Relationship between porcine motilin-induced migrating motor complex-like activity, vagal integrity, and endogenous motilin release in dogs.
Both the vagus nerve and motilin have been implicated in the initiation of phase III of the fasting migrating motor complex. To investigate the contribution of each, the effects of intravenous porcine motilin, vagosympathetic nerve blockade, and atropine were assessed. Intralumenal pressures of the lower esophageal sphincter, stomach, and upper small intestine, and plasma motilin levels were monitored. Porcine and canine motilin in plasma were distinguished by radioimmunoassay using two different antibodies. Injection of porcine motilin (75-370 pmol), initiated dose-dependent phase III-like motor activity in the lower esophageal sphincter, stomach, and small bowel if the vagi were intact; if the vagi were blocked, activity was initiated in the small bowel only. Moreover , a significant (p less than 0.001), dose-dependent peak in canine plasma motilin was observed after the onset of the induced motor activity when the vagi were intact or blocked, with plasma motilin peaks comparable to those occurring spontaneously. In both intact and vagally blocked dogs, atropine abolished both the spontaneous motor activity and associated rise in motilin level, and also abolished porcine motilin-induced activity. However, a diminished, but significant (p less than 0.01) peak in porcine motilin-induced canine motilin persisted in the presence of atropine. These results in dogs indicate that while spontaneous phase II motility in the upper gastrointestinal tract and phase III activity in the lower esophageal sphincter and stomach are dependent on vagally mediated excitatory pathways, spontaneous and induced phase III motor activity in the small intestine are dependent on nonvagal cholinergic innervation. Canine motilin release induced by porcine motilin is mediated primarily by a nonvagal cholinergic (muscarinic) pathway, with minor contributions from vagal noncholinergic, and nonvagal noncholinergic mechanisms. Because spontaneous or induced motilin release peaks well after the onset of phase III motor activity, it is unlikely that motilin is the primary factor responsible for initiation of the migrating motor complex in the dog. Motilin may, however, modulate motility produced by preexisting neural excitation.


Non-Newtonian Flow to the Theoretical Strength of Glasses via Impact Nanoindentation at Room Temperature.
In many daily applications glasses are indispensable and novel applications demanding improved strength and crack resistance are appearing continuously. Up to now, the fundamental mechanical processes in glasses subjected to high strain rates at room temperature are largely unknown and thus guidelines for one of the major failure conditions of glass components are non-existent. Here, we elucidate this important regime for the first time using glasses ranging from a dense metallic glass to open fused silica by impact as well as quasi-static nanoindentation. We show that towards high strain rates, shear deformation becomes the dominant mechanism in all glasses accompanied by Non-Newtonian behaviour evident in a drop of viscosity with increasing rate covering eight orders of magnitude. All glasses converge to the same limit stress determined by the theoretical hardness, thus giving the first experimental and quantitative evidence that Non-Newtonian shear flow occurs at the theoretical strength at room temperature.


Role of bevacizumab for the treatment of non-small-cell lung cancer.
Advanced-stage non-small-cell lung cancer (NSCLC) is a lethal disease that is treated with combination chemotherapy. Although modest survival benefit has been documented with various platinum-based, two-drug combination chemotherapy regimens, an efficacy plateau has been reached. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, is the first molecularly targeted agent that has demonstrated survival advantage when combined with chemotherapy for the treatment of advanced nonsquamous NSCLC. Improvements in all efficacy parameters, including response rate, progression-free survival and overall survival, were noted for advanced nonsquamous NSCLC patients when bevacizumab was added to the combination of carboplatin-paclitaxel compared with the same chemotherapy regimen alone. This has opened the door for expanding the role of bevacizumab in earlier stages of the disease with chemotherapy or radiotherapy. The anti-angiogenesis agents, including the monoclonal antibody and vascular endothelial growth factor tyrosine kinase inhibitors, will be among the most important drugs of the present decade. This article discusses the recent data with bevacizumab in NSCLC and its potential application at various stages of NSCLC.


Monoclonal antibodies against chicken type V collagen: production, specificity, and use for immunocytochemical localization in embryonic cornea and other organs.
Two monoclonal antibodies have been produced against chick type V collagen and shown to be highly specific for separate, conformational dependent determinants within this molecule. When used for immunocytochemical tissue localization, these antibodies show that a major site for the in situ deposition of type V is within the extracellular matrices of many dense connective tissues. In these, however, it is largely in a form unavailable to the antibodies, thus requiring a specific "unmasking" treatment to obtain successful immunocytochemical staining. The specificity of these two IgG antibodies was determined by inhibition ELISA, in which only type V and no other known collagen shows inhibition. In ELISA, mixtures of the two antibodies give an additive binding reaction to the collagen, suggesting that each is against a different antigenic determinant. That both antigenic determinants are conformational dependent, being either in, or closely associated with, the collagen helix is demonstrated by the loss of antibody binding to molecules that have been thermally denatured. The temperature at which this occurs, as assayed by inhibition ELISA, is very similar to that at which the collagen helix melts, as determined by optical rotation. This gives strong additional evidence that the antibodies are directed against the collagen. The antibodies were used for indirect immunofluorescence analyses of cryostat sections of corneas and other organs from 17 to 18-day-old chick embryos. Of all tissues examined only Bowman's membrane gave a strong staining reaction with cryostat sections of unfixed material. Staining in other areas of the cornea and in other tissues was very light or nonexistent. When, however, sections were pretreated with pepsin dissolved in dilute HAc or, surprisingly, with the dilute HAc itself dramatic new staining by the antibodies was observed in most tissues examined. The staining, which was specific for the anti-type V collagen antibodies, was largely confined to extracellular matrices of dense connective tissues. Experiments using protease inhibitors suggested that the "unmasking" did not involve proteolysis. We do not yet know the mechanism of this unmasking; however, one possibility is that the dilute acid causes swelling or conformational changes in a type-V collagen-containing supramolecular structure. Further studies should allow us to determine whether this is the case.


A limited role of NKCC1 in telencephalic glutamatergic neurons for developing hippocampal network dynamics and behavior.
NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of γ-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.


Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development.
Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.


Treatment of myelodysplastic syndromes: practical tools for effective management.
Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies with variability in clinical presentation, disease trajectory, treatment goals, and expected outcomes. The treatment of patients with MDS, therefore, often differs from patient to patient. Tools are needed to aid effective communication with patients, their caregivers, and their dedicated team of healthcare professionals. The use of methods often employed in clinical trials can help healthcare providers diagnose and classify risk status, track trends within patient responses, manage adverse events, set treatment expectations, and provide ongoing supportive care. This article discusses several tools and strategies available for the management of patients with MDS throughout the continuum of their disease.


Gut microbiota in alcohol-related liver disease: pathophysiology and gut-brain cross talk.
Alcohol-related liver disease (ALD) from excessive alcohol intake has a unique gut microbiota profile. The disease progression-free survival in ALD patients has been associated with the degree of gut dysbiosis. The vicious cycles between gut dysbiosis and the disease progression in ALD including: an increase of acetaldehyde production and bile acid secretion, impaired gut barrier, enrichment of circulating microbiota, toxicities of microbiota metabolites, a cascade of pro-inflammatory chemokines or cytokines, and augmentation in the generation of reactive oxygen species. The aforementioned pathophysiology process plays an important role in different disease stages with a spectrum of alcohol hepatitis, ALD cirrhosis, neurological dysfunction, and hepatocellular carcinoma. This review aims to illustrate the pathophysiology of gut microbiota and clarify the gut-brain crosstalk in ALD, which may provide the opportunity of identifying target points for future therapeutic intervention in ALD.


[CTPA in suspected pulmonary embolism: diagnostic strategy].
De Bruin and colleagues recently analysed the performance of the CTPA scan in patients with suspected pulmonary embolism. Their study shows that in a significant number of patients no abnormalities were found on a CTPA scan, a troubling finding given the radiation exposure. Young patients and ambulatory patients, in particular, often had a completely normal CTPA scan. Better stratification of patients with a high suspicion of pulmonary embolism is required, including evaluation of the value of clinical decision rules in ambulatory patients with suspected pulmonary embolism. In addition, the use of perfusion scanning, which involves significantly less radiation exposure, deserves further research in young people. Principally, a diagnostic strategy for pulmonary embolism comprising a clinical decision rule, followed by a D-dimer test if necessary, should be applied in clinical practice. This strategy will significantly reduce the number of CTPA scans showing no pulmonary embolism.


Limbic system dysrhythmia: a diagnostic electroencephalogram procedure utilizing procaine activation.
A diagnostic method is presented that makes it possible to distinguish patients who are most likely to show a positive response to treatment with anticonvulsant medication, thereby cutting across many DSM-III-R diagnoses. Patients are evaluated to determine whether they exhibit at least 4 of 12 groups of symptoms, and the local anesthetic procaine is used, along with an electroencephalogram (EEG) to evaluate for omega band activity (30-50 Hz) of at least 50 microvolts or approximately three times baseline values in the anterior temporal leads. This method was studied in 145 patients with varying diagnoses. Eighty-three percent of patients who were symptom- and procaine-positive responded to anticonvulsants. Specific application to patients with attention-deficit hyperactivity disorder, bipolar disorder, and panic disorder is made. This method may provide a basis for identifying subpopulations of anticonvulsant-responsive patients who often are considered treatment-resistant.


Effects of diet containing extruded full-fat soybeans or butter on the growth, composition, and sensory characteristics of pork.
Ninety-six crossbred barrows were randomly allotted to five replications of four treatments to determine the effects of diets containing 20% extruded full-fat soybeans (FFS) or 4% butter (B) on the growth, composition, and sensory characteristics of finishing pigs. Pigs were housed five per pen, except for one replication that had four pigs per pen, in environmentally regulated barns. Pigs were given ad libitum access to a corn-soybean meal diet for 11 wk (control); a corn-extruded soybeans and soft wheat midds diet for 11 wk (FFS-11); a corn-soybean meal diet for 6 wk, changed to a corn-extruded soybeans and soft wheat midds diet for 5 wk (FFS-5); or a corn-soybean meal diet for 6 wk, changed to a corn-soybean meal, soft wheat midds, and 4% butter diet for 5 wk (B). Feed intake and weight gain were measured once every 2 wk. Pigs were slaughtered and carcass data were collected. Sensory characteristics (tenderness, juiciness, pork flavor intensity, off-flavor intensity, and overall acceptability), shear force, moisture, and fat content were determined for the longissimus muscle. Sensory characteristics (pork flavor, off-flavor, rubbery, cohesiveness, and juiciness) and 2- thiobarbituric acid values were determined for ground pork (30% fat) after 1, 4, and 7 d for control, FFS-11, and B treatments. No differences (P > .05) in ADG were observed between diets. Feed efficiency of the FFS-11 group was better (P < .05) than that of the control or B groups. No consistent differences were observed for carcass, sensory, or shear-force characteristics of the longissimus muscle or ground pork.(ABSTRACT TRUNCATED AT 250 WORDS)


Buttock Ischemia in Venoarterial Extracorporeal Membrane Oxygenation: A Case Series.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a bridging therapy for refractory cardiogenic shock, and limb ischemia is a concern with femoral cannulation. Because of the rich collateral pelvic circulatory supply, buttock ischemia is not common and is usually a complication after aneurysmal aortic repair or internal iliac artery embolization after pelvic trauma. Gluteal necrosis occurring as an extracorporeal membrane oxygenation complication has not been reported in the literature. In this case series, we report three patients with ischemic buttock after initiating VA-ECMO and discuss the risk factors and the clinical and radiological features supportive of the diagnosis. We review the gluteal and pelvic vascular anatomy, postulate how cannula size, ethnicity, catecholamines, and reversal of gluteal arterial flow contributed to this rare entity in our patients and explain how these findings have changed our institution's practice.


[The interrelationship between the inhibitory activity of milk with different types of beta-lactoglobulins and the resistance of cattle to mastitis].
In the course of the investigation of piebald (black-white) cattle it is found that 17,62% animals produce the AA type beta-lactoglobulin, 49,52%--the AB type and 32,86%--the BB type. The higher inhibitory activity of milk with the BB type beta-lactoglobulin was found which retained in dilution 1 : 32. The total flora of teat, cyst and parenchyma milk of animals with the BB type beta-lactoglobulin as well as Enterococcus bacteria were much lower than in milk of cows with the AA type homogenous form. The animals with the first type of milk protein had mastitis more rarely as compared to those with the second type. The animals with heterogenous form of beta-lactoglobulin had intermediate values in most of their characteristics.


Purification and immunochemical characteristics of NADPH-cytochrome P-450 oxidoreductase from tobacco cultured cells.
NADPH-cytochrome P-450 oxidoreductase (EC 22.214.171.124) was purified from the microsomal fraction of tobacco (Nicotiana tabacum) BY2 cells by chromatography on two anion-exchange columns and 2',5' ADP-Sepharose 4B column. The purified enzyme showed a single protein band with a molecular weight of 79 kDa on SDS-PAGE and exhibited a typical flavoprotein redox spectrum, indicating the presence of an equimolar quantity of FAD and FMN. This enzyme followed Michaelis-Menten Kinetics with Km values of 24 microM for NADPH and 16 microM for cytochrome c. An in vitro reconstituted system of the purified reductase with a partially purified tobacco cytochrome P-450 preparation showed the cinnamic acid 4-hydroxylase activity at the rate of 14 pmol min-1 nmol-1 P-450 protein and with a purified rabbit P-4502C14 catalyzed N-demethylation of aminopyrine at the rate of 6 pmol min-1 nmol-1 P-450 protein. Polyclonal antibodies raised against the purified reductase reacted with tobacco reductase but not with yeast reductase on Western blot analysis. Anti-yeast reductase antibodies did not react with the tobacco reductase. This result indicate that the tobacco reductase was immunochemically different from the yeast reductase. The anti-tobacco reductase antibodies totally inhibited the tobacco reductase activity, but not the yeast reductase. Also, Western blot analyses using the anti-tobacco reductase antibodies revealed that leaves, roots and shoots of Nicotiana tabacum plants contained an equal amount of the reductase protein. From these results, it was suggested that there are different antibody binding sites, which certainly participate in enzyme activity, between tobacco and yeast reductase.


Self-assembled near-infrared dye nanoparticles as a selective protein sensor by activation of a dormant fluorophore.
Design of selective sensors for a specific analyte in blood serum, which contains a large number of proteins, small molecules, and ions, is important in clinical diagnostics. While metal and polymeric nanoparticle conjugates have been used as sensors, small molecular assemblies have rarely been exploited for the selective sensing of a protein in blood serum. Herein we demonstrate how a nonspecific small molecular fluorescent dye can be empowered to form a selective protein sensor as illustrated with a thiol-sensitive near-IR squaraine (Sq) dye (λabs= 670 nm, λem= 700 nm). The dye self-assembles to form nonfluorescent nanoparticles (Dh = 200 nm) which selectively respond to human serum albumin (HSA) in the presence of other thiol-containing molecules and proteins by triggering a green fluorescence. This selective response of the dye nanoparticles allowed detection and quantification of HSA in blood serum with a sensitivity limit of 3 nM. Notably, the Sq dye in solution state is nonselective and responds to any thiol-containing proteins and small molecules. The sensing mechanism involves HSA specific controlled disassembly of the Sq nanoparticles to the molecular dye by a noncovalent binding process and its subsequent reaction with the thiol moiety of the protein, triggering the green emission of a dormant fluorophore present in the dye. This study demonstrates the power of a self-assembled small molecular fluorophore for protein sensing and is a simple chemical tool for the clinical diagnosis of blood serum.


Unique aspects of gene expression during Candida albicans mating and possible G(1) dependency.
Taking advantage of the high frequency of conjugation tube formation in mating mixtures and alpha-pheromone-treated a/a cells derived from saturation phase cultures of opaque cells of Candida albicans, 56 up-regulated and 30 down-regulated genes were identified employing microarray and Northern analyses. Combining these results with previous profiling studies of pheromone-induced cells, a more comprehensive transcript profile was developed for comparison with Saccharomyces cerevisiae. This comparison revealed the following: (i) that while a majority of mating-associated genes are regulated similarly between the two species, a significant minority are regulated dissimilarly; (ii) that filamentation genes are uniquely up-regulated and opaque-specific genes uniquely down-regulated during C. albicans mating; and (iii) that a newly identified class of genes is selectively down-regulated in opaque, but not white, cells that have entered saturation phase in a growth culture and then are up-regulated by pheromone. The observations that opaque cells are uniquely mating competent, that saturation phase facilitates mating, and that a newly identified group of genes is down-regulated only in opaque cells that have entered saturation phase led us to hypothesize that entering saturation phase may be requisite for mating. A test of this hypothesis revealed, however, that cells, whether in the exponential or saturation phase, may simply have to be in G(1) of the cell cycle to respond to pheromone and that the response includes G(1) arrest. These results add to the lists of similarities and dissimilarities between the mating processes of C. albicans and S. cerevisiae and underscore the unique regulation of filamentation and switching genes in the C. albicans mating process.


Physical Training Inhibits the Fibrosis Formation in Alzheimer's Disease Kidney Influencing the TGFβ Signaling Pathways.
Alzheimer's disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-β (Aβ) plaques in the kidney. Alterations of transforming growth factor β (TGFβ) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aβ. A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFβ signalization is involved in this effect. The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing wild type and AD organs. Alterations of canonical and non-canonical TGFβ signaling pathways were followed with PCR, western blot, and immunohistochemistry. Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFβ pathways in non-trained mice, while expression levels of signal molecules of both TGFβ pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AβPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFβ signaling plays a role in this phenomenon.


Should all patients with hyperparathyroidism be screened for a CDC73 mutation?
Primary hyperparathyroidism (PH) is a common endocrine abnormality and may occur as part of a genetic syndrome. Inactivating mutations of the tumour suppressor gene CDC73 have been identified as accounting for a large percentage of hyperparathyroidism-jaw tumour syndrome (HPT-JT) cases and to a lesser degree account for familial isolated hyperparathyroidism (FIHP) cases. Reports of CDC73 whole gene deletions are exceedingly rare. We report the case of a 39 year-old woman with PH secondary to a parathyroid adenoma associated with a large chromosomal deletion (2.5 Mb) encompassing the entire CDC73 gene detected years after parathyroidectomy. This case highlights the necessity to screen young patients with hyperparathyroidism for an underlying genetic aetiology. It also demonstrates that molecular testing for this disorder should contain techniques that can detect large deletions. Necessity of genetic screening for young people with hyperparathyroidism.Importance of screening for large, including whole gene CDC73 deletions.Surveillance for patients with CDC73 gene mutations includes regular calcium and parathyroid hormone levels, dental assessments and imaging for uterine and renal tumours.


Does Flexible Arterial Tubing Retain More Hemodynamic Energy During Pediatric Pulsatile Extracorporeal Life Support?
The objective of this study was to evaluate the hemodynamic performance and energy transmission of flexible arterial tubing as the arterial line in a simulated pediatric pulsatile extracorporeal life support (ECLS) system. The ECLS circuit consisted of a Medos Deltastream DP3 diagonal pump head, Medos Hilite 2400 LT oxygenator, Biomedicus arterial/venous cannula (10 Fr/14 Fr), 3 feet of polyvinyl chloride (PVC) arterial tubing or latex rubber arterial tubing, primed with lactated Ringer's solution and packed red blood cells (hematocrit 40%). Trials were conducted at flow rates of 300 to 1200 mL/min (300 mL/min increments) under nonpulsatile and pulsatile modes at 36°C using either PVC arterial tubing (PVC group) or latex rubber tubing (Latex group). Real-time pressure and flow data were recorded using a custom-based data acquisition system. Mean pressures and energy equivalent pressures (EEP) were the same under nonpulsatile mode between the two groups. Under pulsatile mode, EEPs were significantly great than mean pressure, especially in the Latex group (P < 0.05). There was no difference between the two groups with regards to pressure drops across ECLS circuit, but pulsatile flow created more pressure drops than nonpulsatile flow (P < 0.05). Surplus hemodynamic energy (SHE) levels were always higher in the Latex group than in the PVC group at all sites. Although total hemodynamic energy (THE) losses were higher under pulsatile mode compared to nonpulsatile mode, more THE was delivered to the pseudopatient, particularly in the Latex group (P < 0.05). The results showed that the flexible arterial tubing retained more hemodynamic energy passing through it under pulsatile mode while mean pressures and pressure drops across the ECLS circuit were similar between PVC and latex rubber arterial tubing. Further studies are warranted to verify our findings.


Misidentification of Vibrio cholerae O155 isolated from imported shrimp as O serogroup O139 due to cross-agglutination with commercial O139 antisera.
Fish and shellfish products imported into Denmark are routinely analyzed for pathogenic Vibrio spp., particularly Vibrio cholerae, if products originate from subtropical or tropical areas. A V. cholerae strain that agglutinated commercial O139 antiserum but not the O1, Inaba, or Ogawa antisera was isolated from imported raw frozen shrimp. The toxigenicity of the strain was analyzed, and the results of a polymerase chain reaction showed that the V. cholerae strain did not contain the virulence genes ctx, tcpA, and zot, which are normally found in V. cholerae O1 and O139. The strain was resistant to colistin and spectinomycin. The high susceptibility of the strain to antimicrobial agents was confirmed by the lack of an SXT element, a self-transmissible, chromosomal genetic element that is normally present in 0139 strains and encodes resistance to sulfonamides, trimethoprim, and streptomycin. The strain contained two plasmids, in contrast to other O139 strains, which normally do not contain plasmids. The characteristics of the strain led to further agglutination testing with other antisera that are not commercially available, and the strain was found to agglutinate O155 antiserum in repeated testing. Manufacturers of 0139 antiserum should be aware of the closely related O antigens of the O139, O22, and O155 serogroups and should be aware that their commercial diagnostic O139 antiserum must be absorbed to remove cross-reacting agglutinins of O22 and O155 strains.


Multidimensional Prognostic Index and pro-adrenomedullin plasma levels as mortality risk predictors in older patients hospitalized with community-acquired pneumonia: a prospective study.
To evaluate the prognostic accuracy of proadrenomedullin (proADM) in comparison with and in addition to the Multidimensional Prognostic Index (MPI), a validated predictive tool for mortality derived from a comprehensive geriatric assessment (CGA) to predict one-month mortality risk in older patients hospitalized with community-acquired pneumonia (CAP). All patients aged 65 years and older, consecutively admitted to an acute geriatric ward with a diagnosis of CAP from February to July 2012. At admission and at discharge they were submitted to a standard CGA in order to calculate MPI. Moreover, plasma samples were taken at baseline and after one, three and five days of hospitalization for the analysis of pro-ADM. Fifty patients (mean age 86.2±7.5 years), with 31 at high risk of mortality (MPI-3) were enrolled. ProADM and MPI, both at admission and at discharge, were significant predictor of mortality. As expected, MPI at admission showed lower predictive accuracy than MPI at discharge (survival C-statistic 0.667 vs. 0.851). The addition of proADM to the MPI at admission significantly increased accuracy in predicting one-month mortality (C-statistics from 0.667 to 0.731, P=0.018 at baseline; from 0.667 to 0.733, P=0.008 at 1 day; from 0.633 to 0.724; P=0.019 at 3 days; from 0.667 to 0.828; P=0.003 at 5 days). Conversely, adding pro-ADM to the MPI at discharge did not significantly improve the model's prognostic accuracy. ProADM may significantly improve the prognostic accuracy of the MPI at admission in hospitalized elderly patients with CAP.


Melatonin Improves Fatty Liver Syndrome by Inhibiting the Lipogenesis Pathway in Hamsters with High-Fat Diet-Induced Hyperlipidemia.
The aim of this study was to investigate the effect of melatonin on hepatic lipid metabolism in hamsters with high-fat diet (HFD)-induced dyslipidemia. Male Syrian hamsters were kept on either a chow control (C) or HFD for four weeks. After four weeks, animals fed the HFD were further randomly assigned to four groups: high-fat only (P), melatonin low-dosage (L), medium-dosage (M), and high-dosage (H) groups. The L, M, and H groups, respectively, received 10, 20, and 50 mg/kg/day of a melatonin solution, while the P and C groups received the ethanol vehicle. After eight weeks of the intervention, results showed that a low dose of melatonin significantly reduced HFD-induced hepatic cholesterol and triglycerides; decreased plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol; and increased plasma high-density lipoprotein cholesterol (p < 0.05). In addition, melatonin markedly decreased activities of the hepatic lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (p < 0.05), and elevated the relative hepatic carnitine palmitoyltransferase-1α expression in hamsters with HFD-induced hyperlipidemia. Consequently, melatonin reduced activities of the hepatic lipogenic enzymes, ACC and FAS. In summary, chronic melatonin administration improved HFD-induced dyslipidemia and hepatic lipid accumulation in Syrian hamsters with HFD-induced dyslipidemia, which might have occurred through inhibiting the lipogenesis pathway.


Interprofessional perceptions of emotional, social, and ethical effects of multidrug-resistant organisms: A qualitative study.
Multi-drug-resistant organisms (MDRO) are usually managed by separating the infected patients to protect others from colonization and infection. Isolation precautions are associated with negative experiences by patients and their relatives, while hospital staff experience a heavier workload and their own emotional reactions. In 2018, 35 participants (nurses, physicians, pharmacists) in an antimicrobial-stewardship program participated in facilitated discussion groups working on the emotional impact of MDRO. Deductive codings were done by four coders focusing on the five basic emotions described by Paul Ekmans. All five emotions revealed four to 11 codes forming several subthemes: Anger is expressed because of incompetence, workflow-impairment and lack of knowledge. Anxiety is provoked by inadequate knowledge, guilt, isolation, bad prognoses, and media-related effects. Enjoyment is seldom. Sadness is experienced in terms of helplessness and second-victim effects. Disgust is attributed to shame and bad associations, but on the other hand MDROs seem to be part of everyday life. Deductive coding yielded additional codes for bioethics and the Calgary Family Assessment Method. MDRO are perceived to have severe impact on emotions and may affect bioethical and family psychological issues. Thus, further work should concentrate on these findings to generate a holistic view of MDRO on human life and social systems.


AMCP Partnership Forum: Digital Therapeutics-What Are They and Where Do They Fit in Pharmacy and Medical Benefits?
Digital therapeutics (DTx)-software that delivers a clinical mechanism of action, either alone or in combination with other standard-of-care treatments to improve outcomes-is an emerging class of therapeutic interventions that poses many questions for the health care system. To examine the systems and processes that will support the adoption and utilization of DTx, AMCP convened a multidisciplinary stakeholder forum September 17-18, 2019, in Alexandria, Virginia. The goals of the forum were to (a) describe DTx and how managed care organizations evaluate their value; (b) identify where DTx fits within a covered benefit; (c) outline evidentiary standards needed for coverage of DTx; and (d) outline how payers and managed care organizations may leverage DTx for value-based care and patient engagement. Health care leaders representing academia, health plans, integrated delivery systems, DTx manufacturers and industry leaders, pharmaceutical manufacturers, pharmacy benefit managers, employers, federal government agencies, national health care provider organizations, and patient advocacy organizations participated in the forum. Participants identified characteristics of DTx to develop a better understanding of the spectrum of solutions and how they are distinct from other digital health products, such as mobile health devices, monitoring, care coordination, or electronic health records. The evidence needed to evaluate DTx will likely be tiered based on its medical claim or function and should align with standards for clinical evidence. Clinical evidence must be evaluated by appropriate health authorities (e.g., the U.S. Food and Drug Administration) and receive market authorization (e.g., clearance, approval) with a regulatory label. Various benefit coverage options were discussed. While some participants suggested that the unique features of DTx could be best addressed by a novel digital benefit, others argued that creating an additional benefit would result in further health care system fragmentation. They observed that the increasing focus on compensating providers for outcomes supports integrating DTx within existing benefit structures. They noted that some DTx might be more appropriate for the medical benefit and others might be better aligned with the pharmacy benefit. Finally, many participants observed that, while additional DTx-specific education may be needed, pharmacists are trained to have the knowledge and skills that make them well suited to play a key role in guiding appropriate use of DTx. DISCLOSURES: This AMCP forum was sponsored by Akili Interactive Labs, Boehringer Ingelheim, Genentech, Gilead, Lovongo, MedRhythms Therapy, Merck & Co., metaMe Health, MindSciences, Novo Nordisk, Otsuka Pharmaceutical, Pear Therapeutics, Precision for Value, Sandoz, Sanofi, Takeda, Teva Pharmaceuticals, and Xcenda. These proceedings were prepared as a summary of the forum to represent common themes; they are not necessarily endorsed by all attendees nor should they be construed as reflecting group consensus. Cynthia Reilly, MS, BSPharm, correspondent, is an employee of AMCP and declares no conflicts of interest, real or apparent, with any product or service mentioned in this report.


The 1984 Sievert lecture. Sieverts and safety.
The development of sound methods of radiation protection depended upon reliable dosimetry, both for internal and for external radiation. The proper safety of practices involving radiation exposures can only be adequately reviewed in light of the doses to which tissues are exposed by these practices, and of the types and magnitudes of the risks associated with these doses. Evaluation of risk is an essential step in the pursuit of safety.


Binding of complement component C3b to glycoprotein C is modulated by sialic acid on herpes simplex virus type 1-infected cells.
Neuraminidase treatment of cells infected with herpes simplex virus type 1 (HSV-1) markedly enhanced the binding of complement component C3b to HSV 1 glycoprotein C (gC). When HSV-1 was grown in BHK RicR14 cells in which glycoproteins had reduced amounts of N-linked complex oligosaccharides, including sialic acid, the binding of C3b to gC was markedly enhanced. We used neuraminidase treatment to demonstrate that cloning the gC gene from the HSV-1 F strain into an HSV-1 mutant which fails to express gC converted the mutant virus from C3b receptor negative to receptor positive. These results further support a role for gC as a C3b receptor and indicate that sialic acid modifies receptor activity.


Understanding Diffusional Charge Transport within a Pyrene-Based Hydrogen-Bonded Organic Framework.
Electrochemically active hydrogen-bonded organic frameworks (HOFs) offer opportunities to study charge transport in supramolecular systems where the rate of movement of charges is dependent on weak electronic coupling between individual components. Here, we used potential-step chronoamperometric measurements on electrochemically active, drop-cast HOF-102 films to estimate both redox-hopping-based apparent diffusion coefficients for charge transport and rate constants for linker-to-linker charge transfer (hole transfer) in the mesoporous two-dimensional (2D) plane created by interlinker hydrogen bonding. Also present are one-dimensional columns formed by stacking pyrene units. However, because the HOF-102 crystallites containing these columns are oriented parallel to an underlying electrode, dynamics of charge transport (hole-transport) along the column axis, in contrast to the plane, are not directly probed by the electrochemical measurements. Furthermore, we employed electrochemical impedance spectroscopy to measure the electrical conductivity of the as-deposited films biased at various potentials. We found that both the neutral/singly oxidized and the singly oxidized/doubly oxidized pyrene linker redox couples of HOF-102 can engender hopping-based film conductivity within the 2D plane of HOF-102. Consistent with the radical cation and radical dication nature of the singly and doubly oxidized linkers, respectively, HOF-102 films are electrochromic. The measured values of in-plane charge-diffusion coefficients (∼10-10 to 10-11 cm2 s-1) and electrical conductivity (∼10-6 to 10-8 S cm-1) compare favorably with those for related redox-conductive MOFs and suggest that the transport and conductivity parameters for HOF-102 are sufficiently large to support electrocatalysis by subsequently installed catalysts in films─specifically, films of micron or greater thickness, corresponding to the equivalent hundreds of monolayers of closely packed (i.e., face-to-face-packed) pyrene-derivatives, but with solution access (solvent, ion, and reactant access) still readily provided by channels oriented parallel to an underlying planar electrode.


Inhibin-A and inhibin-B in cyclic and pregnant mares, and mares with granulosa-theca cell tumors: Physiological and diagnostic implications.
Studies in mares have examined serum inhibin concentrations using immuno-assays unable to distinguish dimeric inhibin-A from inhibin-B isoforms. Inhibin-A and inhibin-B immuno-assays were used to investigate concentrations in cyclic mares, young and old (6 vs 19 years old, respectively) mares following hemi-ovariectomy, mares during pregnancy and in mares with confirmed granulosa cell tumors (GCTs). Mares with inter-ovulatory intervals of 26 days had ovulatory peaks of inhibin-A averaging 80 pg/mL with a mid-cycle nadir of 5 pg/mL. Inhibin-A and inhibin-B concentrations were highly correlated (r = + 0.79, P < 0.01) though peak and nadir concentrations of inhibin-B were not significantly different. However, the ratio of inhibin-A to inhibin-B (A/B) changed significantly through the cycle, highest at ovulation and <1 (more inhibin-B than -A) at mid-cycle. Two mares with grossly extended inter-ovulatory intervals demonstrated mid-cycle inhibin-A (and inhibin-B) excursions suggestive of follicular waves. Follicle-stimulating hormone was negatively correlated with inhibin-A and -B concentrations in all 6 mares. Hemi-ovariectomy in young mares resulted in a significant decrease in inhibin-A and inhibin-B concentrations one day later (P < 0.05) but older mares did not, suggesting a possible extra-ovarian source(s) of these hormones. Both inhibin isoforms dropped to very low levels during pregnancy (P < 0.0001), inhibin-A (P < 0.0001) more rapidly than -B (P < 0.05), so that inhibin-B became the predominant measured form throughout most of gestation (P < 0.05). Mares with confirmed GCTs had elevated inhibin-B concentrations more reliably than inhibin-A but neither inhibin-A or -B was correlated with anti-Müllerian hormone concentrations. Collectively, concentrations of inhibin-A and -B were aligned with physiological events in healthy mares, though more pronounced cyclic changes were seen with inhibin-A. Inhibin-B concentrations were significantly associated with GCTs (P < 0.01), inhibin-A concentrations were not. While both inhibin-A and -B concentrations track physiological events such as cyclic follicular activity, only inhibin-B concentrations effectively signal ovarian neoplasia in mares.


Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of cutaneous leishmaniasis.
Cutaneous leishmaniasis is a serious public health problem in the developing world. The main therapeutic agent--pentavalent antimony, developed >50 years ago--is expensive, often accompanied by severe adverse effects, and complicated by the emergence of drug resistance. Better therapies are urgently needed. In the present pilot study, we compared the use of imiquimod, an immunomodulatory molecule, to the use of meglumine antimoniate alone and in combination for the initial treatment of cutaneous leishmaniasis. Patients with newly diagnosed cutaneous leishmaniasis were enrolled from a single referral center in Lima, Peru, from August 2005 through October 2005. Patients were randomly assigned to 1 of 3 treatment groups and received either imiquimod 7.5% cream administered topically every other day for 20 days, intravenous meglumine antimoniate administered at a dosage of 20 mg/kg per day every day for 20 days, or combination therapy with both intravenous meglumine antimoniate and imiquimod 7.5% cream. Patients were evaluated weekly and at 1 and 3 months after treatment. Patients who had healed lesions at 3 months were considered to be clinically cured. Although several patients showed initial resolution of symptoms with imiquimod treatment alone, all of these patients experienced relapse after treatment discontinuation. Four (57%) of 7 patients treated with meglumine antimoniate alone and 7 (100%) of 7 patients treated with combination therapy were cured. Combination therapy was not only more effective than the other 2 treatments (P<.05) but also led to faster healing and better cosmetic results. Combination therapy with imiquimod and meglumine antimoniate is a promising regimen for the initial treatment of cutaneous leishmaniasis that warrants additional larger studies.


Lycorine, a candidate for the control of period length in mammalian cells.
Plants of the Amaryllidaceae family have been used as therapeutic agents against CNS related maladies such as Alzheimer's disease. The known primary alkaloid constituents have significant biological activity. We identified the Lycoris alkaloids lycorine and lycoricidinol from Amaryllidaceae using a real-time reporter gene assay system based on NIH3T3 cells. These alkaloids have a wide spectrum of pharmacological actions and dose-dependently lengthen the circadian period. When cells that had been incubated with lycorine or lycoricidinol were washed and then incubated without these alkaloids, period length reverted to that of control cells, suggesting that elongation of the circadian period induced by lycorine and lycoricidinol is reversible. Although one of its major activities is the inhibition of protein synthesis, lycorine induced dose-dependent period elongation regardless of the presence of cycloheximide and moreover, cycloheximide, itself did not affect period length, suggesting that lycorine dose-dependently extends the circadian period by a mechanism other than translational inhibition. Real-time RT-PCR showed that lycorine enhanced RORα and Bmal1 transcription, and exogenous expression and knockdown of Bmal1 also caused long and short periods, respectively, thus confirming the phenotype indicated by lycorine. These data indicate that lycorine and lycoricidinol modulate Bmal1 transcription and the circadian period, and also suggest that Lycoris alkaloids are novel contributors to the control of period length in mammalian cells.


Adaptive optics for dynamic aberration compensation using parallel model-based controllers based on a field programmable gate array.
Adaptive optics (AO) is an effective technique for compensating the aberrations in optical systems and restoring their performance for various applications such as image formation, laser processing, and beam shaping. To reduce the controller complexity and extend the compensation capacity from static aberrations to dynamic disturbances, the present study proposes an AO system consisting of a self-built Shack-Hartmann wavefront sensor (SHWS), a deformable mirror (DM), and field programmable gate array (FPGA)-based controllers. This AO system is developed for tracking static and dynamic disturbances and tuning the controller parameters as required to achieve rapid compensation of the incoming wavefront. In the proposed system, the FPGA estimates the coefficients of the eight Zernike modes based on the SHWS with CameraLink operated at 200 Hz. The estimated coefficients are then processed by eight parallel independent discrete controllers to generate the voltage vectors to drive the DM to compensate the aberrations. To have the DM model for controller design, the voltage vectors are identified offline and are optimized by closed-loop controllers. Furthermore, the controller parameters are tuned dynamically in accordance with the main frequency of the aberration as determined by a fast Fourier transform (FFT) process. The experimental results show that the AO system provides a low complexity and effective means of compensating both static aberrations and dynamic disturbance up to 20 Hz.


Papillary Thyroid Carcinoma with Extensive Cervical Lymph Node Metastasis and Initial Retropharyngeal Lymph Node Metastasis: A Case Report and Literature Review.
Papillary thyroid carcinoma (PTC) is prone to regional lymph node metastasis, which is more common in central lymph nodes and lateral cervical lymph nodes, and retropharyngeal lymph node metastasis (RLNM) is extremely rare. A male with PTC presented with extensive cervical lymph node metastasis and the initial RLNM. After full evaluation by preoperative imaging examination, the patient underwent total thyroidectomy + left central lymph node dissection + left neck lymph node dissection (II III IV V) + left retropharyngeal tumor resection, and the postoperative recovery was good without recurrence long-term complications, and no local recurrence and metastasis were found during one-year follow-up.


The foundations of a policy for the use of social robots in care.
Should we deploy social robots in care settings? This question, asked from a policy standpoint, requires that we understand the potential benefits and downsides of deploying social robots in care situations. Potential benefits could include increased efficiency, increased welfare, physiological and psychological benefits, and experienced satisfaction. There are, however, important objections to the use of social robots in care. These include the possibility that relations with robots can potentially displace human contact, that these relations could be harmful, that robot care is undignified and disrespectful, and that social robots are deceptive. I propose a framework for evaluating all these arguments in terms of three aspects of care: structure, process, and outcome. I then highlight the main ethical considerations that have to be made in order to untangle the web of pros and cons of social robots in care as these pros and cons are related the trade-offs regarding quantity and quality of care, process and outcome, and objective and subjective outcomes.


Progress and Challenges in Microengineering the Dental Pulp Vascular Microenvironment.
The dental pulp is highly vascularized and innervated tissue that is uniquely designed, being highly biologically active, while being enclosed within the calcified structure of the tooth. It is well-established that the dental pulp vasculature is a key requirement for the functional performance of the tooth. Therefore, controlled regeneration of the dental pulp vasculature is a challenge that must be met for future regenerative endeavors in endodontics. In this perspective review, we address recent progress and challenges on the use of microengineering methods and biomaterials scaffolds to fabricate the dental pulp vascular microenvironment. The conditions required to control the growth and differentiation of vascular capillaries are discussed, together with the conditions required for the formation of mature and stable pericyte-supported microvascular networks in 3-dimensional hydrogels and fabricated microchannels. Recent biofabrication methods, such as 3-dimensional bioprinting and micromolding are also discussed. Moreover, recent advances in the field of organs-on-a-chip are discussed regarding their applicability to dental research and endodontic regeneration. Collectively, this short review offers future directions in the field that are presented with the objective of pointing toward successful pathways for successful clinical and translational strategies in regenerative endodontics, with especial emphasis on the dental pulp vasculature.


Enrichment and analysis of anode-respiring bacteria from diverse anaerobic inocula.
One of the limitations currently faced by microbial electrochemical cell (MXC) technologies lies in the shortage of different organisms capable of forming a biofilm and channeling electrons from substrates to the anode at high current densities. Using a poised anode (-0.30 V vs Ag/AgCl) and acetate as the electron donor in a MXC, we demonstrated the presence of highly efficient anode-respiring bacteria (ARB) able to produce high current densities (>1.5 A/m(2) anode) in seven out of thirteen environmental samples. These included marshes, lake sediments, saline microbial mats, and anaerobic soils obtained from geographically diverse locations. Our microbial ecology analysis, using pyrosequencing, shows that bacteria related to the genus Geobacter, a known and commonly found ARB, dominate only two of the biofilm communities producing high current; other biofilm communities contained different known and/or novel ARB. The presence of ARB in geographically diverse locations indicates that ARB thrive in a wide range of ecosystems. Studying ARB from different environmental conditions will allow us to better understand the ubiquity of anode respiration, compare the capabilities of different ARB consortia, and find ARB with useful metabolic capacities for future applications.


Language is More than Speech: A Case Study.
Some individuals face severe challenges with producing oral language (i.e., speech). In this article a case study of a child who experienced severe challenges with speech development is presented. Medical records, historical home videos, audio recordings, and photographs, in conjunction with an extensive journal maintained by the child's mother provide the basis for this report, which profiles the child's development from birth to age 8;0. This child's development demonstrates the necessity of distinguishing between language-the mental representation of concepts and their relations-and speech-one means for communicating mental representations.


Neural correlates of learning accommodation and consolidation in generalised anxiety disorder.
Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD). Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS. Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal. Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.


Epidemiology and factors associated with peripheral neuropathy among HIV infected patients in Gondar, Ethiopia: A cross-sectional study.
Antiretroviral therapy has surely increased the life expectancy of people living with HIV. However, long term complications like HIV associated sensory neuropathy has a negative impact on quality of life among people living with HIV (PLHIV). In Ethiopia, lack of data on magnitude of the burden and predictors of HIV associated sensory neuropathy in many resource limited setting has led to under diagnosis and eventually under management of HIV-SN. Hence, this study was set out to establish the burden of HIV-associated sensory neuropathy and, its association with demographic, health and clinical characteristics among people living with HIV in Ethiopia. Cross-sectional study was conducted to assess the prevalence of HIV-associated sensory neuropathy and the associated factors among adult HIV patients at University of Gondar Teaching Hospital, Gondar, Ethiopia. Brief Peripheral Neuropathy Screening tool validated by AIDs Clinical trial group was used for screening HIV-associated sensory neuropathy. Data were analyzed descriptively and through uni- and multivariate logistic regression. In total 359 adult PLHIV with a mean age of 36.5± 9.07 years participated, their median duration of HIV infection was 60 months (IQR 36-84) and their median CD4 count 143cells/μL (IQR 69.5-201.5). Age above 40 years, anti-tuberculosis regimen, tallness, and exposure to didanosine contained antiretroviral therapy were found to be associated with HIV-associated sensory neuropathy (AOR 1.82, 1.84, 1.98 and 4.33 respectively). More than half of the HIV patients who attended HIV care clinic at University of Gondar hospital during the study period were found to present with peripheral sensory neuropathy. Higher age, tallness, TB medication, and didanosine in ART were significantly associated with HIV-SN as screened by effective diagnostic (BPNS) tool.


Mlc1p promotes septum closure during cytokinesis via the IQ motifs of the vesicle motor Myo2p.
Little is known about the molecular machinery that directs secretory vesicles to the site of cell separation during cytokinesis. We show that in Saccharomyces cerevisiae, the class V myosin Myo2p and the Rab/Ypt Sec4p, that are required for vesicle polarization processes at all stages of the cell cycle, form a complex with each other and with a myosin light chain, Mlc1p, that is required for actomyosin ring assembly and cytokinesis. Mlc1p travels on secretory vesicles and forms a complex(es) with Myo2p and/or Sec4p. Its functional interaction with Myo2p is essential during cytokinesis to target secretory vesicles to fill the mother bud neck. The role of Mlc1p in actomyosin ring assembly instead is dispensable for this process. Therefore, in yeast, as recently shown in mammals, class V myosins associate with vesicles via the formation of a complex with Rab/Ypt proteins. Further more, myosin light chains, via their ability to be transported by secretory vesicles and to interact with class V myosin IQ motifs, can regulate vesicle polarization processes at a specific location and stage of the cell cycle.


A fundamental viewpoint on the hydrogen spillover phenomenon of electrocatalytic hydrogen evolution.
Hydrogen spillover phenomenon of metal-supported electrocatalysts can significantly impact their activity in hydrogen evolution reaction (HER). However, design of active electrocatalysts faces grand challenges due to the insufficient understandings on how to overcome this thermodynamically and kinetically adverse process. Here we theoretically profile that the interfacial charge accumulation induces by the large work function difference between metal and support (∆Φ) and sequentially strong interfacial proton adsorption construct a high energy barrier for hydrogen transfer. Theoretical simulations and control experiments rationalize that small ∆Φ induces interfacial charge dilution and relocation, thereby weakening interfacial proton adsorption and enabling efficient hydrogen spillover for HER. Experimentally, a series of Pt alloys-CoP catalysts with tailorable ∆Φ show a strong ∆Φ-dependent HER activity, in which PtIr/CoP with the smallest ∆Φ = 0.02 eV delivers the best HER performance. These findings have conclusively identified ∆Φ as the criterion in guiding the design of hydrogen spillover-based binary HER electrocatalysts.


Appropriate implantable cardioverter-defibrillator interventions in cardiac resynchronization therapy-defibrillator (CRT-D) patients undergoing device replacement: time to downgrade from CRT-D to CRT-pacemaker? Insights from real-world clinical practice in the DECODE CRT-D analysis.
Ventricular tachycardia (VT)/ventricular fibrillation (VF) occurrence after cardiac resynchronization therapy-defibrillator (CRT-D) replacement is unknown; hence, there is no practical guideline to recommend either CRT-D or CRT-pacemaker at the time of device replacement. We observed the 1-year VT/VF occurrence after CRT-D replacement in a subanalysis of the Detect Long-term Complications after ICD Replacement (DECODE) registry. A total of 332 consecutive patients who had undergone CRT-D replacement from 2013 to 2015 were enrolled in 36 Italian centres. The primary endpoint was the number of patients with any appropriate implantable cardioverter-defibrillator (ICD) interventions during 12-month follow-up. The secondary endpoint comprised death from any cause and appropriate ICD interventions. At replacement, 214 (64.5%) patients had a left ventricular ejection fraction ≤ 35% and 138 (41.6%) patients had a secondary prevention indication for ICD. Seventy (21.1%) patients had no longer indication to ICD therapy. During a median follow-up period of 406.5 (362-533) days, VT/VF requiring therapy delivery occurred in 57 (17%) patients, specifically in 7% of those who no longer had an ICD indication. On multivariate analysis, number of criteria for ICD replacement independently predicted appropriate ICD intervention during follow-up [hazard ratio (HR) = 1.62, 95% confidence interval (CI) 1.07-2.46; log-rank P = 0.02]. The combined endpoint of death from any cause or appropriate ICD therapy occurred in 76 (23%) patients. Only NYHA class remained associated with this combined endpoint (HR = 1.97, 95% CI 1.23-3.14; P = 0.005). The DECODE registry showed the 'real-world' experience of CRT-D recipients approaching device replacement, in which 7% of patients who no longer had an indication for ICD therapy experienced appropriate ICD interventions.


[Effect of neuromediating and neuroblockading hormones on the RNA synthesis in the rat liver nucleus].
It was shown that rRNA and HnRNA synthesis in rat liver nuclei does not change-within 30 min after intraperitoneal injection of acetylcholine (0.005 mg per 100 g of body weight) but decreases after injection of norepinephrine and epinephrine (0.05 mg per 100 g of body weight). The synthesis of rRNA (but not of HnRNA) increases after injection of hydrocortisone (2,5 mg per 100 g of body weight). The synthesis of HnRNA (but not of rRNA) increases after injection of ACTH1-24 (3 ME per 100 g of body weight) and oxytocin (1 ME per 100 g of body weight). The synthesis of rRNA decreases after injection of propranolol and atropine (0.5 mg per 100 g of body weight). At the same time, the synthesis of HnRNA does not change thereby. The inhibitory effect of propranolol and atropine was corrected by electrostimulation of hypothalamus. The content of cAMP and Ca2+ and the phosphorylation degree of nuclear proteins are increased after stimulation of hypothalamus. The phosphorylation of nuclear proteins is increased by 10(-8)-10(-6) M cAMP. The synthesis of RNA in liver nuclei is increased by 10(-6) M cAMP only after addition of cytosol. In this case the activity of RNA-polymerase II increases in a greater degree than that of RNA-polymerase I + III. It is assumed that the regulatory mechanisms of rRNA and HnRNA synthesis are different. The role of hypothalamus electrostimulation, neurotransmitters, hormones, and cAMP in the mechanisms of RNA synthesis in rat liver nuclei is discussed.


Experimental hepatic injury: the sequential changes in drug metabolizing enzyme activities after administration of acetaminophen.
Experimental hepatic necrosis was induced in phenobarbital pretreated rats by means of the intraperitoneal administration of an acetaminophen-dimethyl sulfixide (DMSO) mixture. Cytochrome P-450 content and the specific activities of aminopyrine demethylase, aniline hydroxylase and bilirubin glucuronyl transferase diminished over the three-day study period, as compared with control animals. The reductions, however, were generally modest; not uniform for all the enzymes assayed; and correlated poorly with histologic necrosis and standard liver function tests. It is concluded that in acute liver disease changes in the hepatic in vitro drug metabolizing enzyme capacity may not be closely related to cellular necrosis, per se, and the degree of change in enzyme activities will vary from one enzyme system to another. These findings may explain, in part, the often inconsistent alterations in the disposition and elimination of drugs described in associated liver disease.


Random plasma glucose levels and cause-specific mortality among Chinese adults without known diabetes: an 11-year prospective study of 450,000 people.
We examined the associations between long-term usual random plasma glucose (RPG) levels and cause-specific mortality risks among adults without known diabetes in China. The China Kadoorie Biobank recruited 512,891 adults (59% women) aged 30-79 from 10 regions of China during 2004-2008. At baseline survey, and subsequent resurveys of a random subset of survivors, participants were interviewed and measurements collected, including on-site RPG testing. Cause of death was ascertained via linkage to local mortality registries. Cox regression yielded adjusted HR for all-cause and cause-specific mortality associated with usual levels of RPG. During median 11 years' follow-up, 37,214 deaths occurred among 452,993 participants without prior diagnosed diabetes or other chronic diseases. There were positive log-linear relationships between RPG and all-cause, cardiovascular disease (CVD) (n=14,209) and chronic kidney disease (CKD) (n=432) mortality down to usual RPG levels of at least 5.1 mmol/L. At RPG <11.1 mmol/L, each 1.0 mmol/L higher usual RPG was associated with adjusted HRs of 1.14 (95% CI 1.12 to 1.16), 1.16 (1.12 to 1.19) and 1.44 (1.22 to 1.70) for all-cause, CVD and CKD mortality, respectively. Usual RPG was positively associated with chronic liver disease (n=547; 1.45 (1.26 to 1.66)) and cancer (n=12,680; 1.12 (1.09 to 1.16)) mortality, but with comparably lower risks at baseline RPG ≥11.1 mmol/L. These associations persisted after excluding participants who developed diabetes during follow-up. Among Chinese adults without diabetes, higher RPG levels were associated with higher mortality risks from several major diseases, with no evidence of apparent thresholds below the cut-points for diabetes diagnosis.


Self-weighing among adolescents: associations with body mass index, body satisfaction, weight control behaviors, and binge eating.
Among adolescent girls, the health effects of frequent self-weighing are unclear. This study examines cross-sectional and longitudinal associations between frequency of self-weighing and body mass index (BMI), body satisfaction, weight control behaviors, and binge eating among a diverse population of adolescent girls. The study was conducted in the Minneapolis/St Paul, MN, metropolitan area between 2007 and 2009. The study population included 356 adolescent girls (mean age 15.7 years); 46.2% of the girls were overweight or obese and >75% were from a racial/ethnic minority group. Anthropometric and survey data were collected at baseline and at follow-up 9 months later. Hierarchical linear regression models were developed to test associations. Cross-sectionally, frequent self-weighing was associated with lower body satisfaction (P=0.034) and higher rates of healthy (P=0.002), unhealthy (P=0.016), and extreme (P=0.038) weight control behaviors. A quadratic association was found between frequency of self-weighing and binge eating, with girls who weighed themselves least and most frequently reporting the highest prevalences of binge eating (P=0.014). No association was observed between frequency of self-weighing and girls' BMI (P=0.111). Short-term longitudinal associations between baseline frequency of self-weighing and changes in body satisfaction, weight control behaviors, binge eating, or BMI were not observed. Findings suggest that among adolescent girls, frequent self-weighing is cross-sectionally associated with both healthy and potentially harmful unhealthy weight control behaviors, and does not contribute to weight loss over time. Adolescents should not be encouraged to engage in frequent self-weighing.


Autoinhibition of SNARE complex assembly by a conformational switch represents a conserved feature of syntaxins.
Regulation and specificity of membrane trafficking are required to maintain organelle integrity while performing essential cellular transport. Membrane fusion events in all eukaryotic cells are facilitated by the formation of specific SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes between proteins on opposing lipid bilayers. Although regulation of SNARE complex assembly is not well understood, it is clear that two conserved protein families, the Sx (syntaxin) and the SM (Sec1p/Munc18) proteins, are central to this process. Sxs are a subfamily of SNARE proteins; in addition to the coiled-coil SNARE motif, Sxs possess an N-terminal, autonomously folded, triple-helical (Habc) domain. For some Sxs, it has been demonstrated that this Habc domain exerts an autoinhibitory effect on SNARE complex assembly by making intramolecular contacts with the SNARE motif. SM proteins regulate membrane fusion through interactions with their cognate Sxs. One hypothesis for SM protein function is that they facilitate a switch of the Sx from a closed to an open conformation, thus lifting the inhibitory action of the Habc domain and freeing the SNARE motif to participate in SNARE complexes. However, whether these regulatory mechanisms are conserved throughout the Sx/SM protein families remains contentious as it is not clear whether the closed conformation represents a universal feature of Sxs.


A double layer model of the gas bubble/water interface.
Zeta potential is a physico-chemical parameter of particular importance to describe sorption of contaminants at the surface of gas bubbles. Nevertheless, the interpretation of electrophoretic mobilities of gas bubbles is complex. This is due to the specific behavior of the gas at interface and to the excess of electrical charge at interface, which is responsible for surface conductivity. We developed a surface complexation model based on the presence of negative surface sites because the balance of accepting and donating hydrogen bonds is broken at interface. By considering protons adsorbed on these sites followed by a diffuse layer, the electrical potential at the head-end of the diffuse layer is computed and considered to be equal to the zeta potential. The predicted zeta potential values are in very good agreement with the experimental data of H(2) bubbles for a broad range of pH and NaCl concentrations. This implies that the shear plane is located at the head-end of the diffuse layer, contradicting the assumption of the presence of a stagnant diffuse layer at the gas/water interface. Our model also successfully predicts the surface tension of air bubbles in a KCl solution.


Upconverting luminescent nanoparticles for use in bioconjugation and bioimaging.
Upconverting luminescent nanoparticles (UCNPs) display the unique property of emitting visible light following photoexcitation with near-infrared laser light. This results in features such as virtually zero autofluorescence of (biological) matter and easy separation of the emission peaks from stray light. Other features include rather narrow emission bands, very high chemical stability, the lack of bleaching, and the absence of blinking effects. This article reviews the work performed in the past few years with UCNPs in terms of surface modifications, bioconjugation, and optical (cellular) imaging.


Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells.
Type 2 diabetes develops in the context of both insulin resistance and beta-cell failure. Thiazolidinediones are a class of antidiabetic agents that are known to improve insulin sensitivity in various animal models of diabetes. The improved insulin sensitivity may be achieved either by systemic insulin sensitization or by direct action of peroxisome proliferator-activated receptor (PPAR)-gamma on the transcription of genes involved in glucose disposal. Evidence supporting the direct action of PPAR-gamma on glucose metabolism is observed in the genes involved in insulin-stimulated glucose disposal. We already showed that GLUT2 and beta-glucokinase were directly activated by PPAR-gamma. Recently, we have identified and characterized the functional PPAR response element in the GLUT2 and liver type glucokinase (LGK) promoter of the liver. It is well known that adipose tissue plays a crucial role in antidiabetic action of PPAR-gamma. In addition, PPAR-gamma can directly affect liver and pancreatic beta-cells to improve glucose homeostasis.


Outcomes of invasive meningococcal disease in adults and children in Canada between 2002 and 2011: a prospective cohort study.
Neisseria meningitidis causes 500 000 cases of septicemia and meningitis worldwide annually, with approximately 200 cases in Canada each year. Previous studies describe a case-fatality rate of 5%-15% and up to 20% of survivors suffering from long-term disability. This study was performed in Canada between 2002 and 2011; the study area included >50% of the country's population. We identified risk factors associated with death and the development of complications in children and adults admitted to hospital with confirmed invasive meningococcal disease (IMD). Clinical information was obtained from hospital records. Risk factors for death and complications were analyzed by univariate and multivariable analyses. Of 868 individuals hospitalized with IMD, there were 73 deaths (8.4%) and 157 (18%) developed complications. The most common complications were hearing loss (5.4%), skin scarring (5.4%), amputation (3.4%), renal dysfunction (2.6%), and seizures (2.5%). Mortality was independently associated with shock (adjusted odds ratio [aOR], 23.30; P<.0001), age (aOR, 1.02 per 1-year increased age; P<.0001), symptom onset within 24 hours of admission (aOR, 1.80; P=.0471), and admission to the intensive care unit (aOR, 0.41; P=.0196). Development of complications was independently associated with seizures (aOR, 4.55; P<.0001), shock (aOR, 3.10; P<.0001), abnormal platelet count (aOR, 2.14; P=.0002), bruising (aOR, 3.17; P=.0059), abnormal white blood cell count (aOR, 0.52; P=.0100), and prior antibiotic exposure (aOR, 0.27; P=.0273). Outcomes following IMD remain poor in this resource-rich setting in the 21st century. These data identify priorities for clinical management of adults and children with IMD, and provide prognostic information for affected patients and their families and cost-effectiveness analyses for meningococcal vaccine programs.


Standard versus hypofractionated intensity-modulated radiotherapy for prostate cancer: assessing the impact on dose modulation and normal tissue effects when using patient-specific cancer biology.
Hypofractionation of prostate cancer radiotherapy achieves tumour control at lower total radiation doses, however, increased rectal and bladder toxicities have been observed. To realise the radiobiological advantage of hypofractionation whilst minimising harm, the potential reduction in dose to organs at risk was investigated for biofocused radiotherapy. Patient-specific tumour location and cell density information were derived from multiparametric imaging. Uniform-dose plans and biologically-optimised plans were generated for a standard schedule (78 Gy/39 fractions) and hypofractionated schedules (60 Gy/20 fractions and 36.25 Gy/5 fractions). Results showed that biologically-optimised plans yielded statistically lower doses to the rectum and bladder compared to isoeffective uniform-dose plans for all fractionation schedules. A reduction in the number of fractions increased the target dose modulation required to achieve equal tumour control. On average, biologically-optimised, moderately-hypofractionated plans demonstrated 15.3% (p-value: <0.01) and 23.8% (p-value: 0.02) reduction in rectal and bladder dose compared with standard fractionation. The tissue-sparing effect was more pronounced in extreme hypofractionation with mean reduction in rectal and bladder dose of 43.3% (p-value: < 0.01) and 41.8% (p-value: 0.02), respectively. This study suggests that the ability to utilise patient-specific tumour biology information will provide greater incentive to employ hypofractionation in the treatment of localised prostate cancer with radiotherapy. However, to exploit the radiobiological advantages given by hypofractionation, greater attention to geometric accuracy is required due to increased sensitivity to treatment uncertainties.


Implementation of a short-stay programme after breast cancer surgery.
: Short-stay breast cancer surgery (24 h or day case) is not common practice in Europe. This before-after comparative study was carried out to test the feasibility of systematically implementing a care programme incorporating short-stay admission using strategies tailored to individual hospital needs, and to assess safety and facilitating factors. : Patients with breast cancer from four Dutch hospitals participated. The intervention concerned the programme developed by the Maastricht University Medical Centre. This was implemented through local multidisciplinary meetings and educational outreach visits. : Of 421 eligible patients, 324 (77.0 per cent) gave consent to participate. The proportion of patients who had short-stay treatment increased from 45.3 per cent before to 82.2 per cent after implementation of the programme (P < 0.001). No increase was observed in the rate of complications, readmissions, reoperations or number of visits to the emergency department. Factors associated with an increased chance of short-stay treatment were: breast-conserving surgery, having children and being employed. Being aged over 64 years showed a trend towards a decreased chance. : Introducing a care programme incorporating short stay following breast cancer surgery in four hospitals was feasible and safe.


Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells.
Various membrane ATPases have been tested for their sensitivity to bafilomycin A1, a macrolide antibiotic. F1F0 ATPases from bacteria and mitochondria are not affected by this antibiotic. In contrast, E1E2 ATPases--e.g., the K+-dependent (Kdp) ATPase from Escherichia coli, the Na+,K+-ATPase from ox brain, and the Ca2+-ATPase from sarcoplasmic reticulum--are moderately sensitive to this inhibitor. Finally, membrane ATPases from Neurospora vacuoles, chromaffin granules, and plant vacuoles are extremely sensitive. From this we conclude that bafilomycin A1 is a valuable tool for distinguishing among the three different types of ATPases and represents the first relatively specific potent inhibitor of vacuolar ATPases.


Vaccinating young adults against human papillomavirus: the importance of understanding health decision-making and behaviour.
Vaccination of young teenage females against human papillomavirus (HPV) with a newly licenced quadrivalent vaccine designed to prevent cervical cancer and genital warts has recently been recommended by the Australian government and will be implemented through schools from April 2007. In addition, a fully funded 'catch-up' vaccination program for young women up to age 26 years has been approved for a 2-year period, from July 2007. As general practitioners (GPs) will be the main immunisation providers for this age group, in order to achieve high vaccination coverage and maximal impact on disease, it will be critical for GPs to be opportunistic in recommending this vaccine. An initial study of young Australians' attitudes towards HPV vaccination and hypothetical acceptance of the vaccine was published in this journal. We draw on this study and data published elsewhere to discuss issues of HPV vaccine acceptability, and the likely challenges of a mass vaccination initiative in this age group in Australia. We suggest specific strategies to support GPs, and highlight areas for further research in HPV vaccine acceptability.


[Analysis of various mechanisms of action of lactin on plasma volume restoration in hemorrhagic shock].
Experiments on 52 unconscious male cats have established that intravenous administration of lactin in a dose of 50 U/kg 1.5 hrs after 30% blood loss causes intracellular fluid to move into the extracellular space, which is accompanied by restoration of the plasma volume up to 94% of the baseline value and by enhancement of diuresis without substantial changes in the tissue hydrostatic pressure and osmolar concentration of plasma. The simultaneous use of lactin and verospiron, (3 mg/kg, i.p.), unlike lactin alone, retained the restored plasma volume in survived animals in the first 24 hours of blood loss.


Acute Effects of Connective Tissue Manipulation on Autonomic Function in Healthy Young Women.
Connective tissue manipulation (CTM) has therapeutic effects on diseases with autonomic imbalance, yet its mechanisms of action are not clearly identified. The aim of this study was to investigate acute autonomic responses to CTM in healthy young women with various physical activity levels. The study was designed as a nonrandomized, controlled single-center study. Healthy women aged between 18 and 25 years were assigned to a connective tissue manipulation group (CTMG) (n = 150) or a control group (CG) (n = 60). CTM was applied to the CTMG while the CG did not receive any intervention. Respiratory rate (RR), heart rate, systolic/diastolic blood pressures (SP/DP), oxygen saturation (OS) and body temperature were measured. The International Physical Activity Questionnaire short form was used to determine physical activity levels. -Results: Analysis revealed significant reduction in SP and DP and an increment in RR in the CTMG (p < 0.05). RR increased and SP decreased among inactive, SP decreased among moderately active, and SP and OS decreased among highly active participants in the CTMG (p < 0.05). There were no significant alterations in the CG (p > 0.05). CTM has an immediate reducing effect on sympathetic activity in healthy young women independently from the physical activity level. Future studies are needed to clarify long-term effects of CTM on autonomic functions in healthy individuals.


Identifying variations in quality of care in Queensland hospitals.
Identifying and acting on variations from good practice is one of the critical tasks of clinical governance. We describe one aspect of Queensland's post-Bundaberg clinical governance arrangements: the use of variable life-adjusted displays (VLADs) to monitor outcomes of care in the 87 largest public and private hospitals in Queensland, which together account for 83% of all hospital activity. VLAD control charts were created for 31 clinical indicators using routinely collected data, and are disseminated monthly. About a third of hospitals had a run of cases in the 3-year period that flagged at the 30% level (local level investigation). For three indicators, about one in five hospitals had sufficiently cumulatively more deaths than statistically expected that the hospital was highlighted for state-wide review. VLADs do not provide definitive answers about the quality of care. They are used to develop ideas about why variations in reported outcomes occur and suggest possible solutions, be they ways of improving data quality, improving casemix adjustment, or implementing system changes to improve quality of care. Critical to the approach is that there is not just monitoring - the monitoring is tied in with systems that ensure that investigation, learning and action occur as a result of a flag.


[Addiction and schizophrenia. Nosological, clinical and therapeutic questions. 1. Alcoholism and schizophrenia].
The scientific discussion on the interrelationship of "alcoholism and psychosis" has been dominated by nosological problems for years. Alcohol hallucinosis, a comparatively rare psychosis in chronic alcoholism, can mimic the symptomatology of paranoid schizophrenia. The clinical features (vivid acoustic hallucinations and fear) are often inconclusive, as, unlike other organic psychoses, alcohol hallucinosis does not entail clouding of sensorium and disorientation. On the one hand follow-up studies suggest that alcohol hallucinosis in some cases can take a chronic schizophrenia-like course. Especially in these cases differential diagnosis between both conditions can be difficult. On the other hand a number of recent clinical studies suggest high prevalence rates for substance and esp. alcohol abuse and dependence in schizophrenics. Different approaches account for limitations in comparing the results. In most of the studies prevalence estimates for alcohol abuse and dependence range from 12-43%. In some highly selected clinical populations even higher prevalence estimates have been reported. Epidemiological studies such as the "Epidemiological Catchment Area Study" equally are in support of an appr. 4-fold increased risk for alcoholism in schizophrenics. Schizophrenics with alcohol abuse differ from non-abusing schizophrenics in a variety of clinical symptoms and features. With respect to psychopathological symptomatology schizophrenics with an additional alcohol abuse or dependence show more "positive", psychotic and less "negative" symptoms. Some findings suggest that in comparison with other schizophrenics, dual diagnosis schizophrenics may be superior in terms of a better premorbid functioning. However, during course of illness higher (re-) hospitalization rates and higher rates of suicide attempts have been reported; likewise, aggressivity and delinquency have been encountered. In this review clinical and diagnostic questions concerning the interrelationship between alcoholism and schizophrenic psychosis are discussed and some principles of psychopharmacotherapy in dual diagnosis schizophrenics are outlined.


The relationship between breast size and anthropometric characteristics.
Current clinical selection criteria for mammaplasty use weight-related parameters, and weight loss is recommended as a nonsurgical intervention to reduce breast size. However, research has not firmly established if breast size is related to body size and composition. This study aims to investigate anthropometric characteristics in smaller and larger breasted women and identify predictors of breast mass. A bra fitter determined underband and cup size of 93 A to H cup size women (mean ± standard deviation, age 25.7 ± 5.6 years, height 1.67 ± 0.6 cm, and mass 65.6 ± 11.0 kg). Estimations of breast mass (g) were made, and participants were categorized as smaller (<500 g) or larger (>500 g) breasted. Restricted anthropometric profiles determined body mass, height, body mass index (BMI), waist-to-hip ratio, sum of eight skinfolds, subscapular to triceps skinfold ratio, somatotype, percent body fat, fat and fat-free mass, and suprasternal notch to nipple distance. All variables (excluding height, subscapular to triceps skinfold ratio, and age) were significantly greater in larger breasted women. Body mass-related parameters and suprasternal notch to nipple distance were positively related to breast mass, with BMI and suprasternal notch to nipple distance accounting for half of the variance in breast mass. Smaller and larger breasted women demonstrate differences in anthropometry, with body mass and BMI demonstrating strong relationships to breast mass. Measures of BMI and suprasternal notch to nipple distance enable predictions of breast mass and suggest that weight-related parameters are not appropriate exclusion criteria for mammaplasty.


Clinical evaluation of the modular electromechanical lock actuator for above-elbow prostheses: a preliminary report.
The Modular Electromechanical Lock Actuator (MELA) is the result of research and development (R&D) conducted under the direction of Dudley S. Childress, PhD, at the Northwestern University Prosthetics Research Laboratory (NUPRL), Chicago, Illinois. NUPRL, based upon their experience with prostheses for persons with high-level, upper-limb amputations, developed MELA to provide users with more efficient, versatile control and operation of their existing, cable-operated, positive-locking elbow and wrist components. The design of MELA has advanced to the point where it has the potential to improve the functionality and effectiveness of existing, body-powered or manually positioned above-elbow prostheses. This R&D effort has resulted in a pre-market model that is now ready for the national field evaluation part of the technology transfer process coordinated through the VA Rehabilitation Research and Development Service, Technology Transfer Section.


Weight control and physical exercise in people with multiple sclerosis: Current knowledge and future perspectives.
There is extensive data supporting a high prevalence of both overweight and obesity status in people with multiple sclerosis, and increases in body mass index has been associated with an increased risk of multiple sclerosis. Body composition may influence the course, treatment and management of multiple sclerosis. One proposed strategy for managing overweight and obesity status and associated secondary effects in people with multiple sclerosis involves increasing the levels of physical activity. In fact, increased levels of physical activity affect various physiological (endurance capacity, strength, balance) and biological processes (fat oxidation, insulin sensitivity, anti-inflammation, neurotrophic factors) which are known to be dysfunctional in multiple sclerosis and which may worsen with increases in obesity. When designing personalized exercise programs it should be kept in mind that current exercise recommendations for people with multiple sclerosis should exceed energy expenditure recommendations to efficiently counteract weight gain. Therefore, it is necessary to consider body composition as a primary endpoint in experimental studies. In addition, designing guidelines for weight control or weight loss in people MS is needed. The most comprehensive weight management guidelines are outlined in the American College of Sports Medicine Position Statement, which recommends between 150-250 min per week of moderate-intensity physical activity for preventing weight gain, and between 225-420 min per week of moderate-intensity physical activity for weight loss. These recommendations seem applicable for people with multiple sclerosis.


Novel natural and synthetic inhibitors of solute carriers SGLT1 and SGLT2.
Selective analogs of the natural glycoside phloridzin are marketed drugs that reduce hyperglycemia in diabetes by inhibiting the active sodium glucose cotransporter SGLT2 in the kidneys. In addition, intestinal SGLT1 is now recognized as a target for glycemic control. To expand available type 2 diabetes remedies, we aimed to find novel SGLT1 inhibitors beyond the chemical space of glycosides. We screened a bioactive compound library for SGLT1 inhibitors and tested primary hits and additional structurally similar molecules on SGLT1 and SGLT2 (SGLT1/2). Novel SGLT1/2 inhibitors were discovered in separate chemical clusters of natural and synthetic compounds. These have IC50-values in the 10-100 μmol/L range. The most potent identified novel inhibitors from different chemical clusters are (SGLT1-IC50 Mean ± SD, SGLT2-IC50 Mean ± SD): (+)-pteryxin (12 ± 2 μmol/L, 9 ± 4 μmol/L), (+)-ε-viniferin (58 ± 18 μmol/L, 110 μmol/L), quinidine (62 μmol/L, 56 μmol/L), cloperastine (9 ± 3 μmol/L, 9 ± 7 μmol/L), bepridil (10 ± 5 μmol/L, 14 ± 12 μmol/L), trihexyphenidyl (12 ± 1 μmol/L, 20 ± 13 μmol/L) and bupivacaine (23 ± 14 μmol/L, 43 ± 29 μmol/L). The discovered natural inhibitors may be further investigated as new potential (prophylactic) agents for controlling dietary glucose uptake. The new diverse structure activity data can provide a starting point for the optimization of novel SGLT1/2 inhibitors and support the development of virtual SGLT1/2 inhibitor screening models.


Physicians in health care management: 5. Payment of physicians and organization of medical services.
The financing, payment and organization of medical services are closely related. Canada's health care system is financed publicly, from tax revenue, and administered in each province by a single government payer. Although the chief method of payment to physicians is fee for service (FFS), the need to control costs and organize practice more efficiently has led to increased interest in FFS variants, such as capping payments at a certain level or fixing a budget, and alternative payment methods such as capitation-based payment, salary and combinations of these methods. Although solo practice is reportedly still the chief method of practice organization, it is being steadily replaced by arrangements in which physicians share expenses or calls, and by formal partnerships and group and team practices. As medical practice in Canada continues to shift from solo to group and team practice alternative payment methods that facilitate these models will become more common.


Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results.
Functional reference limits describe key changes in the physiological relationship between a pair of physiologically related components. Statistically, this can be represented by a significant change in the curvature of a mathematical function or curve (e.g., an observed plateau). The point at which the statistical relationship changes significantly is the point of curvature inflection and can be mathematically modeled from the relationship between the interrelated biomarkers. Conceptually, they reside between reference intervals, which describe the statistical boundaries of a single biomarker within the reference population, and clinical decision limits that are often linked to the risk of morbidity or mortality and set as thresholds. Functional reference limits provide important physiological and pathophysiological insights that can aid laboratory result interpretation. Laboratory professionals are in a unique position to harness data from laboratory information systems to derive clinically relevant values. Increasing research on and reporting of functional reference limits in the literature will enhance their contribution to laboratory medicine and widen the evidence base used in clinical decision limits, which are currently almost exclusively contributed to by clinical trials. Their inclusion in laboratory reports will enhance the intellectual value of laboratory professionals in clinical care beyond the statistical boundaries of a healthy reference population and pave the way to them being considered in shaping clinical decision limits. This review provides an overview of the concepts related to functional reference limits, clinical examples of their use, and the impetus to include them in laboratory reports.


Sialic acids (N,7-O-diacetylneuraminic acid and N-acetylneuraminic acid) in Escherichia coli. I. Isolation and identification.
DeWitt, Charles W. (The Upjohn Co., Kalamazoo, Mich.) and Janet A. Rowe. Sialic acids (N,7-O-diacetylneuraminic acid and N-acetylneuraminic acid) in Escherichia coli. I. Isolation and identification. J. Bacteriol. 82:838-848. 1961.-Two sialic acids, N-acetylneuraminic acid and N,7-O-diacetylneuraminic acid, were obtained in crude mixtures from whole cells of Escherichia coli and from its endotoxin by weak acid hydrolysis followed by anion exchange resin chromatography. Yields from whole cells were 0.1 to 0.2% (dry weight) with 50 to 60% purity. Identification of the sialic acids was by comparative paper chromatography and colorimetric assays using the acidic p-dimethylaminobenzaldehyde (direct Ehrlich), resorcinol and thiobarbituric acid reactions. The N-acetyl derivative was also shown to be susceptible to hydrolysis by clostridial N-acetylneuraminic aldolase and the end products identified, N-acetylamannosamine by paper chromatography and pyruvic acid by oxidation of DPNH with lactic acid dehydrogenase. The two sialic acids were separated on paper chromatograms, eluted, and assays for total and ester acyl groups showed the suspected N-acetyl derivative to contain 0.11 O-acyl and 1.16 N-acetyl groups per mole sialic acid and the diacetyl derivative to have 1.10 O-acyl and 0.93 N-acetyl groups per mole. The O-acyl group was identified as acetyl by preparation of the hydroxamate.