placental specimen revealed poorly differentiated adenocarcinoma cells diffused into the intervillous space. Postpartum chemotherapy consisted of S-1 plus oxaliplatin. Unfortunately, this treatment was ineffective, and the patient died 3 months after delivery. The infant did well, without clinical or laboratory manifestations of metastasis. In patients with advanced gastric cancer during pregnancy, it is important to perform a microscopic examination of the placenta to evaluate for metastatic involvement.


Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum.
BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.


Different mechanisms of fear extinction dependent on length of time since fear acquisition.
Fear extinction is defined as a decline in conditioned fear responses (CRs) following nonreinforced exposure to a feared conditioned stimulus (CS). Behavioral evidence indicates that extinction is a form of inhibitory learning: Extinguished fear responses reappear with the passage of time (spontaneous recovery), a shift of context (renewal), and unsignaled presentations of the unconditioned stimulus (reinstatement). However, there also is evidence to suggest that extinction is an "unlearning" process corresponding to depotentiation of potentiated synapses within the amygdala. Because depotentiation is induced more readily at short intervals following LTP induction and is not inducible at all at a sufficient delay, it may be that extinction initiated shortly following fear acquisition preferentially engages depotentiation/"unlearning," whereas extinction initiated at longer delays recruits a different mechanism. We investigated this possibility through a series of behavioral experiments examining the recoverability of conditioned fear following extinction. Consistent with an inhibitory learning mechanism of extinction, rats extinguished 24-72 h following acquisition exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction.


Automatic detection of false annotations via binary property clustering.
Computational protein annotation methods occasionally introduce errors. False-positive (FP) errors are annotations that are mistakenly associated with a protein. Such false annotations introduce errors that may spread into databases through similarity with other proteins. Generally, methods used to minimize the chance for FPs result in decreased sensitivity or low throughput. We present a novel protein-clustering method that enables automatic separation of FP from true hits. The method quantifies the biological similarity between pairs of proteins by examining each protein's annotations, and then proceeds by clustering sets of proteins that received similar annotation into biological groups. Using a test set of all PROSITE signatures that are marked as FPs, we show that the method successfully separates FPs in 69% of the 327 test cases supplied by PROSITE. Furthermore, we constructed an extensive random FP simulation test and show a high degree of success in detecting FP, indicating that the method is not specifically tuned for PROSITE and performs well on larger scales. We also suggest some means of predicting in which cases this approach would be successful. Automatic detection of FPs may greatly facilitate the manual validation process and increase annotation sensitivity. With the increasing number of automatic annotations, the tendency of biological properties to be clustered, once a biological similarity measure is introduced, may become exceedingly helpful in the development of such automatic methods.


Assessment of the use of RNA quality metrics for the screening of articular cartilage specimens from clinically normal dogs and dogs with osteoarthritis.
To assess 2 methods of RNA purification by use of different quality metrics and identify the most useful metric for quality assessment of RNA extracted from articular cartilage from dogs with osteoarthritis. 40 articular cartilage specimens from the femoral heads of 3 clinically normal dogs and 37 dogs with osteoarthritis. RNA was extracted from articular cartilage by 2 purification methods. Quality metrics of each sample were determined and recorded by use of a UV spectrophotometer (Spec I; to determine the 260 to 280 nm absorbance ratio [A(260):A(280) ratio]), a second UV spectrophotometer (Spec II; to determine A(260):A(280) and A(260):A(230) absorbance ratios), and a microfluidic capillary electrophoresis analyzer (to determine the ribosomal peak ratio [RR], degradation factor [DF], and RNA integrity number [RIN]). The RNA was extracted from affected (osteoarthritic) articular cartilage and assessed with the same quality metrics. Metric results were compared with visual analysis of the electropherogram to determine the most useful RNA quality metric. No differences in methods of RNA purification were determined by use of quality metrics. The RNA extracted from unaffected (normal) cartilage was of higher quality than that extracted from affected (osteoarthritic) cartilage, as determined by the RIN and Spec II A(260):A(230) ratio. The RIN and RR were the most sensitive metrics for determining RNA quality, whereas the DF was most specific. A significant proportion (32%) of RNA extracted from osteoarthritic articular cartilage specimens was determined as being of low quality. No single metric provided a completely sensitive and specific assessment of the quality of RNA recovered from articular cartilage.


Pannexin 1 regulates adipose stromal cell differentiation and fat accumulation.
Pannexin 1 (Panx1) is a channel-forming glycoprotein important in paracrine signaling and cellular development. In this study, we discovered that mice globally lacking Panx1 (KO) have significantly greater total fat mass and reduced lean mass compared to wild type (WT) mice under a normal diet. Despite having higher fat content, Panx1 KO mice on a high fat diet exhibited no differences in weight gain and blood markers of obesity as compared to WT controls, except for an increase in glucose and insulin levels. However, metabolic cage data revealed that these Panx1 KO mice display significantly increased activity levels, higher ambulatory activity, and reduced sleep duration relative to their WT littermates on a high-fat diet. To uncover the cellular mechanism responsible for the increased fat content in the KO, we isolated primary cultures of adipose-derived stromal cells (ASCs) from WT and KO fat pads. In WT ASCs we observed that Panx1 protein levels increase upon induction into an adipogenic lineage. ASCs isolated from Panx1 KO mice proliferate less but demonstrate enhanced adipogenic differentiation with increased intracellular lipid accumulation, glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, and adipokine secretion, as compared to WT ASCs. This was consistent with the increased adipocyte size and decreased adipocyte numbers observed in subcutaneous fat of the Panx1 KO mice compared to WT. We concluded that Panx1 plays a key role in adipose stromal cells during the early stages of adipogenic proliferation and differentiation, regulating fat accumulation in vivo.


Formulations of NaOCl-based in liquid, gel form or with surfactants on dentin deproteinization before fiber post cementation.
The objective of the study was to evaluate the effects of dentin deproteinization protocols for post space using different formulations containing sodium hypochlorite before fiber post cementation with self-adhesive resinous cement. The groups were divided according to the irrigation protocol (DWC, SHS, SHT and SHG). The residue cleanliness, bond strength, adhesive failure pattern, and tag formation at the adhesive interface between the self-adhesive cement and the dentin were evaluated. For this, analysis in scanning electron microscope, push-out test and confocal laser scanning microscopy were performed. The SHT protocol showed the highest residue cleanliness on the dentin surface of the post space (p<0.05). In addition, SHT protocol showed highest bond strength and tag formation in the cervical and middle thirds (p<0.05). Dentin deproteinization with sodium hypochlorite with surfactant provided the best dentin cleaning of residues, bond strength and tag formation after cementation of the fiber post with self-adhesive cement.


ENOD40 Gene Expression and Cytokinin Responses in the Nonnodulating, Nonmycorrhizal (NodMyc) Mutant, Masym3, of Melilotus alba Desr.
Several nonnodulating, nonmycorrhizal (Nod(-)Myc(-)) mutants of Melilotus alba Desr. (white sweetclover) have been described. However, the details of their responses to Sinorhizobium meliloti have not been fully elucidated. We investigated rhizobial entry and colonization using Confocal Scanning Laser Microscopy on the Masym1-5 mutants and isolated an early nodulin (ENOD40) gene from wild-type M. alba. We focused on Masym3, the least responsive of the mutants to S. meliloti and VA-fungi, to determine its response to cytokinin. Cytokinin appears to be a downstream signal in the nodule developmental pathway based not only on our previous observations whereby Nod(-)Myc(-) alfalfa roots treated with cytokinin accumulated several ENOD gene transcripts, but also on recent reports showing the importance of cytokinin receptors for nodulation. Here we show that applying 10(-6) M 6-benzylaminopurine to uninoculated Masym3 roots elicited ENOD40 transcript accumulation. In addition, Masym3 root hairs inoculated with either wild-type S. meliloti or Nod(-)S. meliloti expressing the trans-zeatin synthase gene of Agrobacterium tumefaciens exhibited tip swelling, suggesting that cytokinin mediated this response. However, Masym3 root hair tips swelled following inoculation with Nod(-)S. meliloti or after mock-inoculation, a response resembling the phenotype of root hairs, after handling, of the Medicago truncatula mutant, dmi2. Mtdmi2 is Nod(-)Myc(-) due to a defect in a gene encoding a Nodule Receptor Kinase (NORK). Like Mtdmi2, the root hair swelling response appears in part to be mediated by touch because Masym3 root hairs not contacted by either bacteria or drops of water or buffer remain elongated and do not exhibit tip swelling.


Relationship between sodium transport and intracellular ATP in isolated perfused rabbit proximal convoluted tubule.
The effect of alterations in sodium transport on cell ATP content and pH in the isolated perfused proximal convoluted tubule (PCT) of the rabbit was examined. Stimulating sodium transport by the addition of luminal glucose and alanine decreased cell ATP from 4.44 +/- 0.93 to 2.69 +/- 0.62 mM (n = 4), increased intracellular pH by 0.13 +/- 0.02 (n = 7), and increased cell volume by 0.10 +/- 0.02 nl/mm (n = 4). Blocking the sodium pump with 10(-4) M strophanthidin in tubules in which sodium transport had been stimulated increased cell ATP from 2.04 +/- 0.24 to 2.42 +/- 0.32 mM (n = 6). In parallel experiments the same dose of strophanthidin depolarized the basolateral membrane from -52.6 +/- 1.9 to -6.4 +/- 1.6 mV, depolarized the transepithelial potential from -3.2 +/- 0.3 to -0.1 +/- 0.1 mV, and reduced the basolateral membrane potassium transference number from 0.47 to 0.26 indicating a reduction in basolateral potassium conductance. Since strophanthidin caused a cell alkalinization of 0.15 +/- 0.03, this latter effect cannot be due to changes of intracellular pH. Strophanthidin caused no change in cell volume over the period studied, suggesting that stretch-activated potassium channels are not involved either. Instead, potassium conductance inhibition may be the result of the closure of ATP-sensitive potassium channels. These same channels might thus be partly responsible for the increase in potassium conductance commonly observed during stimulation of sodium transport.


Quantification of Unsupported Thin-Film X-ray Spectra Using Bulk Standards.
A quantification model which uses standard X-ray spectra collected from bulk materials to determine the composition and mass thickness of single-layer and multilayer unsupported thin films is presented. The multivariate model can be iteratively solved for single layers in which each element produces at least one visible characteristic X-ray line. The model can be extended to multilayer thin films in which each element is associated with only one layer. The model may sometimes be solved when an element is present in multiple layers if additional information is added in the form of independent k-ratios or model assumptions. While the algorithm is suitable for any measured k-ratios, it is particularly well suited to energy-dispersive X-ray spectrometry where the bulk standard spectra can be used to deconvolve peak interferences in the thin-film spectra. The algorithm has been implemented and made available in the Open Source application National Institute of Standards and Technology DTSA-II. We present experimental data and Monte Carlo simulations supporting the quantification model.


Development of an in vitro Microtuberization and Temporary Immersion Bioreactor System to Evaluate Heat Stress Tolerance in Potatoes (Solanum tuberosum L.).
High temperature (heat) stress reduces tuber yield and quality of potatoes. Screening potatoes for heat tolerance is increasingly important, considering the climate change scenario and expansion of potatoes to countries where heat stress is an issue. In vitro screening for tolerance to abiotic stresses offers several advantages, including quick evaluation of numerous genotypes (clones) in reduced space, controlled environmental conditions (temperature and photoperiod), and free from confounding variables inherent to greenhouse and field conditions. In this study, we explored the feasibility of using a temporary immersion bioreactor system for heat tolerance screening of potatoes. We determined the best hormone-free microtuberizing media for this system (MSG with 8% sucrose) to enhance microtuber number and size. Comparisons of microtubers produced at 30°C as heat treatment, with 16°C as normal condition, allowed to identify heat tolerant and susceptible potato clones. The use of bioreactors allowed distinguishing well-formed (non-deformed) from deformed microtubers. Heat stress increased the total biomass of plant tissues in all the clones. However, the effect of heat stress on microtuber number and weight varied among the clones. Incubation at 30°C decreased the weight and number of non-deformed microtubers in all the clones except for Reveille Russet in which the weight of non-deformed microtubers was significantly increased and the count of non-deformed microtubers was not affected. The potato variety Reveille Russet, which was selected under high-temperature field conditions in Texas, had many non-deformed microtubers per explant and the highest microtuber weight among four clones evaluated under heat stress. We described a faster and reliable in vitro microtuberization system for abiotic stress tolerance screening, identified Reveille Russet as a promising heat-tolerant potato variety, and confirmed Russet Burbank and Atlantic as susceptible heat-tolerant checks.


Functional effects of levosimendan in rat basilar arteries in vitro.
Levosimendan is a novel calcium sensitizer that is an established treatment for congestive heart failure. In coronary vessels, levosimendan has a vasorelaxant, endothelium-independent effect and an antagonistic effect on endothelin-1 (ET-1). There is also some data for a neuroprotective effect in a traumatic brain injury model, and levosimendan can prevent the reduction of the luminal area of the basilar artery. We considered that patients who suffer heart attack after subarachnoid hemorrhage (SAH) might respond well to levosimendan, which might also be useful to induce hypertension in patients with cerebral vasospasm.However, the functional effects of levosimendan in the cerebrovasculature are unknown. Here, we investigated the functional role of levosimendan on rat basilar artery by assessing vasocontractile reactivity in response to ET-1, sarafotoxin S6c, acetylcholine, sodium nitroprusside, cGMP, and prostaglandin F2α (PGF).Contrary to observations in coronary vessels, levosimendan did not affect the ET-1 system in cerebral arteries; neither ET(A)-receptor-induced contraction nor ET(B)-receptor-dependent relaxation were changed. For the nitric oxide (NO) pathway, only a slight increase was detected. Rather, levosimendan caused significant and dose-dependent relaxation after PGF precontraction.To our knowledge, this is the first report that describes levosimendan-induced functional changes of cerebrovascular contractility and relaxation. Under physiological conditions, levosimendan did not influence ET(A)/ET(B)-receptor signaling or the NO pathway. Interestingly, levosimendan seemed to affect the prostaglandin system and dosedependently reversed PGF- induced contraction. We did not detect a vasospastic potential for levosimedan in cerebral arteries, suggesting that it would be safe for use in SAH patients.


Bioactive Polyketides from the Natural Complex of the Sea Urchin-Associated Fungi Penicillium sajarovii KMM 4718 and Aspergillus protuberus KMM 4747.
The marine-derived fungal strains KMM 4718 and KMM 4747 isolated from sea urchin Scaphechinus mirabilis as a natural fungal complex were identified as Penicillium sajarovii and Aspergillus protuberus based on Internal Transcribed Spacer (ITS), partial β-tubulin (BenA), and calmodulin (CaM) molecular markers as well as an ribosomal polymerase two, subunit two (RPB2) region for KMM 4747. From the ethyl acetate extract of the co-culture, two new polyketides, sajaroketides A (1) and B (2), together with (2'S)-7-hydroxy-2-(2'-hydroxypropyl)-5-methylchromone (3), altechromone A (4), norlichexanthone (5), griseoxanthone C (6), 1,3,5,6-tetrahydroxy-8-methylxanthone (7), griseofulvin (8), 6-O-desmethylgriseofulvin (9), dechlorogriseofulvin (10), and 5,6-dihydro-4-methyl-2H-pyran-2-one (11) were identified. The structures of the compounds were elucidated using spectroscopic analyses. The absolute configurations of the chiral centers of sajaroketides A and B were determined using time-dependent density functional theory (TDDFT)-based calculations of the Electronic Circular Dichroism (ECD) spectra. The inhibitory effects of these compounds on urease activity and the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans were observed. Sajaroketide A, altechromone A, and griseofulvin showed significant cardioprotective effects in an in vitro model of S. aureus-induced infectious myocarditis.


DNR and ECMO: a paradox worth exploring.
Extracorporeal membrane oxygenation (ECMO) provides continuous circulation and/or oxygenation to adults with cardiac failure, pulmonary dysfunction, or both. The technology is similar to the traditional heart-lung bypass machines used during surgical procedures, however ECMO may be used outside the confines of the operating room and for extended periods of time. This paper explores the complexities, both clinical and ethical, of a do-not-resuscitate (DNR) order for patients with cardiopulmonary failure on veno-arterial (VA-ECMO), a type of ECMO that provides resuscitation superior to the chest compressions that DNR is intended to prevent. Clinically, a DNR order has limited utility for patients on VA-ECMO and its presence can serve to create confusion. Symbolically, however, the designation may serve as a stepping-stone for surrogates facing difficult end-of-life decisions. The paper concludes by suggesting that it is prudent to avoid DNR discussions in the context of VA-ECMO


Passive transfer of tolerance to pyrogenicity of bacterial endotoxin.
The typical febrile response of normal rabbits given bacterial endotoxin intravenously may be modified by prior administration of plasma or, less effectively, serum of endotoxin-tolerant donors. This altered response is characterized by disappearance of the second rise in fever and by a striking reduction in fever index. It thus resembles the course of fever shown by rabbits made tolerant to endotoxin by one or more previous daily doses. This transfer of tolerance by plasma or serum depends critically upon the manner in which tolerance is induced in the donors. The plasma of donor rabbits made tolerant, then given an RES-blocking dose of carbon, still confers tolerance upon normal recipient rabbits. Such donors have lost their tolerance and are highly sensitive to endotoxin at the time their blood is taken. The implications of these findings for endotoxin tolerance and for transfer of this phenomenon are discussed. The evidence is consistent with the hypothesis that both tolerance and its transfer are based upon RES function and are independent of antibody.


Perceived job insecurity, job predictability, personality, and health.
The present study sought to determine whether job insecurity is associated with personality traits and beliefs. In addition, it was tested whether aspects of personality confounded the relationships between job insecurity and health, or moderated this association. At the first data collection, 5163 persons participated, and at the second data collection, 1946 persons of a random sample participated. Data were obtained from Oslo Health Study. The job insecurity aspect concerning confidence in having a good job in 2 years was more strongly related to the health variables, and particularly with mental distress, compared with other aspects of job insecurity. Type-A behavior predicted an increase in upper back pain (beta 0.07), while optimism predicted a change in lower back pain (beta -0.07). Job insecurity is associated with health; this association is strongest for mental distress and self-reported health, and weaker for back-pain.


Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies.
Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects.


Properties of Wood-Plastic Composites Manufactured from Two Different Wood Feedstocks: Wood Flour and Wood Pellets.
Driven by the motive of minimizing the transportation costs of raw materials to manufacture wood-plastic composites (WPCs), Part I and the current Part II of this paper series explore the utilization of an alternative wood feedstock, i.e., pellets. Part I of this study reported on the characteristics of wood flour and wood pellets manufactured from secondary processing mill residues. Part II reports on the physical and mechanical properties of polypropylene (PP)-based WPCs made using the two different wood feedstocks, i.e., wood flour and wood pellets. WPCs were made from 40-mesh wood flour and wood pellets from four different wood species (white cedar, white pine, spruce-fir and red maple) in the presence and absence of the coupling agent maleic anhydride polypropylene (MAPP). With MAPP, the weight percentage of wood filler was 20%, PP 78%, MAPP 2% and without MAPP, formulation by weight percentage of wood filler was 20% and PP 80%. Fluorescent images showed wood particles' distribution in the PP polymer matrix was similar for both wood flour and ground wood pellets. Dispersion of particles was higher with ground wood pellets in the PP matrix. On average, the density of composite products from wood pellets was higher, tensile strength, tensile modulus and impact strength were lower than the composites made from wood flour. Flexural properties of the control composites made with pellets were higher and with MAPP were lower than the composites made from wood flour. However, the overall mechanical property differences were low (0.5-10%) depending on the particular WPC formulations. Statistical analysis also showed there was no significant differences in the material property values of the composites made from wood flour and wood pellets. In some situations, WPC properties were better using wood pellets rather than using wood flour. We expect if the material properties of WPCs from wood flour versus wood pellets are similar and with a greater reduction in transportation costs for wood pellet feedstocks, this would be beneficial to WPC manufacturers and consumers.


Amphetamine self-administration in light and moderate drinkers.
Light and moderate drinkers respond differently to the effects of abused drugs, including stimulants such as amphetamine. The purpose of this study was to determine whether light and moderate drinkers differ in their sensitivity to the reinforcing and subjective effects of d-amphetamine. We hypothesized that moderate drinkers (i.e., participants that reported consuming at least seven alcohol-containing beverages per week) would be more sensitive to the reinforcing and positive subject-rated effects of d-amphetamine than light drinkers. Data from four studies that employed similar d-amphetamine self-administration procedures and subject-rated drug-effect measures were included in the analysis. Light (n = 17) and moderate (n = 16) drinkers sampled placebo, low (8 to 10 mg), and high (16 to 20 mg) doses of oral d-amphetamine administered in eight capsules. Following sampling sessions, participants worked for a maximum of eight capsules, each containing 12.5% of the previously sampled dose, on a modified progressive-ratio schedule of reinforcement. Both active doses of d-amphetamine functioned as a reinforcer in the moderate drinkers, while only the high dose did so in the light drinkers. The moderate drinkers worked for significantly more capsules that contained the high dose of d-amphetamine than did the light drinkers. d-Amphetamine produced prototypical stimulant-like subjective effects (e.g., dose-dependent increases in ratings of Good Effects; Like Drug and Willing to Take Again). Moderate drinkers reported significantly greater subjective effects than the light drinkers. These results are consistent with those from previous laboratory experiments and suggest that moderate alcohol consumption may increase vulnerability to the abuse-related effects of stimulants.


Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease.
The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability-autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.


Pandemic influenza A/H1N1 vaccination uptake among health care workers in Qatar: motivators and barriers.
Influenza A/H1N1 new vaccine helps control disease spread. Cross-sectional survey was conducted at PHC & Emergency Departments in Qatar to determine influenza A/H1N1 vaccination rate among HCWs and associated factors, 523 HCWs were enrolled. The study showed that 13.4% HCWs received vaccination. Feeling protected strongly influenced vaccination decision (OR = 14.5). Uncertainty about vaccine efficacy and fear of side effects strongly influenced decision to reject the vaccine (OR = 0.3 and 0.2 respectively). Vaccination coverage was very low. The most common barriers were uncertainty about vaccine efficacy and fear of side effects. Health authorities should build message highlighting how the benefit of vaccination outweighs risk.


Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms.
In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation-independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.


New approaches for the selection and evaluation of anti-prion organic compounds.
Transmissible spongiform encephalopathies (TSEs) are infectious neurodegenerative disorders for which symptomatic, curative, or prophylactic treatments are not available. TSEs arise as a consequence of the conversion of soluble cellular prion protein (PrP(C)) into the scrapie isoform (PrP(Sc)), which aggregates and accumulates in the central nervous system. Proposed drugs against TSEs range from small organic compounds to antibodies; various therapeutic strategies have been proposed, including blocking the conversion of PrP(C) to PrP(Sc), increasing PrP(Sc) clearance, and/or stabilizing PrP(C). While several compounds have been effective in vitro and in animal models, none have proven effective in clinical studies to date. Such lack of in vivo efficacy is attributable to high compound toxicity and the lack of permeability of the selected compounds across the blood-brain barrier. In this review, we discuss recent advances in the screening and evaluation of organic compounds for anti-prion activity using multiple approaches, including initial screening in prion-infected cell cultures, in silico prediction of pharmacokinetic and physicochemical properties, ex vivo evaluation of cellular toxicity, and in vitro assays using purified recombinant prion proteins. The main challenges for effective discrimination of candidate lead compounds as therapeutic agents for TSEs, and the disadvantages of each screening strategy are discussed. We propose that a combination of in vitro, ex vivo, and in silico approaches would be useful for the rapid identification of novel anti-prion drug candidates with suitable pharmacokinetic and pharmacodynamic properties that would support their use as drugs.


Risk of left atrial appendage thrombus in older patients with atrial fibrillation.
We aimed to compare the prevalence of left atrial appendage (LAA) thrombus and its predictors between old and young patients with atrial fibrillation (AF). The study included 1970 patients aged ≥ 65 (n = 822 (41.7%)) and < 65 (n = 1148 (58.3%)) referred for AF cardioversion or ablation preceded by transoesophageal echocardiography (TEE). Oral anticoagulation (OAC) was prescribed in 799 (97.2%) patients aged ≥ 65 years and in 1054 (91.8%) of those aged < 65 years (p < 0.001). In patients treated with OAC, those aged ≥ 65 years less often received vitamin K antagonist (VKA) (267 (33.4%) vs. 416 (39.5%)) and more often non-VKA-OAC (NOAC) (532 (66.6%) vs. 638 (60.5%), p = 0.008, p = 0.008) compared to patients < 65 years. On TEE, LAA thrombus was more often observed in patients aged ≥ 65 years than those aged < 65 years (63 (7.7%) vs. 46 (4.0%), p < 0.001), with an absolute but not statistically significant difference between patients aged 65-74 and ≥ 75 years (47 (7.3%) vs. 16 (8.8%), p = 0.528). In patients aged ≥ 65 years, there was no difference in the prevalence of LAA thrombus between patients treated with VKA and NOAC, in contrast to patients aged < 65 years, in whom such a difference was observed (27 (6.5%) vs. 16 (2.5%), p = 0.002). In multivariate logistic regression, predictors of LAA thrombus in both age groups were older age, non-paroxysmal AF, and heart failure, whereas only in patients aged < 65 years - VKA use, and in those aged ≥ 65 years - lower glomerular filtration rate and platelet count. Despite OAC use, older patients with AF remain at high risk of LAA thrombus formation. Older age, non-paroxysmal AF, and heart failure are predictors of LAA thrombus, irrespective of age.


Probing the serpin structural-transition mechanism in ovalbumin mutant R339T by proteolytic-cleavage kinetics of the reactive-centre loop.
A mutant ovalbumin (R339T), but not the wild-type protein, is transformed into the canonical loop-inserted, thermostabilized form after the P1-P1' cleavage [Yamasaki, Arii, Mikami and Hirose (2002) J. Mol. Biol. 315, 113-120]. The loop-insertion mechanism in the ovalbumin mutant was investigated by proteolytic-cleavage kinetics. The nature of the inserted loop prevented further cleavage of the P1-P1' pre-cleaved R339T mutant by subtilisin, which cleaved the second P8-P7 loop site in the P1-P1' pre-cleaved wild-type protein. After subtilisin proteolysis of the intact R339T, however, two final products that corresponded to the single P1-P1' and double P1-P1'/P8-P7 cleavages were generated with variable ratios depending on the proteolysis conditions. This was accounted for by the occurrence of two mutually competitive reactions: the loop-insertion reaction and the proteolytic cleavage of the second P8-P7 site in the immediate intermediate after the P1-P1' cleavage. The competitive nature of the two reactions enabled us to establish a kinetic method to determine the rate constants of the reactions. The first-order rate constant for the loop insertion was determined to be 4.0 x 10(-3)/s in the R339T mutant. The second-order rate constant for the P8-P7 cleavage in the immediate P1-P1' cleavage product for the R339T mutant was >10 times compared with that for its wild-type counterpart. This highly accessible loop nature may play a crucial role in the loop-insertion mechanism for R339T mutant ovalbumin.


Anticaries effect of dentifrices with calcium citrate and sodium trimetaphosphate.
Because of the growing concerns regarding fluoride ingestion by young children and dental fluorosis, it is necessary to develop new dentifrices. The aim of this study was to evaluate the effect of dentifrices with calcium citrate (Cacit) and sodium trimetaphosphate (TMP) on enamel demineralization. Enamel blocks (n=70), previously selected through surface hardness analysis, were submitted to daily treatment with dentifrices diluted in artificial saliva and to a pH-cycling model. The fluoride concentration in dentifrices was 0, 250, 450, 550, 1,000 and 1,100 µg F/g. CrestTM was used as a positive control (1,100 mg F/g). Cacit (0.25%) and TMP (0.25%) were added to dentifrices with 450 and 1,000 µg F/g. Surface hardness was measured again and integrated loss of subsurface hardness and fluoride concentration in enamel were calculated. Parametric and correlation tests were used to determine difference (p<0.05) and dose-response relationship between treatments. The addition of Cacit and TMP did not provide a higher fluoride concentration in enamel, however it reduced (p<0.05) mineral loss when compared to other dentifrices; the dentifrice with Cacit and TMP and a low fluoride concentration presented similar results when compared to a dentifrice with 1,100 mg F/g (p>0.05). Dentifrices with 450 and 1,000 µg F/g, Cacit and TMP were as effective as a gold standard one.


Short-term practice effects in mild cognitive impairment: Evaluating different methods of change.
Practice effects are improvements on cognitive tests as a result of repeated exposure to testing material. However, variability exists in the literature about whether patients with amnestic mild cognitive impairment (MCI) display practice effects, which may be partially due to the methods used to calculate these changes on repeated tests. The purpose of the current study was to examine multiple methods of assessing short-term practice effects in 58 older adults with MCI. The cognitive battery, which included tests of memory (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised) and processing speed (Symbol Digit Modalities Test and Trail Making Test Parts A and B), was administered twice across one week. Dependent t tests showed statistically significant improvement on memory scores (ps < .01, ds = 0.8-1.3), but not on processing speed scores. Despite this, the sample showed no clinically meaningful improvement on any cognitive scores using three different reliable change indices. Regression-based change scores did identify relatively large groups of participants who showed smaller than expected practice effects, which may indicate that this method is more sensitive in identifying individuals who may portend a declining trajectory. Practice effects remain a complex construct, worthy of continued investigation in diverse clinical conditions.


Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.
Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.


Bmi1 is critical to prevent Ikaros-mediated lymphoid priming in hematopoietic stem cells.
Preservation of hematopoietic hierarchy requires a constant and reciprocal interplay between chromatin-specific epigenetic regulators and lineage-modifying transcription factors. The polycomb member Bmi1 is a key factor in hematopoietic stem cell (HSC) maintenance, but its specific physiological role in subsequent hematopoietic lineage-specific commitments is unclear. Here, we generated conditional Bmi1 knockout (Bmi1-KO) mice. Selective ablation of Bmi1 in the hematopoietic system induced extensive upregulation of Ikaros and concomitant Ikaros-dependent lymphoid-lineage transcriptional priming, which is marked by their loss of H2A ubiquitination and increased H3K4 trimethylation in Bmi1-KO long-term HSCs (LT-HSCs). Removal of Ikaros in Bmi1-null LT-HSCs significantly diminished the hematopoietic defects seen in conditional Bmi1-KO mice. These alterations resulted in recovering the Bmi1-KO exhausted quiescent stem-cell pool, whereas the block in Bmi1-KO lymphoid-progenitor differentiation was rescued, allowing the development of mature lymphoid cells. Together, our results indicate that Ikaros is a critical Bmi1 target in vivo that prevents premature lineage specification of HSCs.


Blood volume analysis can distinguish true anemia from hemodilution in critically ill patients.
Peripheral hematocrit (pHct) is traditionally used as a marker for blood loss. In critically ill patients who are fluid resuscitated, pHct may not adequately represent red blood cell volume (RBCV). We hypothesize that the use of pHct alone may overestimate anemia, potentially leading to unnecessary interventions. Patients admitted to the intensive care unit underwent blood volume analysis. Serial blood samples were collected after injection of I-albumin. Samples were then processed by the Blood Volume Analyzer-100. RBCV and total blood volume (TBV) were calculated using the directly measured plasma volume (PV) and pHct. A computed normalized hematocrit (nHct) adjusts pHct to the patient's ideal blood volume. Thirty-six patients (21 men), aged 49.8 years ± 18.4 years, Acute Physiology And Chronic Health Evaluation II score 14.9 ± 8.1, and injury severity score 29.4 ± 12.4 had 84 blood volume analyses performed on 3 consecutive days. Using ratios of TBV compared with ideal TBV, patients were stratified into three separate groups: hypovolemic (16 of 84), normovolemic (23 of 84), and hypervolemic (45 of 84). Mean differences between pHct and nHct in each group were 4.5% ± 3.1% (p≤0.01), 0.0% ± 1.2% (p=0.85), and -6.5% ± 4.1% (p≤0.01), respectively. pHct, when compared with nHct, diagnosed anemia (Hct <30) nearly equal within the hypovolemic and normovolemic groups. However, pHct overdiagnosed anemia in 46.7% of hypervolemic patients. Use of blood volume analysis in critically ill patients may help to distinguish true anemia from hemodilution, potentially preventing unnecessary interventions.


Abnormal Gesture Perception and Clinical High-Risk for Psychosis.
Individuals diagnosed with psychotic disorders exhibit abnormalities in the perception of expressive behaviors, which are linked to symptoms and visual information processing domains. Specifically, literature suggests these groups have difficulties perceiving gestures that accompany speech. While our understanding of gesture perception in psychotic disorders is growing, gesture perception abnormalities and clues about potential causes and consequences among individuals meeting criteria for a clinical high-risk (CHR) syndrome is limited. Presently, 29 individuals with a CHR syndrome and 32 healthy controls completed an eye-tracking gesture perception paradigm. In this task, participants viewed an actor using abstract and literal gestures while presenting a story and eye gaze data (eg, fixation counts and total fixation time) was collected. Furthermore, relationships between fixation variables and both symptoms (positive, negative, anxiety, and depression) and measures of visual information processing (working memory and attention) were examined. Findings revealed that the CHR group gazed at abstract gestures fewer times than the control group. When individuals in the CHR group did gaze at abstract gestures, on average, they spent significantly less time fixating compared to controls. Furthermore, reduced fixation (ie, count and time) was related to depression and slower response time on an attentional task. While a similar pattern of group differences in the same direction appeared for literal gestures, the effect was not significant. These data highlight the importance of integrating gesture perception abnormalities into vulnerability models of psychosis and inform the development of targeted treatments for social communicative deficits.


Silencing of GLUT-1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia.
During tumor development, cells are exposed to a hypoxic microenvironment. Tumor hypoxia also has a profound influence on the sensitivity of cancer chemotherapy. The objective of this study was to investigate the mechanism of cisplatin (CDDP) resistance of oral squamous cell carcinoma (OSCC) cells under hypoxia by analyzing gene expression profiles to identify key genes and factors involved. Cell viability was measured following culture of the cells in the presence or absence of CDDP, under normoxic or hypoxic conditions, using a CCK-8 assay. Analysis of the expression of HIF target genes in hypoxia-treated cells was performed using an HIF-regulated cDNA plate array. Changes in the mRNA expression of selected HIF target genes were analyzed using RT-PCR, and changes in the protein levels of these genes were analyzed by Western blotting. Tumor cell apoptosis was assessed by flow cytometry. The OSCC cell lines responded differently to CDDP under normoxic and hypoxic conditions. The expression of glucose transporter protein-1 (GLUT-1) was up-regulated in human squamous cell carcinoma of mouth (HSC-2) cells under hypoxia. Furthermore, there was little correlation between the cisplatin sensitivity of human squamous cell carcinoma of tongue (SAS) in normoxia and hypoxia. After GLUT-1 knockdown, CDDP treatment resulted in increased rates of apoptosis under hypoxia as compared with normoxia in cell lines HSC-2, Ca9-22, and SAS (P = 0.025). The results of this study suggest that knockdown of GLUT-1 inhibits sensitization of oral squamous cells to CDDP during hypoxia in HSC-2, Ca9-22, and SAS cells.


Etiologic factors in lead nephropathy.
The rare occurrence of lead nephropathy in widely differing circumstances has suggested that additional causative factors might be required for its production. Seventeen cases of interstitial nephritis associated with severe chronic lead poisoning were reviewed in an attempt to identify these. Data suggested that alcoholism and preexistent hypertension, and also previous or minor urinary tract disease, may potentiate the injurious effects of lead. We recommend that the diagnosis of lead nephropathy should be a positive one, not one of exclusion, and that stored lead should be removed, particularly in persons with hypertension or previous urinary tract diseases.


Master-Leader-Slave Cuckoo Search with Parameter Control for ANN Optimization and Its Real-World Application to Water Quality Prediction.
Artificial neural networks (ANNs) have been employed to solve a broad variety of tasks. The selection of an ANN model with appropriate weights is important in achieving accurate results. This paper presents an optimization strategy for ANN model selection based on the cuckoo search (CS) algorithm, which is rooted in the obligate brood parasitic actions of some cuckoo species. In order to enhance the convergence ability of basic CS, some modifications are proposed. The fraction Pa of the n nests replaced by new nests is a fixed parameter in basic CS. As the selection of Pa is a challenging issue and has a direct effect on exploration and therefore on convergence ability, in this work the Pa is set to a maximum value at initialization to achieve more exploration in early iterations and it is decreased during the search to achieve more exploitation in later iterations until it reaches the minimum value in the final iteration. In addition, a novel master-leader-slave multi-population strategy is used where the slaves employ the best fitness function among all slaves, which is selected by the leader under a certain condition. This fitness function is used for subsequent Lévy flights. In each iteration a copy of the best solution of each slave is migrated to the master and then the best solution is found by the master. The method is tested on benchmark classification and time series prediction problems and the statistical analysis proves the ability of the method. This method is also applied to a real-world water quality prediction problem with promising results.


[Effectiveness of maintenance azathioprine therapy without oral cyclosporine after severe attacks of ulcerative colitis refractory to endovenous steroids].
Intravenous (i.v.) cyclosporine (CsA) has proved effective in controlling acute attacks of ulcerative colitis unresponsive to IV steroids. After the initial response to i.v. CsA, two alternatives for maintaining remission have been proposed: either double or triple association with immunosuppressors. The aim of this study was to evaluate the effectiveness of i.v. CsA, its adverse effects, and the subsequent long-term effectiveness of azathioprine/6-mercaptopurine without oral CsA. Intravenous CsA was administered for 10 days, at a dose of 4 mg/kg per day, to 20 patients diagnosed with a severe attack of ulcerative colitis who did not respond to IV steroid treatment. Patients who responded to CsA and could be discharged were administered azathioprine or 6-mercaptopurine associated with a decreasing dose of oral steroids, without oral CsA. Sixty per cent (12/20) of the patients showed clinical-biological improvement after CsA administration, thus avoiding colectomy, and were discharged from hospital. Nine of the 12 responders (three withdrew from the study) were followed-up long term. Of these nine patients, four (44.4%) underwent colectomy, all before the sixth month of discharge. All adverse effects were mild, except for one death. Intravenous CsA is effective in inducing remission of ulcerative colitis in severe attacks resistant to i.v. steroids. When treatment with azathioprine is administered without oral CsA, patients requiring colectomy need this procedure within the first 6 months of discharge.


The risks of using the chi-square periodogram to estimate the period of biological rhythms.
The chi-square periodogram (CSP), developed over 40 years ago, continues to be one of the most popular methods to estimate the period of circadian (circa 24-h) rhythms. Previous work has indicated the CSP is sometimes less accurate than other methods, but understanding of why and under what conditions remains incomplete. Using simulated rhythmic time-courses, we found that the CSP is prone to underestimating the period in a manner that depends on the true period and the length of the time-course. This underestimation bias is most severe in short time-courses (e.g., 3 days), but is also visible in longer simulated time-courses (e.g., 12 days) and in experimental time-courses of mouse wheel-running and ex vivo bioluminescence. We traced the source of the bias to discontinuities in the periodogram that are related to the number of time-points the CSP uses to calculate the observed variance for a given test period. By revising the calculation to avoid discontinuities, we developed a new version, the greedy CSP, that shows reduced bias and improved accuracy. Nonetheless, even the greedy CSP tended to be less accurate on our simulated time-courses than an alternative method, namely the Lomb-Scargle periodogram. Thus, although our study describes a major improvement to a classic method, it also suggests that users should generally avoid the CSP when estimating the period of biological rhythms.


Gene therapy for carcinoma of the breast: Genetic immunotherapy.
Advances in gene transfer technology have greatly expanded the opportunities for developing immunotherapy strategies for breast carcinoma. Genetic immunotherapy approaches include the transfer of genes encoding cytokines and costimulatory molecules to modulate immune function, as well as genetic immunization strategies which rely on the delivery of cloned tumor antigens. Improved gene transfer vectors, coupled with a better understanding of the processes that are necessary to elicit an immune response and an expanding number of target breast tumor antigens, have led to renewed enthusiasm that effective immunotherapy may be achieved. It is likely that immunotherapeutic interventions will find their greatest clinical application as adjuvants to traditional first-line therapies, targeting micrometastatic disease and thereby reducing the risk of cancer recurrence.


Pattern of prenatal care and infant immunization status in a comprehensive adolescent-oriented maternity program.
To examine the relationship between patterns of prenatal care utilization and the subsequent pattern of preventive infant health care utilization among patients in a comprehensive, multidisciplinary, adolescent-oriented maternity program. We hypothesized that the mothers of incompletely immunized 8-month-olds were less compliant with their own prenatal care appointments than were mothers of fully immunized 8-month-olds. We retrospectively reviewed the medical records of 150 consecutively delivered infants and their adolescent mothers. Data concerning the pattern of prenatal and postnatal use of preventive health care services and potentially confounding maternal characteristics were collected. Of the 150 infants aged 8 months, 22 (14.7%) were incompletely immunized. Mothers of completely and incompletely immunized infants did not differ in age, school enrollment status, or compliance with prenatal appointments. However, the latter group initiated prenatal care later, obtained fewer prenatal visits, returned later for postpartum care, and were more likely to be black and to report inadequate family support after delivery. Three of the 5 characteristics entered a logistic regression function that predicted the risk of incomplete immunizations at 8 months of age: third-trimester initiation of prenatal care (odds ratio, 4.05; 95% confidence interval, 1.19-13.7), inadequate family support (odds ratio, 3.42; 95% confidence interval, 1.17-10.0), and black race (odds ratio, 3.14; 95% confidence interval, 1.19-8.69). The total model chi 2 was 15.8 (P < .001). Among patients in a comprehensive adolescent-oriented maternity program, the timing of the first prenatal visit helps to identify infants who are at increased risk for incomplete primary immunization status. Our findings favor preferential allocation of scarce, costly outreach services to infants born to adolescent mothers who enter prenatal care during the third trimester.


Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.
Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid β (Aβ) biomarker for central nervous system amyloid deposition. We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aβ38, Aβ40, and Aβ42 in human plasma. Aβ isoforms have a half-life of approximately 3 hours in plasma. Aβ38 demonstrated faster turnover kinetics compared with Aβ40 and Aβ42. Faster fractional turnover of Aβ42 relative to Aβ40 and lower Aβ42 and Aβ42/Aβ40 concentrations in amyloid-positive participants were observed. Blood plasma Aβ42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aβ. The stability and sensitivity of plasma Aβ measurements suggest this may be a useful screening test for central nervous system amyloidosis.


Cost-Effectiveness of Primary and Revision Surgery for Adult Spinal Deformity.
Retrospective comparative study. The purpose of this study is to compare functional outcomes, hospital resource utilization, and spine-related costs during 2 years in patients who had undergone primary or revision surgery for adult spinal deformity (ASD). After surgery for ASD, patients may require revision for pseudarthrosis, implant complications, or deformity progression. Data evaluating cost-effectiveness of primary and, in particular, revision surgery, for ASD are sparse. We retrospectively reviewed records for 119 consecutive patients who had undergone primary or revision surgery for ASD. Two-year total spine-related medical costs were derived from hospital charge data. Functional outcome scores were extracted from prospectively collected patient data. Cost utility ratios (cost/quality-adjusted life-year [QALY]) at 2 years were calculated and assessed against a threshold of $154,458/QALY gained (three times the 2015 US per-capita gross domestic product). The primary surgery cohort (n = 56) and revision cohort (n = 63) showed significant improvements in health-related quality-of-life scores at 2 years. Median surgical and spine-related 2-year follow-up costs were $137,990 (interquartile range [IQR], $84,186) for primary surgery and $115,509 (IQR, $63,753) for revision surgery and were not significantly different between the two groups (P = 0.12). We report 2-year QALY gains of 0.36 in the primary surgery cohort and 0.40 in the revision group (P = 0.71). Primary instrumented fusion was associated with a median 2-year cost per QALY of $197,809 (IQR, $187,350) versus $129,950 (IQR, $209,928) for revision surgery (P = 0.31). Revision surgery had lower total 2-year costs and higher QALY gains than primary surgery for ASD, although the differences were not significant. Although revision surgery for ASD is known to be technically challenging and to have a higher rate of major complications than primary surgery, revision surgery was cost-effective at 2 years. The cost/QALY ratio for primary surgery for ASD exceeded the threshold for cost effectiveness at 2 years. 3.


Instability-associated changes in contact stress and contact stress rates near a step-off incongruity.
Intra-articular fractures can result in articular surface incongruity and joint instability, both of which can lead to posttraumatic osteoarthritis. The purpose of this study was to quantify changes in contact stresses and contact stress rates in incongruous human cadaveric ankles that were either stable or unstable. It was hypothesized that joint instability, superimposed on articular incongruity, would cause significant increases in contact stresses and contact stress rates. Intact human cadaveric ankles were subjected to quasi-physiologic stance-phase motion and loading, and instantaneous contact stresses were captured at 132 Hz. The anterior one-third of the distal part of the tibia was displaced proximally by 2.0 mm, and testing was repeated. Anterior/posterior forces were modulated during loading to cause incongruous ankles to either remain stable or become unstable during loading. Transient contact stresses and contact stress rates were measured for seven ankles under intact, stable-incongruous, and unstable-incongruous conditions. Peak and 95th percentile values of contact stress and contact stress rates for all three conditions were compared to determine the pathomechanical effects of incongruity and instability. The addition of instability caused 95th percentile and peak contact stresses to increase approximately between 20% and 25% in the unstable-incongruous specimens compared with the stable-incongruous specimens. In contrast, the addition of instability increased the magnitude of peak positive and peak negative contact stress rates by 115% and 170% in the unstable-incongruous specimens compared with the stable-incongruous specimens. Similarly, the 95th percentile contact stress rates increased 112% in the unstable-incongruous specimens compared with the stable-incongruous specimens. In human cadaveric ankles, instability superimposed on an existing articular surface incongruity causes disproportionate increases in contact stress rates compared with the increases in contact stresses.


DNA capping agent control of electron transfer from silver nanoparticles.
Silver nanoparticles capped with either DNA or citrate are investigated electrochemically using stripping voltammetry and nano-impacts. Whilst the citrate capped particles are readily oxidised to silver cations at 0.7 V, the DNA capped particles undergo electron transfer from the silver core to the electrode in two distinct potential ranges -0.8 to 1.1 V and 1.125 to 1.2 V, and only undergo complete oxidation at the higher potential range. These potentials reflect the oxidation of guanine and adenine respectively, with a potential sufficient to oxidise both base pairs being necessary to observe full silver oxidation. The DNA thus serves as a tunnelling barrier to electrically insulate the particle, and allows for selective oxidation to occur by controlling the potential applied.


A community-based approach to evaluation of health outcomes and costs for telepsychiatry in a rural population: preliminary results.
A pilot trial was established to support visiting psychiatric services and local public and private practitioners through the use of videoconferencing. The purpose of the trial was to determine whether people in the community received better health-care with telemedicine. A community-based approach was used to evaluate health outcomes, costs, utilization, accessibility, quality and needs for such services in a rural community in Queensland. Over a two-year period data were collected from 124 subjects who met the criteria of having a mental health problem or mental disorder. Nine further subjects refused to participate in the study. Only 32 subjects used videoconferencing to receive mental health services. Preliminary results did not show any significant improvements in wellbeing or quality of life, although the time span was relatively short. However, the results confirmed that the people were no worse off from a consumer or a practitioner perspective from using videoconferencing. Most consumers found that videoconferencing with a psychiatrist moderately or greatly helped them in managing their treatment, with 98% of them preferring to be offered videoconferencing in combination with local services. Overall, videoconferencing is a crucial part of enhancing psychiatry services in rural areas. However, it is not necessarily cost-effective for all consumers, general practitioners, psychiatrists, or the public mental health service.


A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease.
To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy). We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center. In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation.


Reveal the relationship between the quality and the cuticle composition of Satsuma mandarin (Citrus unshiu) by postharvest heat treatment.
To investigate the influence of heat treatment (HT) on Satsuma mandarin fruit's postharvest quality and cuticle composition, we immersed the fruit for 3 min in hot water at 52°C and subsequently stored them at room temperature (25°C) for 28 days, and fruit quality parameters, such as good fruit rate, weight loss rate, firmness, total soluble solids, total titratable acidity, and ascorbic acid content, were monitored. Additionally, changes in the peel's cuticle composition were analyzed, and wax crystal morphologies on the fruit surface were examined using scanning electron microscopy (SEM). The findings revealed that appropriate HT effectively preserved fruit quality. The main compositions of wax and cutin on the fruit's surface remained consistent between the HT and the CK during storage. The total content of wax and cutin initially increased, peaking on the 14th day of storage, and then decreased, falling below the levels observed on day 0. Notably, the total amount of cutin in the HT group exceeded that of the control group. Specifically, ω-hydroxy fatty acids with mid-chain oxo groups and mid-oh-ω-hydroxy fatty acids constituted approximately 90% of the total cutin content. Moreover, the HT group exhibited higher (p < 0.05) total wax content in relation to the control. Fatty acids and alkanes were the predominant components, accounting for approximately 87.5% of the total wax. SEM analysis demonstrated that HT caused wax crystals to melt and redistribute, effectively filling wax gaps. It suggests that HT holds promising potential as a green, safe, and eco-friendly commercial treatment for preserving the postharvest quality of Satsuma mandarin. PRACTICAL APPLICATION: In this study, Satsuma citrus (Citrus unshiu) underwent heat treatment (HT) and was subsequently preserved at room temperature (25°C) for 28 days. The findings revealed that HT significantly improved fruit quality compared to the control group. These findings provide valuable insights into the advancement of eco-friendly and pollution-free citrus preservation methods, offering essential strategies and process parameters for their practical application.


Midinfrared broadband achromatic astronomical beam combiner for nulling interferometry.
Integrated optic beam combiners offer many advantages over conventional bulk optic implementations for astronomical imaging. To our knowledge, integrated optic beam combiners have only been demonstrated at operating wavelengths below 4 μm. Operation in the midinfrared wavelength region, however, is highly desirable. In this paper, a theoretical design technique based on three coupled waveguides is developed to achieve fully achromatic, broadband, polarization-insensitive, lossless beam combining. This design may make it possible to achieve the very deep broadband nulls needed for exoplanet searching.


Awareness about HIV infection among the paramedical staff in a tertiary care hospital in Delhi, India.
In India, acquired immunodeficiency syndrome (AIDS) is a growing epidemic involving all sections of the society. Health care personnel are at increased risk of acquiring blood borne diseases like AIDS, hepatitis, etc. We aimed to assess the level of awareness of HIV infection among the paramedical staff working in a tertiary care hospital. A total number of 207 paramedical staff were asked to complete a questionnaire covering the various aspects of HIV and AIDS which was then critically reviewed. We observed that 57.54% of the staff was aware of the different aspects of HIV infection. Our results highlighted that awareness regarding the different facets of HIV varied among the nurses, lab technicians and support staff. Transmission of blood borne infections through needle stick injury is a harsh reality involving health care personnel. There is an urgent need to teach basic knowledge about HIV infection among high-risk populations.


Burden of Clostridium difficile Infections in French Hospitals in 2014 From the National Health Insurance Perspective.
OBJECTIVE To describe the hospital stays of patients with Clostridium difficile infection (CDI) and to measure the hospitalization costs of CDI (as primary and secondary diagnoses) from the French national health insurance perspective DESIGN Burden of illness study SETTING All acute-care hospitals in France METHODS Data were extracted from the French national hospitalization database (PMSI) for patients covered by the national health insurance scheme in 2014. Hospitalizations were selected using the International Classification of Diseases, 10 th revision (ICD-10) code for CDI. Hospital stays with CDI as the primary diagnosis or the secondary diagnosis (comorbidity) were studied for the following parameters: patient sociodemographic characteristics, mortality, length of stay (LOS), and related costs. A retrospective case-control analysis was performed on stays with CDI as the secondary diagnosis to assess the impact of CDI on the LOS and costs. RESULTS Overall, 5,834 hospital stays with CDI as the primary diagnosis were included in this study. The total national insurance costs were €30.7 million (US $33,677,439), and the mean cost per hospital stay was €5,267±€3,645 (US $5,777±$3,998). In total, 10,265 stays were reported with CDI as the secondary diagnosis. The total national insurance additional costs attributable to CDI were estimated to be €85 million (US $93,243,725), and the mean additional cost attributable to CDI per hospital stay was €8,295±€17,163, median, €4,797 (US $9,099±$8,827; median, $5,262). CONCLUSION CDI has a high clinical and economic burden in the hospital, and it represents a major cost for national health insurance. When detected as a comorbidity, CDI was significantly associated with increased LOS and economic burden. Preventive approaches should be implemented to avoid CDIs. Infect Control Hosp Epidemiol 2017;38:906-911.


Disseminated High-grade Glioma in a Long-term Survivor of Medulloblastoma: Implications and Management of Radiation-induced Malignancies.
We describe a gentleman diagnosed with a posterior fossa medulloblastoma in 1998, successfully treated with craniospinal radiation therapy (RT) and posterior fossa RT boost, followed by 12 months of adjuvant chemotherapy. Nineteen years later, at the age of 28, the patient presented with multiple cranial neuropathies and was found to have disseminated high-grade glioma with leptomeningeal dissemination. In addition to the salient features of this case, we provide a brief review of RT-induced malignancies and the need for further research regarding surveillance and prevention strategies.


Engaging older people to explore the age-friendliness of a rural community in Northern England: A photo-elicitation study.
An ageing society brings with it increased health costs due to the prevalence of long term conditions increasing with age. It is therefore vital to support good health in older people, both to improve their quality of life and to reduce the financial implications of an ageing society. Isolation and loneliness can put people at risk of dying early, and increasing opportunities for social interaction and engagement could mitigate some of the health effects of ageing. However, this requires society to create the conditions that enable older people to participate fully. The World Health Organization's Age-Friendly Cities programme has identified factors that make urban areas Age-Friendly, but research shows that older rural dwellers have unique unmet needs preventing full engagement in their communities. This article describes a pilot project which adapted photo-elicitation to explore the age-friendliness of a rural area in Calderdale, Northern England. It shows that photo-elicitation is a successful method for identifying what older people think is important in making their community age-friendly and it reveals differences between ageing in a city and in a rural setting. This rich data can be used to inform the development of policy in rural areas which is more closely aligned to the needs, preferences and interests of the growing population of older residents. The project also demonstrates the engagement potential of this methodology. Participants continued as co-researchers, learning new skills and taking responsibility for a variety of dissemination activities such as photographic exhibitions, a public report and presentations. This suggests that adapted photo-elicitation is a useful tool for engaging older people in research.


Mannan endo-1,4-β-mannosidase from Kitasatospora sp. isolated in Indonesia and its potential for production of mannooligosaccharides from mannan polymers.
Mannan endo-1,4-β-mannosidase (commonly known as β-mannanase) catalyzes a random cleavage of the β-D-1,4-mannopyranosyl linkage in mannan polymers. The enzyme has been utilized in biofuel production from lignocellulose biomass, as well as in production of mannooligosaccharides (MOS) for applications in feed and food industries. We aimed to obtain a β-mannanase, for such mannan polymer utilization, from actinomycetes strains isolated in Indonesia. Strains exhibiting high mannanase activity were screened, and one strain belonging to the genus Kitasatospora was selected. We obtained a β-mannanase from this strain, and an amino acid sequence of this Kitasatospora β-mannanase showed a 58-71% similarity with the amino acid sequences of Streptomyces β-mannanases. The Kitasatospora β-mannanase showed a significant level of activity (944 U/mg) against locust bean gum (0.5% w/v) and a potential for oligosaccharide production from various mannan polymers. The β-mannanase might be beneficial particularly in the enzymatic production of MOS for applications of mannan utilization.


Age and psychological influences on immune responses to trivalent inactivated influenza vaccine in the meditation or exercise for preventing acute respiratory infection (MEPARI) trial.
Strategies to improve influenza vaccine protection among elderly individuals are an important research priority. Mindfulness-based stress reduction (MBSR) and exercise have been shown to affect aspects of immune function in some populations. We hypothesized that influenza vaccine responses may be enhanced with meditation or exercise training as compared with controls. No differences in vaccine responses were found comparing control to MBSR or exercise. Individuals achieving seroprotective levels of influenza antibody ≥160 units had higher optimism, less anxiety, and lower perceived stress than the nonresponders. Age correlated with influenza antibody responses, but not with IFNγ or IL-10 production. The MBSR and exercise training evaluated in this study failed to enhance immune responses to influenza vaccine. However, optimism, perceived stress, and anxiety were correlated in the expected directions with antibody responses to influenza vaccine. Healthy individuals≥50 y were randomly assigned to exercise (n=47) or MBSR (n=51) training or a waitlist control condition (n=51). Each participant received trivalent inactivated influenza vaccine after 6 weeks, and had blood draws prior to and 3 and 12 weeks after immunization. Serum influenza antibody, nasal immunoglobulin A, and peripheral blood mononuclear cell interferon-γ (IFNγ) and interleukin-10 (IL-10) concentrations were measured. Measures of optimism, perceived stress, and anxiety were obtained over the course of the study. Seroprotection was defined as an influenza antibody concentration≥160 units. Vaccine responses were compared using ANOVA, t tests, and Kruskal-Wallis tests. The correlation between vaccine responses and age was examined with the Pearson test.


Context-dependent genetic architecture of Drosophila life span.
Understanding the genetic basis of variation in life span is a major challenge that is difficult to address in human populations. Evolutionary theory predicts that alleles affecting natural variation in life span will have properties that enable them to persist in populations at intermediate frequencies, such as late-life-specific deleterious effects, antagonistic pleiotropic effects on early and late-age fitness components, and/or sex- and environment-specific or antagonistic effects. Here, we quantified variation in life span in males and females reared in 3 thermal environments for the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and an advanced intercross outbred population derived from a subset of DGRP lines. Quantitative genetic analyses of life span and the micro-environmental variance of life span in the DGRP revealed significant genetic variance for both traits within each sex and environment, as well as significant genotype-by-sex interaction (GSI) and genotype-by-environment interaction (GEI). Genome-wide association (GWA) mapping in both populations implicates over 2,000 candidate genes with sex- and environment-specific or antagonistic pleiotropic allelic effects. Over 1,000 of these genes are associated with variation in life span in other D. melanogaster populations. We functionally assessed the effects of 15 candidate genes using RNA interference (RNAi): all affected life span and/or micro-environmental variance of life span in at least one sex and environment and exhibited sex-and environment-specific effects. Our results implicate novel candidate genes affecting life span and suggest that variation for life span may be maintained by variable allelic effects in heterogeneous environments.


Plasma atrial natriuretic peptide concentrations during exercise in sodium replete and deplete normal man.
To explore the effects of exercise on plasma atrial natriuretic peptide (ANP) concentrations, eight normotensive volunteers performed maximal treadmill exercise in sodium replete and deplete states. Baseline immunoreactive plasma ANP concentrations were significantly lower during sodium depletion. During exercise plasma ANP rose in all subjects on both occasions. Plasma peptide responses were attenuated by sodium depletion with peak exercise levels only double baseline values, in contrast to the threefold increase in ANP concentrations observed when subjects were sodium replete. Plasma renin and aldosterone concentrations also rose with exercise. In contrast to changes in plasma ANP, the responses of both were enhanced by sodium depletion.


[Morphogenetic characteristics of the mammary glands of autoimmune F1 mice (NZB x NZW)].
The morphogenesis of mammary glands was studied in the normal and autoimmune F1(NZW X NZB) mice. In the lactation cycle of the autoimmune mice the normal course of structural-functional rearrangements of parenchyma and stroma in the developing and involuting mammary glands was disturbed. A conclusion has been reached that the modification of stromal elements, first of all involved in the autoimmune disease, is the leading link in the abnormal development of mammary glands.


Prophylactic urokinase in the management of long-term venous access devices in children: a Children's Oncology Group study.
Infection and thrombosis are serious complications of long-term vascular access devices in children undergoing chemotherapy. Since routine fibrinolytic therapy may decrease these complications, the purpose of this study was to compare the efficacy of an every-2-week administration of urokinase with standard heparin flushes in reducing the incidence of device-related infections and occlusions. This study was a prospective, randomized phase III multicenter trial conducted by the Children's Cancer Group, in which patients with implantable ports or tunneled catheters received either urokinase or heparin every 2 weeks for 12 months. Study end points were time to first occlusion or time to first device-related infection. Five hundred seventy-seven patients from 29 institutions were enrolled, of whom 51% had external catheters and 49% had ports. Urokinase administration resulted in fewer occlusive events than heparin (23% v 31%; P =.02), a longer time to first occlusive event (log-rank analysis, P =.006), and a 1.6-fold difference in the rate of occlusive events (Poisson regression, P =.003). Similar results were noted when comparing ports and tunneled catheters. The urokinase group also had a 1.4-fold difference in the rate of infection (Poisson regression, P =.05) and longer time to first infection (log-rank, P =.07), but the difference was significant only in tunneled catheters. Urokinase administration every 2 weeks significantly affects the rate of occlusive events in ports and tunneled catheters and of infectious events in external catheters compared with heparin administration.


[Identification of cholesterol esters using topological criteria].
Cholesterol esters obtained from biological sources were separated using highly-effective liquid chromatography. Identification of individual molecular forms of these esters was carried out by means of linear correlation between the period of their retaining and the topological indices by Balaban and Randich, describing the structure of descriptors (acyl group) in cholesterol esters.


Palladium-Catalyzed Cross-Coupling of gem-Difluorocyclopropanes with gem-Diborylalkanes for the Synthesis of Boryl-Substituted Fluorinated Alkenes.
This study presents a novel method for the regioselective coupling of gem-difluorinated cyclopropanes with gem-diborylmethane, utilizing a Pd-catalyst system. This innovative approach enables the synthesis of 2-fluoroalkenyl monoboronate scaffolds with high Z-selectivity. The resulting products undergo further transformations, including oxidation, Suzuki cross-coupling, and trifluoroborylation, all of which are achieved with good yields. This work introduces a valuable synthetic pathway to access important fluorinated compounds for various applications in organic chemistry.


TEX14 interacts with CEP55 to block cell abscission.
In somatic cells, abscission, the physical separation of daughter cells at the completion of cytokinesis, requires CEP55, ALIX, and TSG101. In contrast, cytokinesis is arrested prior to abscission in differentiating male germ cells that are interconnected by TEX14-positive intercellular bridges. We have previously shown that targeted deletion of TEX14 disrupts intercellular bridges in all germ cells and causes male sterility. Although these findings demonstrate that intercellular bridges are essential for spermatogenesis, it remains to be shown how TEX14 and other proteins come together to prevent abscission and form stable intercellular bridges. Using a biochemical enrichment of male germ cell intercellular bridges, we identified additional bridge proteins, including CEP55. Although CEP55 is highly expressed in testes at the RNA level, there is no report of the presence of CEP55 in germ cells. We show here that CEP55 becomes a stable component of the intercellular bridge and that an evolutionarily conserved GPPX3Y motif of TEX14 binds strongly to CEP55 to block similar GPPX3Y motifs of ALIX and TSG101 from interacting and localizing to the midbody. Thus, TEX14 prevents the completion of cytokinesis by altering the destiny of CEP55 from a nidus for abscission to an integral component of the intercellular bridge.


A novel obesity locus on chromosome 4q: the Strong Heart Family Study.
Obesity is a growing and important public health problem in Western countries and worldwide. There is ample evidence that both environmental and genetic factors influence the risk of developing obesity. Although a number of genes influencing obesity and obesity-related measures have been localized, it is clear that others remain to be identified. The rate of obesity is particularly high in American Indian populations. This study reports the results of a genome-wide scan for loci influencing BMI and weight in 963 individuals in 58 families from three American Indian populations in Arizona, Oklahoma, and North and South Dakota participating in the Strong Heart Family Study. Short tandem repeat markers were genotyped, resulting in a marker map with an average spacing of 10 centimorgans. Standard multipoint variance component linkage methods were used. Significant evidence of linkage was observed in the overall sample, including all three study sites, for a locus on chromosome 4q35 [logarithm of the odds (LOD)=5.17 for weight, 5.08 for BMI]. Analyses of the three study sites individually showed that the greatest linkage support for the chromosome 4 locus came from Arizona (LOD=2.6 for BMI), but that LOD scores for weight were >1 in all three samples. Suggestive linkage signals (LOD>2) were also observed on chromosomes 5, 7, 8, and 10. The chromosome 4 locus detected in this scan is in a region lacking any obvious positional candidate genes with known functions related to obesity. This locus may represent a novel obesity gene.


[Comparative clinico-instrumental characteristics of different morphological variants of hypertrophic cardiomyopathy].
Six morphologic variants of hypertrophic cardiomyopathy (HCMP) have been identified on the basis of the echocardiographically-documented extent and localization of left-ventricular hypertrophy in 34 patients with HCMP. More than half of the patients had no complaints. The more characteristic echocardiographic features of the disease included a considerable thickening of one or more departments within the left ventricle, the size of its cavity being diminished. In most cases, HCMP was associated with considerably enlarged R waves on the electrocardiograms from 35 precordial leads that were usually combined with ST segment depression and T wave inversion. The latter two features often provided grounds for a hyperdiagnosis of coronary heart disease (CHD). What distinguishes HCMP from CHD is the discrepancy between marked and persistent pathologic electrocardiographic changes and a relatively uneventful clinical picture of the disease. The comparison of echocardiographic and ECG charting data allows a more detailed assessment of the kind of left-ventricular hypertrophy in HCMP patients, and can be used in the differential diagnosis of HCMP vs. CHD.