Sublingual 'oral tolerance' induction with antigen conjugated to cholera toxin B subunit generates regulatory T cells that induce apoptosis and depletion of effector T cells.
Sublingual (s.l.) immunotherapy has in the last decade emerged as an effective approach to desensitize patients with pollen, food and insect sting allergies. This treatment has recently also attracted interest as a potential modality to control self-reactive T-cell responses associated with autoimmune disorders. Here, we show that s.l. administration of ovalbumin (OVA) conjugated to cholera toxin B subunit (CTB) (OVA/CTB) can efficiently suppress peripheral effector T (Teff) cell responses to OVA in mice that had adoptively received OVA-specific T-cell receptor (TCR) transgenic CD4(+) T cells, and that the suppression was associated with the development of OVA-specific Foxp3(+)CD25(+)CD4(+) regulatory T (Treg) cells as well as with apoptosis (Annexin V(+)) and depletion of OVA-specific Teff cells in peripheral lymph nodes. The induction of Teff cell apoptosis by s.l. OVA/CTB administration was found to be critically dependent on CD25(+) Treg cells but independent of IL-10 production. Our results suggest that s.l administration of a CTB-conjugated antigen can efficiently induce peripheral Teff cell tolerance through the induction of antigen-specific Treg cells that both inhibit Teff cell proliferation and cytokine production and induce Teff cell apoptosis and depletion.


Nickel-Catalyzed C-Heteroatom Cross-Coupling Reactions under Mild Conditions via Facilitated Reductive Elimination.
The formation of C-heteroatom bonds represents an important type of bond-forming reaction in organic synthesis and often provides a fast and efficient access to privileged structures found in pharmaceuticals, agrochemical and materials. In contrast to conventional Pd- or Cu-catalyzed C-heteroatom cross-couplings under high-temperature conditions, recent advances in homo- and heterogeneous Ni-catalyzed C-heteroatom formations under mild conditions are particularly attractive from the standpoint of sustainability and practicability. The generation of NiIII and excited NiII intermediates facilitate the reductive elimination step to achieve mild cross-couplings. This review provides an overview of the state-of-the-art approaches for mild C-heteroatom bond formations and highlights the developments in photoredox and nickel dual catalysis involving SET and energy transfer processes; photoexcited nickel catalysis; electro and nickel dual catalysis; heterogeneous photoredox and nickel dual catalysis involving graphitic carbon nitride (mpg-CN), metal organic frameworks (MOFs) or semiconductor quantum dots (QDs); as well as more conventional zinc and nickel dual catalyzed reactions.


Impact of warming on biofouling communities in the northern Persian Gulf.
While the impact of ocean warming on single species is well described, the impact on marine biofouling communities is not well understood. Effluents of power plants have higher temperatures and can be used as natural large-scale test sites to investigate warming effects on marine ecosystems. In the present study, we evaluated the impact of elevated temperatures in the vicinity of a power plant on macro-biofouling communities in the northern coast of the Persian Gulf. The impact site was on average 2 °C warmer than the control site. Our results demonstrate a significantly different structure and composition of biofouling communities between control and impact sites. Warming led to a 1.5-fold increase in the mean coverage of biofouling communities and slightly decreased functional and species richness. Our results indicated that future warming will likely increase biofouling pressure, while decreasing diversity of communities, particularly in habitats where organisms exist at their upper tolerance limits of temperature.


In Your Face(t)-Personality Traits Interact With Prototypical Personality Faces in Economic Decision Making.
In everyday life, assumptions about our peers' as well as our own personality shape social interactions. We investigated whether self-rated personality and inferences drawn from partners' faces influence economic decisions. Participants (N = 285) played the trust game in the role of the trustor as well as the ultimatum game in the role of the proposer and interacted with trustees and receivers represented by prototypical personality faces. Participants also evaluated both their own traits and the personality of the faces. In the trust game, trustees represented by faces rated higher on agreeableness yielded higher transferred amounts. This effect was more pronounced for trustors low on dispositional trust, whereas trustors high on dispositional trust did not relate their decisions to the faces. Trustees represented by faces rated higher on conscientiousness yielded higher transferred amounts only for trustors high on dispositional anxiety. In the ultimatum game, receivers represented by faces rated higher on conscientiousness yielded lower offers only for proposers high on dispositional assertiveness. These results extend previous findings on the inferences drawn from facial features and the influence of personality on decision making. They highlight the importance of considering the personality of both interaction partner, as well as potential interactions of players' traits.


Improved Inversion of Monthly Ammonia Emissions in China Based on the Chinese Ammonia Monitoring Network and Ensemble Kalman Filter.
Ammonia (NH3) emission inventories are an essential input in chemical transport models and are helpful for policy-makers to refine mitigation strategies. However, current estimates of Chinese NH3 emissions still have large uncertainties. In this study, an improved inversion estimation of NH3 emissions in China has been made using an ensemble Kalman filter and the Nested Air Quality Prediction Modeling System. By first assimilating the surface NH3 observations from the Ammonia Monitoring Network in China at a high resolution of 15 km, our inversion results have provided new insights into the spatial and temporal patterns of Chinese NH3 emissions. More enhanced NH3 emission hotspots, likely associated with industrial or agricultural sources, were captured in northwest China, where the a posteriori NH3 emissions were more than twice the a priori emissions. Monthly variations of NH3 emissions were optimized in different regions of China and exhibited a more distinct seasonality, with the emissions in summer being twice those in winter. The inversion results were well-validated by several independent datasets that traced gaseous NH3 and related atmospheric processes. These findings highlighted that the improved inversion estimation can be used to advance our understanding of NH3 emissions in China and their environmental impacts.


An investigation into human pandemic influenza virus (H1N1) 2009 on an Alberta swine farm.
On May 2, 2009 the Canadian Food Inspection Agency notified the World Organization for Animal Health that an emerging novel influenza A virus (pandemic H1N1 2009) had been confirmed on a swine farm in Alberta. Over a 4-week period pigs in this farrow-to-finish operation were clinically affected by respiratory disease consistent with an influenza A virus infection and the presence of active viral infection was confirmed in all production areas by real-time polymerase chain reaction (RT-PCR). Despite clinical recovery of animals, there was reluctance by purchasers to receive animals from this operation due to concerns about the effect on both domestic and international markets. The owner decided to depopulate the entire herd due to impending welfare issues associated with overcrowding and economic concerns resulting from the inability to market these animals. Carcasses were rendered or composted and did not enter the human food or animal feed chain. The source of virus in this herd was determined to be an infected human. Zoonotic transmission to 2 individuals responding to the outbreak was suspected and recommendations to prevent occupational exposure are discussed.


A Genome Scale Model of Geobacillus thermoglucosidasius (C56-YS93) reveals its biotechnological potential on rice straw hydrolysate.
Rice straw is a major crop residue which is burnt in many countries, creating significant air pollution. Thus, alternative routes for disposal of rice straw are needed. Biotechnological treatment of rice straw hydrolysate has potential to convert this agriculture waste into valuable biofuel(s) and platform chemicals. Geobacillus thermoglucosidasius is a thermophile with properties specially suited for use as a biocatalyst in lignocellulosic bioprocesses, such as high optimal temperature and tolerance to high levels of ethanol. However, the capabilities of G. thermoglucosidasius to utilise sugars in rice straw hydrolysate for making bioethanol and other platform chemicals have not been fully explored. In this work, we have created a genome scale metabolic model (denoted iGT736) of the organism containing 736 gene products, 1159 reactions and 1163 metabolites. The model was validated both by purely theoretical approaches and by comparing the behaviour of the model to previously published experimental results. The model was then used to determine the yields of a variety of platform chemicals from glucose and xylose - two primary sugars in rice straw hydrolysate. A comparison with results from a model of Escherichia coli shows that G. thermoglucosidasius is capable of producing a wider range of products, and that for the products also produced by E. coli, the yields are comparable. We also discuss strategies to utilise arabinose, a minor component of rice straw hydrolysate, and propose additional reactions to lead to the synthesis of xylitol, not currently produced by G. thermoglucosidasius. Our results provide additional motivation for the current exploration of the industrial potential of G. thermoglucosidasius and we make our model publicly available to aid the development of metabolic engineering strategies for this organism.


Pharmacokinetic considerations in the treatment of pediatric behavioral issues.
A review of psychopharmacology and the genetic considerations with pharmokinetics is followed through a case study to demonstrate the optimal clinical treatment of the child with pediatric behavioral issues. The knowledge of the pharmacokinetic and pharmacodynamic consequences of medications in clinical practice is of the utmost importance for all pediatric nurse practitioners. Drug interactions occur when the efficacy or toxicity of a medication is changed with the addition of another medication or dosage change. An integrative literature review from nursing, medicine, psychology, and child psychiatry. The current climate of a child psychiatric specialist shortage leaves the charge of this vulnerable population in the hands of the primary care provider. Pediatric primary care now requires a clear understanding of the psychostimulant and non-stimulant medications, thorough screening of each child, appropriate dosage regulation, and close monitoring of all outcomes. It is imperative that pediatric nurse practitioners understand the pharmacological interactions and safety in the treatment of children with behavioral issues.


Experiences in a general practitioner workshop.
The organization and working of a general practitioner workshop are described, with analyses of subjects, participants, and group dynamics. An unusual form of peer group has arisen, with trainees, trainers, and principals all contributing on an equal basis. The workshop group is suggested as a useful method of continuing education for general practitioners, using existing postgraduate facilities, with minimal financial outlay.


Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.
Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1. Other ENPP1-related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1-associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow-up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.


Evidence and future potential of mobile phone data for disease disaster management.
Global health threats such as the recent Ebola and Zika virus outbreaks require rapid and robust responses to prevent, reduce and recover from disease dispersion. As part of broader big data and digital humanitarianism discourses, there is an emerging interest in data produced through mobile phone communications for enhancing the data environment in such circumstances. This paper assembles user perspectives and critically examines existing evidence and future potential of mobile phone data derived from call detail records (CDRs) and two-way short message service (SMS) platforms, for managing and responding to humanitarian disasters caused by communicable disease outbreaks. We undertake a scoping review of relevant literature and in-depth interviews with key informants to ascertain the: (i) information that can be gathered from CDRs or SMS data; (ii) phase(s) in the disease disaster management cycle when mobile data may be useful; (iii) value added over conventional approaches to data collection and transfer; (iv) barriers and enablers to use of mobile data in disaster contexts; and (v) the social and ethical challenges. Based on this evidence we develop a typology of mobile phone data sources, types, and end-uses, and a decision-tree for mobile data use, designed to enable effective use of mobile data for disease disaster management. We show that mobile data holds great potential for improving the quality, quantity and timing of selected information required for disaster management, but that testing and evaluation of the benefits, constraints and limitations of mobile data use in a wider range of mobile-user and disaster contexts is needed to fully understand its utility, validity, and limitations.


Estrogen receptor β regulates the tumoral suppressor PTEN to modulate pituitary cell growth.
In this study, we focused on ERβ regulation in the adenohypophysis under different estrogenic milieu, by analyzing whether ER modulates the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and its subcellular localization on anterior pituitary glands from Wistar rats and GH3 lactosomatotroph cells that over-expressed ERβ. ERβ was regulated in a cyclic manner, and underwent dynamic changes throughout the estrous cycle, with decreased ERβ+ cells in estrus and under E2 treatment, but increased in ovariectomized rats. In addition, the ERα/β ratio increased in estrus and under E2 stimulation, but decreased in ovariectomized rats. Double immunofluorescence revealed that lactotroph and somatotroph ERβ+ were significantly decreased in estrus. Also, variations in the PTEN expression was observed, which was diminished with high E2 conditions but augmented with low E2 milieu. The subcellular localization of this phosphatase was cell cycle-dependent, with remarkable changes in the immunostaining pattern: nuclear in arrested pituitary cells but cytoplasmic in stimulated cells, and responding differently to ER agonists, with only DPN being able to increase PTEN expression and retaining it in the nucleus. Finally, ERβ over-expression increased PTEN with a noticeable subcellular redistribution, and with a significant nuclear signal increase in correlation with an increase of cells in G0/G1 phase. These results showed that E2 is able to inhibit ERβ expression and suggests that the tumoral suppressor PTEN might be one of the signaling proteins by which E2, through ERβ, acts to modulate pituitary cell proliferation, thereby adapting endocrine populations in relation with hormonal necessities.


[Pharmacological treatment of obesity].
The foundation on which the treatment of obesity rests is made up of the procedures aimed at unbalancing the equation of energy balance in favour of calorie consumption. Pharmacological treatment is aimed at favouring a reduction of calorie intake or stimulating calorie production. Depending on their mechanism of action, the drugs that are used in the treatment of obesity can be divided into appetite inhibitors, inhibitors of food intake or blockers of fat digestion and stimulators of thermogenesis. Amongst the appetite inhibitors, besides the adrenergic agents such as those of the amphetamine type, which are forbidden because of their addictive effect, are the serotonin uptake inhibitors such as dexfenfluramine (withdrawn in 1997) and fluoxetine. The recent commercialisation of sibutramine, a serotonin and norepinephrine reuptake inhibitor with an appetite inhibiting and thermogenesis stimulating effect, offer new perspectives in this field. Amongst inhibitors, mention is deserved by orlistat that inhibits the absorption of upto 30% of ingested fat without causing secondary effects of significance. In the area of thermogenic drugs there are the ephedrine-caffeine association, and the adrenergic beta antagonists, which are still being researched. There are numerous future perspectives amongst which are leptin, analogs of GLP-1 and cholecystokinin and neuropeptide Y antagonists. It is necessary to have reliable predictive elements that make it possible to know the most useful drugs, as well as the sort of patients who will benefit most from the different pharmacological treatments.


Induced human bone marrow stromal cells differentiate into neural cells by bFGF and cocultured with olfactory ensheathing cells.
Bone marrow stromal cells (BMSCs) were considered as one of the strongest candidates for cell transplantations to treat neurological disorders. Previously, we had showed that BMSCs isolated from rats could be induced to differentiate into neural cells being cocultured with olfactory ensheathing cells (OECs). In this study, we further demonstrated the neural differentiation of human BMSCs (hBMSCs) when cocultured with OECs and daily supplement of bFGF (basic fibroblast growth factor). Transwell culture dishes with a 0.4-mm pore size were used to coculture hBMSCs and OECs. At different time points (12h, 24h, 3d, 7d, 14d), the induced hBMSCs were morphologically observed and performed immunocytofluorescence and quantitative RT-PCR (qRT-PCR). The number of neural markers-positive cells significantly increased after coculture, and gene expression of NSE, β-III-tubulin, MAP2, GFAP also dramatically increased. Our study suggested that hBMSCs could be induced into neuron-like cells under conditions of coculture with OECs and daily supplement of bFGF. The differentiated autologous hBMSCs had a great potential for transplantation to treat CNS lesion.


High-Precision In Situ 87Sr/86Sr Analyses through Microsampling on Solid Samples: Applications to Earth and Life Sciences.
An analytical protocol for high-precision, in situ microscale isotopic investigations is presented here, which combines the use of a high-performing mechanical microsampling device and high-precision TIMS measurements on micro-Sr samples, allowing for excellent results both in accuracy and precision. The present paper is a detailed methodological description of the whole analytical procedure from sampling to elemental purification and Sr-isotope measurements. The method offers the potential to attain isotope data at the microscale on a wide range of solid materials with the use of minimally invasive sampling. In addition, we present three significant case studies for geological and life sciences, as examples of the various applications of microscale 87Sr/86Sr isotope ratios, concerning (i) the pre-eruptive mechanisms triggering recent eruptions at Nisyros volcano (Greece), (ii) the dynamics involved with the initial magma ascent during Eyjafjallajökull volcano's (Iceland) 2010 eruption, which are usually related to the precursory signals of the eruption, and (iii) the environmental context of a MIS 3 cave bear, Ursus spelaeus. The studied cases show the robustness of the methods, which can be also be applied in other areas, such as cultural heritage, archaeology, petrology, and forensic sciences.


Involvement of neutrophils in ischemic injury. I. Biochemical and histopathological investigation of the effect of FK506 on dorsal skin flaps in rats.
The purpose of this study was to investigate the role of neutrophils in ischemic tissue injury and the possible inhibition by pretreatment with FK506, a neutrophilic modulating agent. A dorsal caudally based skin flap (3 x 9 cm) was used as an ischemic injury model in experimental groups. Prior to flap elevation, FK506 at doses of 0.3 mg per kilogram (group 2), 0.5 mg per kilogram (group 3), and 1.0 mg per kilogram (group 4) was given for 3 days intramuscularly. The relationship among neutrophil accumulation (histopathologically), myeloperoxidase (MPO) activity, malondialdehyde (MDA) content (biochemically) of the flap tissue, and flap survival were studied. Skin flaps showed reduced necrosis in the FK506-treated groups (p < 0.08, p < 0.0001, and p < 0.0001 respectively). The increase in accumulation of neutrophils, and MDA and MPO levels (which were induced by ischemia) observed 1 and 24 hours after flap elevation was diminished by FK506 pretreatment. The increased neutrophilic infiltration, and raised tissue MDA content and MPO activity revealed involvement of both free radical production and neutrophils in ischemia. This injury was decreased by FK506, probably by inhibition of neutrophilic chemotaxis, infiltration, and releasing factors.


Autophagy and Lipid Droplets in the Liver.
Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.


The Management of Congenital Microphthalmia With Orbital Cyst: A Case Series.
To describe a series of patients treated for congenital microphthalmia associated with orbital cyst and recommend a management protocol. This retrospective case series comprised 6 patients (7 eyes) who attended an oculoplastic tertiary medical center from 2001 to 2018. Clinical, treatment, and outcome data were collected from the electronic files. Main outcome measures were preservation of vision and cosmetic appearance. Four patients were diagnosed at birth. Six cysts were located inferiorly and one superiorly. Two patients had a visual potential of light perception or better in the affected eye. In 4 eyes, the cyst was initially retained and the eye was fitted with a custom-made conformer. In 1 eye, the fornices were too shallow for a conformer, warranting fornix reconstruction and cyst excision. Early surgery was required in 1 eye for an expanded cyst and large orbit volume, and in another eye the cyst had overgrown the orbit, causing bone erosion and remodeling. Cosmetic results were good in 3 of the eyes in which the cyst was retained in early childhood, stimulating orbital growth. Congenital microphthalmia with orbital cyst is rare. Management should focus on preserving visual potential, especially in unilateral cyst cases when the other eye is also microphthalmic. Otherwise cosmetic symmetry is the main concern; cyst retention combined with ocular conformers may stimulate socket expansion. The authors found that, in most cases, if treated early, enucleation was avoidable during cyst excision. Early assessment, meticulous follow-up, and individually tailored treatment are warranted. [J Pediatr Ophthalmol Strabismus. 2022;59(3):192-199.].


Outcomes of rapid response team implementation in tertiary private hospitals: a prospective cohort study.
Cardiopulmonary arrest may result in high mortality rate in hospitals where the rapid response team is not implemented. A rapid response system can recognize patients at high risk of cardiopulmonary arrest and provide the needed medical management to prevent further deterioration. The rapid response system has shown a dramatic reduction in mortality rate and cardiopulmonary arrest. To evaluate the effectiveness of the rapid response team (RRT) implementation in reducing the mortality rate, number of cardiopulmonary arrests, and number of ICU admission. A pre- and post-rapid response team system implementation. Four tertiary private hospitals in Saudi Arabia. A total of 154,869 patients in the 3-year before rapid response system period (January 2010 to December 2012) and a total of 466,161 during the 2.5-year post-RRT implementation period (January 2014 to June 2016). Results indicated that ward nurses activated RRT more often than physicians (1104 activations [69%] vs. 499 activations [31%]), with cardiovascular and respiratory abnormalities being the most common triggers. Serious concern about the patient condition by the ward staff was the trigger for 181 (11.29%) activations. The RRT provided a variety of diagnostic and therapeutic interventions. Most patients cared for by RRT were admitted to ICU 1103 (68.81%), and the rest 500 (31.19%) were managed in the ward. After the implementation of the RRT project, the hospital mortality rate dropped from 7.8 to 2.8 per 1000 hospital admission. Hospital cardiopulmonary arrest rate has dropped from 10.53 per 1000 hospital admissions to 2.58. Rapid response team implementation also facilitated end-of-life care discussions. Implementation of the RRT project has shown a dramatic reduction in the total ICU admissions, average ICU occupancy rate, total hospital mortality, and total ICU mortality. These findings reinforce the evidence that RRT implementation is effective in reducing hospital mortality and cardiopulmonary arrest rates in addition to other outcomes related to healthcare quality.


Insights into Ru-based molecular water oxidation catalysts: electronic and noncovalent-interaction effects on their catalytic activities.
A series of Ru-bda water oxidation catalysts [Ru(bda)L2] (H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; L = [HNEt3][3-SO3-pyridine], 1; 4-(EtOOC)-pyridine, 2; 4-bromopyridine, 3; pyridine, 4; 4-methoxypyridine, 5; 4-(Me2N)-pyridine, 6; 4-[Ph(CH2)3]-pyridine, 7) were synthesized with electron-donating/-withdrawing groups and hydrophilic/hydrophobic groups in the axial ligands. These complexes were characterized by (1)H NMR spectroscopy, high-resolution mass spectrometry, elemental analysis, and electrochemistry. In addition, complexes 1 and 6 were further identified by single crystal X-ray crystallography, revealing a highly distorted octahedral configuration of the Ru coordination sphere. All of these complexes are highly active toward Ce(IV)-driven (Ce(IV) = Ce(NH4)2(NO3)6) water oxidation with oxygen evolution rates up to 119 mols of O2 per mole of catalyst per second. Their structure-activity relationship was investigated. Electron-withdrawing and noncovalent interactions (attraction) exhibit positive effect on the catalytic activity of Ru-bda catalysts.


Implementation of Systemic Hedgehog Inhibitors in Daily Practice as Neoadjuvant Therapy.
The most common cancer in both men and women is basal cell carcinoma (BCC). Although most primary and recurrent BCCs have high cure rates with standard therapies, advanced BCCs present a greater treatment challenge, especially in cosmetically and functionally sensitive areas. In patients unable to undergo surgery or radiation therapy, hedgehog inhibitors can be used neoadjuvantly to reduce tumor size, decreasing the extent and complexity of any subsequent surgery and providing either a cure or palliation. The goal of this review is to summarize the pharmacology, efficacy, and safety of systemic hedgehog inhibitors, as well as their role in daily practice as neoadjuvant therapy. Relevant English-language literature was identified and evaluated based on results from database searches of PubMed. Terms searched included, but were not limited to, "vismodegib," "Erivedge," "sonidegib," "DE225," "BCC," and "neoadjuvant treatment." Additional literature was identified from the reference lists of previously identified articles. The authors' personal experience in treating advanced BCC using hedgehog inhibitors has been incorporated into the recommendations made herein.


Inhibition of human low-density lipoprotein oxidation in vitro by ginger extracts.
Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in atherosclerotic plaque formation. Currently, there is a renewed interest in ginger because of its antioxidants and cardioprotective properties. The effects of ethanol, methanol, ethyl acetate, and hexane solvent extracts of ginger and pure major ginger constituents on Cu(2+)-induced oxidation of human LDL in vitro were examined. The LDL oxidation inhibition by ethanol, methanol, ethyl acetate, and hexane extracts of ginger was 71%, 76%, 67%, and 67%, respectively, at their optimum extraction conditions. Inhibition of LDL oxidation by water extracts of ginger, which was prepared by ultrasonic-assisted extraction conditions of 52°C for 15 min, was about 43%. Phenolic bioactives of ginger-6-gingerols, 8-gingerols, 10-gingerols, and 6-shogaol-seem to be strong inhibitors of Cu(+2)-induced LDL oxidation. Overall, ginger extracts, including the water extract possess the antioxidant activities to inhibit human LDL oxidation in vitro.


Improved targeting of brain tumors using dexrazoxane rescue of topoisomerase II combined with supralethal doses of etoposide and teniposide.
Dexrazoxane (ICRF-187) is a catalytic inhibitor of the nuclear enzyme DNA topoisomerase II (topo II). It protects cells against topo II poisons, such as etoposide and teniposide, by hindering the DNA cleavage reaction of the target enzyme. We have previously shown that this antagonism also extends to an in vivo model. Thus, ICRF-187 protected mice against supralethal doses of etoposide and amsacrine, and the etoposide LD10 dose increased as much as 3.6-fold when combined with ICRF-187 (B. Holm, Cancer Chemother. Pharmacol., 38: 203-209, 1996). We describe here how scheduling of this drug combination can be optimized and used. Interestingly, ICRF-187 can protect when it is given after etoposide. Although timing is very critical here, ICRF-187 was able to completely protect when given 10 min after etoposide. This rescue principle resembles methotrexate rescue by folinic acid. We also found scheduling to be crucial because ICRF-187 did not protect when etoposide was given once a day for five days, whereas effective protection was seen when etoposide was used three times, once every four days. Similar investigations were performed with teniposide in combination with ICRF-187. The combination with ICRF-187 allowed a 3.4-fold teniposide dose escalation. Such dose escalations could be advantageous in specific situations. One such case is when the tumor is situated in a pharmacological sanctuary, e.g., in the brain. ICRF-187 is hydrophilic and does not cross the blood-brain barrier, whereas the lipophilic etoposide and teniposide do. Therefore, ICRF-187 would protect normal tissues and allow a cytotoxic dose of etoposide to reach the central nervous system (CNS). We therefore studied the combinations using L1210 or EHR2 cells inoculated into the CNS of mice. L1210 presented a leukemic CNS model with leptomeningeal spread and infiltration of liver, spleen, and lymph nodes, whereas EHR2 cells acted as a solid tumor with no evidence of extracerebral disease. In all experiments, the combination of high-dose etoposide and ICRF-187 was significantly superior to an equitoxic dose of etoposide alone. Such superiority was also seen when treatment was given on days 4, 8, and 12 after tumor inoculation. Here etoposide alone resulted in a mean increased life span of 12.3%, whereas the rescue regimen yielded an increase of 47% (P < 0.0001). In conclusion, DNA topo II rescue by catalytic inhibitors is a new strategy enabling significant epipodophyllotoxin dose escalations; in this study, we have demonstrated the superiority of this strategy in two in vivo CNS tumor models. This concept is now being tested in a clinical trial.


Drug metabolism in isolated proximal tubule cells: aldehyde dehydrogenase.
The mammalian kidney is composed of numerous cell populations associated with the interstitial spaces, vasculature and various portions of the nephron. Not surprisingly, mammalian kidneys also exhibit an array of drug metabolizing activities, including the pyridine nucleotide-linked aldehyde dehydrogenase(s) (ALDH). To define the ALDH activity in segment 2 of the proximal tubule, a portion of the nephron which frequently shows drug-induced pathology, proximal tubules were isolated by purely mechanical methods from female rabbits. Isopycnic centrifugation of tubule-derived postnuclear supernates in linear sucrose gradients resulted in propionaldehyde (5 mM)-driven ALDH activity being distributed in a manner consistent with both a mitochondrial and cytosolic localization. Mitochondrial and cystosolic fractions yielded biphasic reciprocal plots when propionaldehyde was used as substrate. Km values of 282 microM and 4 mM were obtained from the mitochondrial enzymes, whereas the cytosolic enzymes gave KmS of 132 microM and 2.4 mM. The apparent Vmax values (nanomoles of NADH produced per minute per milligram of protein) are 16.3 and 37.8 for the mitochondrial enzymes and 23.5 and 19.0 for the cytosolic enzymes. Thus, the S2 proximal tubule cells contain ALDH activities at levels and subcellular sites comparable to those found in the liver. Because the proximal tubules constitute approximately 40% of the renal cortical mass, the high levels of ALDH activity observed in these cells may protect other cortical cells and more distal nephron components by detoxifying potentially cytotoxic aldehydes.


Implementation of a Personalized, Cost-Effective Physical Therapy Approach (Coach2Move) for Older Adults: Barriers and Facilitators.
This article reports on a recent randomized clinical trial that showed a personalized approach to physical therapy (Coach2Move) by a physical therapist specialized in geriatrics (PTG) to be more cost-effective than usual physical therapy care in people with mobility problems (n = 130, mean age = 78 years). We used an explanatory mixed-methods sequential design alongside the randomized clinical trial to gain insight into (a) the contrast between the 2 interventions, (b) the fidelity of the Coach2Move delivery; (c) PTGs' experiences of Coach2Move; and (d) possible barriers and facilitators for future implementation. The study included 13 PTGs educated in the strategy and 13 physical therapists with expertise in geriatrics delivering the usual care. In total, 106 medical records were available for assessment: 57 (85%) Coach2Move, 49 (75%) usual care. Quantitative process indicators were used to analyze electronic medical records to determine contrasts in the phases of clinical reasoning. The fidelity of the delivery was tested using indicator scores focusing on 4 key elements of Coach2Move. In-depth interviews with Coach2Move therapists were thematically analyzed to explore experiences and facilitators/barriers related to implementation. Indicator scores showed significant and clinically relevant contrasts in all phases of clinical reasoning, with consistently higher scores among PTGs, except for the treatment plan. Moreover, the fidelity of Coach2Move delivery was more than 70% in all phases, except the evaluation phase (53%). Experiences of Coach2Move were positive. In particular, extended intake allowing motivational interviewing, physical examination and an in-depth problem analysis, and shared goal setting were considered valuable. Facilitators for implementation were the addition of a Coach2Move medical record, frequent coaching by the researcher, and readiness to change in the therapist. Barriers were (1) having to use 2 parallel electronic medical record systems, (2) having to clear the calendar to schedule an intake of 90 minutes, (3) fear of losing income, (4) the sense that patients do not want to change their lifestyle, and (5) not acknowledging that increasing physical activity is an important goal for older adults with mobility problems. Physical therapy based on the Coach2Move strategy is substantially different from usual care. Future implementation should focus on increasing regular evaluation and feedback, taking into account individuals' contextual factors, and improving organizational facilities while mitigating income loss.


Involvement of TRPV2 activation in intestinal movement through nitric oxide production in mice.
Transient receptor potential channel vanilloid 2 (TRPV2) can detect various stimuli such as temperature (>52 °C), stretch, and chemicals, including 2-aminoethoxydiphenyl borate, probenecid, and lysophospholipids. Although expressed in many tissues, including sensory and motor neurons, TRPV2 expression and function in the gastrointestinal tract is poorly understood. Here, we show TRPV2 expression in the murine intestine and its involvement in intestinal function. Almost all mouse intestinal intrinsic sensory and inhibitory motor neurons, both cell bodies and nerve fibers, showed TRPV2 immunoreactivity. Several known TRPV2 activators increased cytosolic Ca²+ concentrations and evoked TRPV2-like current responses in dissociated myenteric neurons. Interestingly, mechanical stimuli activated inward currents in a strength-dependent manner, which were inhibited by a TRPV2 inhibitor tranilast. TRPV2 activation in isolated intestine inhibited spontaneous circular muscle contraction, which did not occur in the presence of the TRPV2 antagonist, tetrodotoxin or nitro oxide (NO) synthase pathway inhibitors. Also, increased intestinal NO production was observed in response to a TRPV2 agonist, and gastrointestinal transit in vivo was accelerated by TRPV2 agonists or an NO donor. In conclusion, TRPV2 may contribute to intestinal motility through NO production, and TRPV2 is a promising target for controlling intestinal movement.


Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression.
To test the hypothesis that oral desogestrel (DSG) plus testosterone would uniformly and rapidly suppress sperm concentrations in young men as effectively as levonorgestrel (LNG) plus testosterone and cause less high-density lipoprotein (HDL) suppression and weight gain. Single-blind, randomized trial. VA Puget Sound and University of Washington, Seattle, Washington. Twenty-four healthy young men, aged 20-49. Subjects were randomized to three groups of men who were administered 6 months of therapy with oral DSG plus im testosterone enanthate: 150 microg of DSG plus 50 mg of testosterone (DSG 150-T 50), 150 microg of DSG plus 100 mg of testosterone (DSG 150-T 100) or 300 microg of DSG plus 100 mg of testosterone (DSG 300-T 100). We compared these three groups to two groups of historical controls of 100 mg of im testosterone alone or 150 microg of oral LNG plus 100 mg of im testosterone (LNG 125-T 100 group) enrolled in similar studies. Suppression of sperm counts to severe oligoazoospermia (sperm counts <1 x 10(6)/mL) and azoospermia, weight gain, and serum high-density cholesterol (HDL) suppression. Azoospermia was achieved in all eight men receiving DSG 150-T 100 and seven of the eight men in the DSG 300-T 100 group. DSG 150 or 300 plus T 100 suppressed spermatogenesis as effectively as LNG 125-T 100 and more effectively than DSG 50-T 100 or testosterone alone. All groups tended to gain weight compared with their baseline, but the weight gain was greatest (and statistically significant) in the DSG 150-T 100, DSG 300-T 100, and LNG 125-T 100 groups. Serum HDL levels were modestly suppressed in all groups, and this effect was greatest in the DSG 300-T 100 and LNG 125-T 100 groups. The combination of DSG plus testosterone is a very effective regimen for suppression of spermatogenesis and has acceptably low side effects.


Bond strengths and adhesive remnant index of self-etching adhesives used to bond brackets to instrumented and uninstrumented enamel.
This study evaluated bond strengths of orthodontic brackets to instrumented and uninstrumented enamel using self-etching adhesive systems when compared to a total-etch adhesive system. The adhesive remnant index (ARI) was also determined after debonding. 140 bovine incisors were included in acrylic resin, and divided randomly in two groups: instrumented vs. uninstrumented enamel. For the instrumented enamel, specimens had their facial enamel ground flat to 600-grit. In each group, specimens were subdivided into four experimental subgroups according to the adhesive technique used: Transbond Plus, Adper Prompt L-Pop, iBond, and Adper Single Bond, applied following manufacturers' instructions. Orthodontic brackets were bonded to the treated instrumented or uninstrumented enamel with Transbond XT light-cured resin-based composite cement, and the bond strength was tested in shear mode after 7 days. One group where no etch and no adhesive were used served as a control. ARI scores were determined after debonding. There was no statistically significant difference in mean bond strengths between instrumented and uninstrumented enamel for any of the adhesive systems (P > or = 0.05). No significant differences were observed for bond strengths among the adhesives tested (P = 0.308), and all experimental groups resulted in mean bond strengths significantly higher than the controls (P < 0.05). Statistically significant differences were identified when ARI scores were compared, with less adhesive remnants being observed for iBond (uninstrumented enamel) and the control groups (P < 0.05).


Engaging Pediatric Resident Physicians in Quality Improvement Through Resident-Led Morbidity and Mortality Conferences.
Increasingly, medical disciplines have used morbidity and mortality conferences (MMCs) to address quality improvement and patient safety (QI/PS), as well as teach systems-based improvement to graduate trainees. The goal of this educational intervention was to establish a pediatric resident physician–led MMC that not only focused on QI/PS principles but also engaged resident physicians in QI/ PS endeavors in their clinical learning environments. Following a needs assessment, pediatric resident physicians at the Stanford University School of Medicine (Stanford, California) established a new MMC model in February 2010 as part of a required QI rotation. Cases were identified, explored, analyzed, and presented by resident physicians using the Johns Hopkins Learning from Defects tool. Discussions during the MMCs were resident physician– directed and systems-based, and resulted in projects to address care delivery. Faculty advisors assessed resident physician comprehension of QI/PS. Conferences were evaluated through the end of the 2012–2013 academic year and outcomes tracked through the 2013–2014 academic year to determine trainee involvement in systems change resulting from the MMCs. The MMC was well received and the number of MMCs increased over time. By the end of the 2013–2014 academic year, resident physicians were involved in address ing 14 systems-based issues resulting from 25 MMCs. Examples of the resident physician–initiated improvement work included increasing use of the rapid response team, institution of a gastrostomy (g)-tube order set, and establishing a face-to-face provider handoff for pediatric ICU–to-acute-care-floor transfers. A resident physician–run MMC exposes resident physicians to QI/PS concepts and principles, enables direct faculty assessment of QI/PS knowledge, and can propel resident physicians into real-time engagement in the culture of safety in a complex hospital environment.


Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses.
Rheumatoid arthritis is an autoimmune disorder that affects the joints and other organs. Pulmonary complications contribute significantly to rheumatoid arthritis mortality. Retinoic acid and its synthetic compound AM80 play roles in immunoregulation but their effect on mucosal autoimmunity remains largely unknown. T follicular helper (Tfh) and Th17 cells are known to promote inflammation and autoantibody production. Using the K/BxN autoimmune arthritis model, we elucidate a novel mechanism whereby oral AM80 administration suppressed lung mucosa-associated Tfh and autoantibody responses by increasing the gut-homing α4β7 integrin expression on Tfh cells. This diverted Tfh cells from systemic (non-gut) inflamed sites such as the lung into the gut-associated lymphoid tissues, Peyer's patches, and thus reduced the systemic autoantibodies. AM80 also inhibited the lung Th17 response. AM80's effect in the lungs was readily applied to the joints as AM80 also inhibited Tfh and Th17 responses in the spleen, the major autoantibody producing site known to correlate with K/BxN arthritis severity. Finally, we used anti-β7 treatment as an alternative approach, demonstrating that manipulating T cell migration between the gut and systemic sites alters the systemic disease outcome. The β7 blockade prevented both Tfh and Th17 cells from entering the non-immunopathogenic site, the gut, and retained these T effector cells in the systemic sites, leading to augmented arthritis. These data suggest a dual beneficial effect of AM80, targeting both Tfh and Th17 cells, and warrant strict safety monitoring of gut-homing perturbing agents used in treating intestinal inflammation.


Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA.
Ovarian cancer remains the most lethal disease among gynecological malignancies despite the plethora of research studies during the last decades. The majority of patients are diagnosed in an advanced stage and exhibit resistance to standard chemotherapy. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) represent the main liquid biopsy approaches that offer a minimally invasive sample collection. Both have shown a diagnostic, prognostic and predictive value in many types of solid malignancies and recent studies attempted to shed light on their role in ovarian cancer. This review is mainly focused on the clinical value of both CTCs and ctDNA in ovarian cancer and, more specifically, on their potential as diagnostic, prognostic and predictive tumor biomarkers.


Longitudinal nail biopsy in evaluation of acquired nail dystrophies.
We reviewed longitudinal nail biopsies performed at Henry Ford Hospital on patients with acquired nail dystrophies to see whether the procedure did, indeed, provide useful diagnostic information and to see which microscopic features were most helpful in histopathologic diagnosis. Clinical diagnoses included psoriasis, lichen planus, Darier's disease, isolated longitudinal defects, and diffuse thickening. We found that clinical diagnosis could be supported by histopathologic findings in eight of twenty cases of acquired nail dystrophy. Specifically, we were able to make a diagnosis of psoriasis in four cases, lichen planus in three cases, and Darier's disease in one case. The other twelve cases showed nonspecific eczematous changes. We conclude that the longitudinal nail biopsy may be a useful diagnostic tool in certain cases of acquired nail dystrophy.


Symptomatic treatment of the cough in whooping cough.
Whooping cough is an important cause of childhood morbidity and mortality. There are 20 to 40 million cases of whooping cough annually world-wide, 90% of which occur in developing countries, resulting in an estimated 200 to 300 000 fatalities each year. Much of the morbidity is due to the effects of the paroxysmal cough. Corticosteroids, salbutamol (beta 2 - adrenergic stimulant), and pertussis-specific immunoglobulin have been proposed as standard treatment for the cough. Antihistamines have also been administered. No systematic review of the effectiveness of any of these interventions or others has been performed. To assess the effectiveness and safety of interventions used to reduce the severity of the coughing paroxysms in whooping cough in children and adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 2, 2003); MEDLINE (January 1966 to June 2003); EMBASE (1990 to June 2003) and LILACS (1982 to November 2001). We also scanned reference lists of identified trials and contacted authors of identified trials and relevant pharmaceutical companies. Randomised and quasi-randomised controlled trials of any intervention aimed at suppressing the cough in whooping cough; excluding antibiotics and vaccines. Two reviewers independently selected studies and extracted data. Our primary outcome was frequency of paroxysms of coughing. Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis, development of serious complications, mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay. Disagreements were resolved by discussion. Nine studies satisfied the inclusion criteria but four had insufficient data for meta - analysis of pre-specified outcomes. Studies were small and poorly reported. The largest study had a sample size of 49 and the smallest study 18. All studies were performed in industrialised settings. Eligible studies assessed diphenhyramine, pertussis immunoglobulin, dexamethasone and salbutamol. No statistically significant benefit was found for any of the interventions. Diphenhydramine did not change coughing spells (mean increase of coughing spells per 24 hours 1.9 with 95%CI - 4.7 to 8.5) and pertussis immunoglobulin no change in hospital stay (0.7 days 95% CI -3.8 to 2.4), and a mean reduction of 3.1 whoops per 24 hours [95% CI -6.2; 0.02]. Dexamethasone did not show a clear decrease in hospital stay (-3.5 days 95% CI - 15.3 to 8.4) and salbutamol showed no change in coughing paroxysms per 24 hours [-0.22 95% CI - 4.13 to 3.69]. Insufficient evidence exists to draw conclusions about the effects of any intervention for the cough in whooping cough.


Dent disease 1-linked novel CLCN5 mutations result in aberrant location and reduced ion currents.
Dent disease is a rare renal tubular disease with X-linked recessive inheritance characterized by low molecular weight proteinuria (LMWP), hypercalciuria, and nephrocalcinosis. Mutations disrupting the 2Cl-/1H+ exchange activity of chloride voltage-gated channel 5 (CLCN5) have been causally linked to the most common form, Dent disease 1 (DD1), although the pathophysiological mechanisms remain unclear. Here, we conducted the whole exome capture sequencing and bioinformatics analysis within our DD1 cohort to identify two novel causal mutations in CLCN5 (c.749 G > A, p. G250D, c.829 A > C, p. T277P). Molecular dynamics simulations of ClC-5 homology model suggested that these mutations potentially may induce structural changes, destabilizing ClC-5. Overexpression of variants in vitro revealed aberrant subcellular localization in the endoplasmic reticulum (ER), significant accumulation of insoluble aggregates, and disrupted ion transport function in voltage clamp recordings. Moreover, human kidney-2 (HK-2) cells overexpressing either G250D or T277P displayed higher substrate adhesion, migration capability but reduced endocytic function, as well as substantially altered transcriptomic profiles with G250D resulting in stronger deleterious effects. These cumulative findings supported pathogenic role of these ClC-5 mutations in DD1 and suggested a cellular mechanism for disrupted renal function in Dent disease patients, as well as a potential target for diagnostic biomarker or therapeutic strategy development.


The relative importance of barriers to the prescription of warfarin for nonvalvular atrial fibrillation.
Despite the publication of a number of randomized, controlled trials demonstrating a substantial reduction in stroke with anticoagulation in patients with nonvalvular atrial fibrillation, the 'real world' use of warfarin is sub-optimal. Previous surveys have attempted to explain this problem but have significant limitations. The purpose of this study was to assess the relative importance of various barriers that may influence the prescription of warfarin in patients with nonvalvular atrial fibrillation. This cross-sectional survey was mailed to all practising cardiologists, neurologists and internists, as well as a random sample of family physicians within Alberta. Physicians caring for patients with NVAF rated the relative importance of potential barriers using a Likert scale. Sixty-seven per cent of all physicians returned the survey. Overall, barriers pertaining to the patient's clinical characteristics were rated to be more important than those pertaining to the physician or to the organization required when prescribing these therapies. Specifically, an ongoing history of falls, a history of bleeding within the previous year and an inability to comply with therapy were rated as important barriers by 64%, 55% and 53% of physicians, respectively. Most physicians strongly believed that patients should receive information on the benefits and risks of warfarin (96%) and that patients should have a say in whether warfarin is prescribed (86%). This study suggests that most of the barriers to warfarin use pertain to patient clinical characteristics and the need for patients to be involved in the decision to initiate therapy. The use of decision support technologies would facilitate involvement of the patient and serve to educate both the patient and physician on the risks and benefits of warfarin therapy.


Systematic use of half normal saline during ablation of ventricular tachycardia in structural heart disease.
Efficiency and safety of ablation using half normal saline (HNS) has been shown in refractory ventricular tachycardia (VT), but no evaluation in unselected larger populations has been made. To evaluate the efficiency and safety of systematic HNS ablation in VT ablation. All successive VT ablations in patients with structural heart disease from 2018 to 2021 used HNS in our center and were retrospectively included. One hundred seventy-seven successive VT ablation procedures using HNS have been performed in 148 patients (91% males, mean 64 ± 12 years, ischemic cardiomyopathy 64%, left ventricular ejection fraction 38 ± 13%). A mean of 19 ± 7.5 min of RF was delivered, with a mean power of 44 ± 7 W. Relevant complications happened in 9% (strokes 2%, tamponades 3%, atrioventricular block during septal ablations 5%). Over a mean follow-up of 15 ± 9 months, VT recurred in 46%. Final recurrence rate after one or several procedures was 36% (18 months follow-up). Number of VT episodes decreased from 14 ± 35 before to 2.5 ± 10 after ablation (p < .0001) and number of ICD shocks decreased from 4.8 ± 6.8 to 1.5 ± 0.8 (p = .027). Systematic use of HNS during VT ablations in patients with structural heart disease leads to long-term recurrences rates and complications in the range of what is reported using normal saline. Although controlled studies are needed for demonstrating the superiority of such attitude, the use of HNS in every scar-related VT ablation seems safe for standard cases and may be furthermore useful in case of refractory arrhythmias due to difficult-to-ablate substrates.


Pilot study of biological monitoring of four antineoplastic drugs among Canadian healthcare workers.
Purpose There are health risks to workers occupationally exposed to antineoplastic drugs. We hypothesized that implementing a biological monitoring program would be feasible. The goal was to present the results of our pilot cross-sectional study of biological monitoring of four antineoplastic drugs. Methods We recruited workers from the hematology-oncology department and control workers in a mother-child university health center. This study was preceded by an information period during which we aimed at enhancing the workers' awareness and knowledge of the risks of occupational exposure. Participants filled out a journal containing activities performed and personal protective equipment worn. One urine sample was collected at the end of their shift. Samples were analyzed by UPLC/MS-MS for the presence of cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (5-fluorouracile's main urinary metabolite). Results The participation rate was 85.7% (102/119). No urine sample had detectable concentrations of any of the four drugs evaluated (0/101; 0/74 nurses, 0/11 pharmacists, 0/9 pharmacy technicians, and 0/7 doctors). In the 5 days before sampling, 67/92 (72.8%) hematology-oncology participants performed at least one activity with antineoplastic drugs. Nurses wore all of the recommended protection for technical activities (86.2%), but rarely for non-technical activities (14.9%). Pharmacists and pharmacy technicians wore all of the recommended protection for all activities (100.0%). Conclusions This pilot study had a good participation rate. The absence of positive samples was a good indication that the measures in place ensured workers' safety, even though we found areas where the worker protection can be enhanced.


An open electromagnetic tracking framework applied to targeted liver tumour ablation.
Electromagnetic tracking is a core platform technology in the navigation and visualisation of image-guided procedures. The technology provides high tracking accuracy in non-line-of-sight environments, allowing instrument navigation in locations where optical tracking is not feasible. EMT can be beneficial in applications such as percutaneous radiofrequency ablation for the treatment of hepatic lesions where the needle tip may be obscured due to difficult liver environments (e.g subcutaneous fat or ablation artefacts). Advances in the field of EMT include novel methods of improving tracking system accuracy, precision and error compensation capabilities, though such system-level improvements cannot be readily incorporated in current therapy applications due to the 'blackbox' nature of commercial tracking solving algorithms. This paper defines a software framework to allow novel EMT designs, and improvements become part of the global design process for image-guided interventions. An exemplary framework is implemented in the Python programming language and demonstrated with the open-source Anser EMT system. The framework is applied in the preclinical setting though targeted liver ablation therapy on an animal model. The developed framework was tested with the Anser EMT electromagnetic tracking platform. Liver tumour targeting was performed using the tracking framework with the CustusX navigation platform using commercially available electromagnetically tracked needles. Ablation of two tumours was performed with a commercially available ablation system. Necropsy of the tumours indicated ablations within 5 mm of the tumours. An open-source framework for electromagnetic tracking was presented and effectively demonstrated in the preclinical setting. We believe that this framework provides a structure for future advancement in EMT system in and customised instrument design.


Stillbirth: Genome-wide copy number variation profiling in archived placental umbilical cord samples with pathologic and clinical correlation.
Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the United States. Formalin-fixed, paraffin-embedded (FFPE) umbilical cord samples are available for many stillbirths. Our aim was to validate the use of these samples in identifying genetic variations in stillbirth through microarray analysis. This is a retrospective case-control study from a single institution of stillbirths ≥ 23 weeks gestational age and control liveborn infants. Fetal genomic DNA was extracted from FFPE umbilical cord samples of stillborn and control placentas, and genotyping was performed using the Illumina HumanOmniExpresss-12v1 Beadchip. Array results were verified with qPCR. 31 case-specific CNVs (17 deletions and 14 amplifications) with an average size of 294 kb for amplifications and 74 kb for deletions were identified among 94 FFPE samples (86 cases; 8 controls). In total 38 (44%) of the stillbirth samples had a CNV detected. Validation of a subset of microarray findings with qPCR confirmed deletions on 1p (2 cases), 11q (4 cases) and amplifications on 18 (1 case). Placental underperfusion changes were seen in stillborns with deletions on 1p, a region containing complement regulatory genes which have been shown to play a role in preeclampsia. This study validated the use of archived FFPE umbilical cord samples for genome-wide copy number profiling in stillbirths, and demonstrates specific CNV deletions and amplifications. Microarray analysis in an expanded cohort of stillbirth FFPE samples has the potential to identify biomarkers involved in stillbirth pathogenesis.


Beliefs related to diet adherence of patients treated with oral anticoagulants.
Identify the beliefs related to adherence to diet of patients treated with oral anticoagulant. Descriptive study, guided by the Theory of Reasoned Action, conducted with 57 patients in continuous use of oral anticoagulants, attended at a general cardiology outpatient clinic in João Pessoa and specialized in anticoagulation in Recife. Data were collected from February to May 2017, with an application form with open questions, through an interview, and submitted to a descriptive analysis. The most mentioned positive behavioral beliefs were to improve health/treatment in the general outpatient clinic and to control coagulation, in the specialized service. Children, spouses, doctors, and parents stood out proportionally in both scenarios as positive normative beliefs. In the outpatient clinic specializing in oral anticoagulation, patients add more specific beliefs about the interference of vitamin K-rich diet on coagulation, when compared to those in the general cardiology outpatient clinic.


Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults.
Research indicates that the chronic consumption of flavonoids is associated with cognitive benefits in adults with mild cognitive impairment and neurodegenerative disease, although to our knowledge, there have been no such studies in healthy older adults. Furthermore, the effects of commonly consumed orange juice flavanones on cognitive function remain unexplored. We investigated whether 8 wk of daily flavanone-rich orange juice consumption was beneficial for cognitive function in healthy older adults. High-flavanone (305 mg) 100% orange juice and an equicaloric low-flavanone (37 mg) orange-flavored cordial (500 mL) were consumed daily for 8 wk by 37 healthy older adults (mean age: 67 y) according to a crossover, double-blind, randomized design separated by a 4-wk washout. Cognitive function, mood, and blood pressure were assessed at baseline and follow-up by using standardized validated tests. Global cognitive function was significantly better after 8-wk consumption of flavanone-rich juice than after 8-wk consumption of the low-flavanone control. No significant effects on mood or blood pressure were observed. Chronic daily consumption of flavanone-rich 100% orange juice over 8 wk is beneficial for cognitive function in healthy older adults. The potential for flavanone-rich foods and drinks to attenuate cognitive decline in aging and the mechanisms that underlie these effects should be investigated.


Some effects of selection strategies on linkage analysis.
A study was designed to address the relative merits of different sampling strategies for detecting linkage. Genotypes of pedigree members were generated by the use of a single genetic model, and the pedigrees were subdivided into dominant-appearing, recessive-appearing, and "interesting" subsets. An investigator blind to how the data had been generated applied two different selection rules to determine which individuals in each pedigree would be "typed" for linkage analysis. Linkage analyses were then conducted on these pedigree subsets, as well as on the combined data, by the use of three autosomal dominant models, three autosomal recessive models, and the generating (i.e., "true") model. Results suggest (1) that linkage is likely to be detected even in the absence of knowledge of the mode of transmission, if a range of models can be examined; (2) that false evidence for heterogeneity will not necessarily result when pedigrees are selected according to apparent mode of transmission for analysis; (3) that recessive-appearing pedigrees (i.e., those with multiplex sibships) may be particularly useful for detecting linkage; and (4) that including information on unaffected second-degree relatives adds little to linkage studies of affected individuals and their first-degree relatives.


The effect of population-based mammography screening in Dutch municipalities on breast cancer mortality: 20 years of follow-up.
Long-term follow-up data on the effects of screening are scarce, and debate exists on the relative contribution of screening versus treatment to breast cancer mortality reduction. Our aim was therefore to assess the long-term effect of screening by age and time of implementation. We obtained data on 69,630 breast cancer deaths between 1980 and 2010 by municipality (N = 431) and age of death (40-79) in the Netherlands. Breast cancer mortality trends were analyzed by defining the municipality-specific calendar year of introduction of screening as Year 0. Additionally, log-linear Poisson regression was used to estimate the turning point in the trend after Year 0, per municipality, and the annual percentage change (APC) before and after this point. Twenty years after introduction of screening breast cancer mortality was reduced by 30% in women aged 55-74 and by 34% in women aged 75-79, compared to Year 0. A similar and significant decrease was present in municipalities that started early (1987-1992) and late (1995-1997) with screening, despite the difference in availability of effective adjuvant treatment. In the age groups 55-74 and 75-79, the turning point in the trend in breast cancer mortality was estimated in Years 2 and 6 after the introduction of screening, respectively, after which mortality decreased significantly by 1.9% and 2.6% annually. These findings show that the implementation of mammography screening in Dutch municipalities is associated with a significant decline in breast cancer mortality in women aged 55-79, irrespective of time of implementation.


A long-lived peptide-conjugated iridium(iii) complex as a luminescent probe and inhibitor of the cell migration mediator, formyl peptide receptor 2.
Formyl peptide receptors play important biological and therapeutic roles in wound repair and inflammatory diseases. In this work, we present a luminescent iridium(iii) complex (6) conjugated with the peptide agonist WKYMVm as a luminescent formyl peptide receptor 2 (FPR2) imaging probe in living cells. Complex 6 displayed ideal cell imaging characteristics, high photostability and low cytotoxicity. Competition assays with a known FPR2 antagonist, WRW4, and siRNA knockdown experiments both revealed that complex 6 selectively targeted FPR2 in living HUVEC cells. Moreover, complex 6 regulated FPR2 signalling in HUVEC cells as shown using a mechanical scratch assay. Finally, complex 6 reduced epithelial cell migration capacity and inhibited lipoxin A4 (LXA4)-triggered cell migration in HUVEC cells, demonstrating the ability of this complex to inhibit FPR2 in living cells. To our knowledge, this is the first long-lived probe for imaging FPR2 in living cells.


[Consensus Document. Update on latex exposure and use of gloves in Italian health care settings].
This consensus document was prepared by an Italian working group including occupational health professionals involved for many years in the management of glove- and latex-related problems in health care settings. The aim of this document was to address the most significant technical, epidemiological, clinical, environmental and prevention problems related to the use of gloves and latex. The group's recommendations are based on scientific evidence and practical experience but they cannot be considered as final. These topics need to be periodically revised. The following points should be taken into account: glove quality seems to have improved considerably but the information on glove features provided by the manufacturers is often still inaccurate or incomplete; the regulations in force provide that the manufacturers perform tests to supply evidence for the quality of the products but they do not indicate which analytical method should be used and they do not require that the results be reported in the technical data sheets. Thus the manufacturers have only to declare that their products are "in accordance with the rules"; therefore, purchasers should require the manufacturing companies to supply detailed information and verify their reliability. Moreover, the rules should be adapted to higher quality standards; occupational physicians must be involved for the correct choice and purchase of protective gloves; the use of gloves (in particular latex gloves) and latex devices in health care settings should be based on specific criteria: procedures must be available stating which kind of gloves are suitable for specific tasks. When exposure to latex cannot be avoided it is necessary to choose products that have good biocompatibility (e.g., powder free-gloves with low allergen content); once and for all latex powdered gloves should no longer be commercially available! labels for latex devices (including gloves) should report the extractable latex allergen content. Limit values for extractable latex allergens should be established; the use of synthetic rubber gloves should be encouraged since some materials (e.g., neoprene and nitrile rubber) appear to have physical properties and protective efficacy similar to latex, plus good biocompatibility; more studies should be promoted to verify the protective efficacy of new synthetic materials; health care workers should be informed about the advisability and usefulness of using materials other than latex; health care services should not cause additional risks but rather highlight the advantages for workers and patients if the use of latex gloves and devices is minimized.


MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors.
We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 microg MT110 on days 0-4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 microg doses of MT110 on days 8-12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.


Pericardiocentesis using echocardiography.
Echocardiography is the procedure of choice for the detection and localization of pericardial effusion. It should be performed in all patients prior to elective pericardiocentesis to confirm the diagnosis and to determine the size and location of the effusion in order to minimize the risk and to maximize the yield of pericardiocentesis. When pericardial tamponade is suspected, echocardiography should be performed, time permitting, to document the presence of effusion, because other clinical entities, such as right ventricular failure, may mimic tamponade. Additionally, the finding of diastolic posterior motion of the right ventricular wall, or "diastolic collapse" of the right ventricle, is further evidence for the presence of tamponade and, at times, may eliminate the need for invasive hemodynamic diagnosis. Echocardiography is also useful when performed during pericardiocentesis, to evaluate the size and location of the effusion as the procedure progresses. Contrast echocardiography can determine the position of the pericardiocentesis needle quickly and safely. Thus the appropriate use of echocardiography has increased the safety and improved the yield of diagnostic and therapeutic pericardiocentesis.


Attitudes and beliefs of marriage and family therapists regarding psychotropic drugs and therapy.
Clinical members of AAMFT were solicited by means of a randomized multi-staged clustering technique to identify their attitudes and beliefs regarding psychotropic drugs. All participants were blind to the overall purpose of the study (n = 322) and were directed to read a clinical vignette and then identify what course of action they would take with the client. They were then asked to complete a small questionnaire regarding their attitudes and beliefs regarding psychotropic drugs. Results of the study showed that 35.7% of the clinicians identified medication and a medication referral as a viable treatment option they might pursue with a client meeting criteria for major depressive episode. Clinicians who reported having a dedicated university class (17.2%) in psychopharmacology were more likely to identify medication referral as a treatment option. However, 80% of the AAMFT clinicians we surveyed reported that they were not adequately trained about psychotropic medications in their graduate programs. Further implications regarding diagnostic practices are also discussed, as 26% of clinicians failed to explicitly diagnose the client in the case vignette with depression.


[Impact of atmospheric by-product-coking emission on malignancy morbidity].
A statistically significant direct strong correlation was found and an interval was determined between the annual volumes of atmospheric emission from OAO "KOKS" and the standardized (lung, gastric, skin, thyroid, breast, and ovarian) malignancy morbidity rates in Kemerovo. There were gender differences in the incidence of malignancies. The calculated regression coefficients can predict a probable rise in malignancy morbidity in Kemerovo from 2010 due to the increased volumes of atmospheric emission by OAO "KOKS since 2001.


Phylogenetic analysis of the acetyl-CoA carboxylase and 3-phosphoglycerate kinase loci in wheat and other grasses.
We have applied a two-gene system based on the sequences of nuclear genes encoding multi-domain plastid acetyl-CoA carboxylase (ACCase) and plastid 3-phosphoglycerate kinase (PGK) to study grass evolution. Our analysis revealed that these genes are single-copy in most of the grass species studied, allowing the establishment of orthologous relationships between them. These relationships are consistent with the known facts of their evolution: the eukaryotic origin of the plastid ACCase, created by duplication of a gene encoding the cytosolic multi-domain ACCase gene early in grass evolution, and the prokaryotic (endosymbiont) origin of the plastid PGK. The major phylogenetic relationships among grasses deduced from the nucleotide sequence comparisons of ACCase and PGK genes are consistent with each other and with the milestones of grass evolution revealed by other methods. Nucleotide substitution rates were calculated based on multiple pairwise sequence comparisons. On a relative basis, with the divergence of the Pooideae and Panicoideae subfamilies set at 60 million years ago (MYA), events leading to the Triticum/Aegilops complex occurred at the following intervals: divergence of Lolium (Lolium rigidum) at 35 MYA, divergence of Hordeum (Hordeum vulgare) at 11 MYA and divergence of Secale (Secale cereale) at 7 MYA. On the same scale, gene duplication leading to the multi-domain plastid ACCase in grasses occurred at 129 MYA, divergence of grass and dicot plastid PGK genes at 137 MYA, and divergence of grass and dicot cytosolic PGK genes at 155 MYA. The ACCase and PGK genes provide a well-understood two-locus system to study grass phylogeny, evolution and systematics.


[Degradation and uptake of 14C labeled casein peptides by mixed bacteria of the rumen].
This work studied the in vitro degradation by mixed rumen bacteria of various 14C-labelled fractions of casein peptides, of known molecular size, added to a total unlabelled casein hydrolysate. Size exclusion HPLC was used in order to segregate the casein peptides according to their molecular weights. Radioactivity associated with the bacteria increased over time. The way 14C was incorporated into the bacteria depended on the size of the labelled peptides initially added. Small peptides (1 to 2 kDa) were very rapidly assimilated, whereas radioactivity coming from larger peptides (5 to 10 kDa) tended to accumulate far more slowly in the bacterial pellet. The disappearance rates of the radioactivity differed between the fractions. The longest peptides disappeared more quickly than the medium-sized ones, which in turn were hydrolysed more rapidly than the smallest ones. Here, the uptake of small peptides seems to be the limiting step of the peptides utilization by bacteria.


Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations.
BRAF mutations occur in non-small-cell lung cancer. Therapies targeting BRAF mutant tumors have recently been identified. We undertook this study to determine the clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. We reviewed data from consecutive patients with lung adenocarcinoma whose tumors underwent BRAF, EGFR, and KRAS mutation testing as well as fluorescence in situ hybridization for ALK rearrangements. Patient characteristics including age, sex, race, performance status, smoking history, stage, treatment history, and overall survival were collected. Among 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). Mutations in EGFR were present in 24%, KRAS in 25%, and ALK translocations in 6%. In contrast to patients with EGFR mutations and ALK rearrangements who were mostly never smokers, all patients with BRAF mutations were current or former smokers (P < .001). The median overall survival of advanced-stage patients with BRAF mutations was not reached. In comparison, the median overall survival of patients with EGFR mutations was 37 months (P = .73), with KRAS mutations was 18 months (P = .12), and with ALK rearrangements was not reached (P = .64). BRAF mutations occur in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The incidence of BRAF mutations other than V600E is significantly higher in lung cancer than in melanoma.


Extension of conditional probability and measures of belief and disbelief in a hypothesis based on uncertain evidence.
Conditional probability is extended so as to be conditioned by an uncertain proposition of which truth value is ¿ (0 ¿ ¿ ¿ 1). Using the extended conditional probability, the measure of increased belief and disbelief in a hypothesis resulting from the observation of uncertain evidence are derived from MYCIN's measures based on certain evidence. On the comparison with our measures, it is shown that MYCIN's intuitive measures based on uncertain evidence, called the strength of evidence, utilize affirmative information which increases belief in the uncertain evidence but ignore negative information which causes new doubt in the uncertain evidence. An interpretation of the disregard of the negative information is presented from the viewpoint of cognitive psychology. It is pointed out that this disregard of the negative information is reasonable for a model of human inference but the negative information must also be utilized in order to evaluate a hypothesis correctly, or impartially on the basis of uncertain evidence. Our measures provide a means for utilizing both the affirmative and negative information on uncertain evidence. It is shown that inference based on the negation of evidence, which is contained in one of our measures, is difficult for an expert. A method for estimating the measure is presented which does not demand the difficult inference from an expert. The significance of the method is explained from the viewpoint of cognitive psychology.


DNA methylation profiling in nanochannels.
We report the profiling of the 5-methyl cytosine distribution within single genomic-sized DNA molecules at a gene-relevant resolution. This method linearizes and stretches DNA molecules by confinement to channels with a dimension of about 250×200 nm(2). The methylation state is detected using fluorescently labeled methyl-CpG binding domain proteins (MBD), with high signal contrast and low background. DNA barcodes consisting of methylated and non-methylated segments are generated, with both short and long concatemers demonstrating spatially resolved MBD binding. The resolution of the technique is better than 10 kbp, and single-molecule read-lengths exceeding 140 kbp have been achieved.


DNA Replication Origins and Fork Progression at Mammalian Telomeres.
Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions.


Personalized Multitask Learning for Predicting Tomorrow's Mood, Stress, and Health.
While accurately predicting mood and wellbeing could have a number of important clinical benefits, traditional machine learning (ML) methods frequently yield low performance in this domain. We posit that this is because a one-size-fits-all machine learning model is inherently ill-suited to predicting outcomes like mood and stress, which vary greatly due to individual differences. Therefore, we employ Multitask Learning (MTL) techniques to train personalized ML models which are customized to the needs of each individual, but still leverage data from across the population. Three formulations of MTL are compared: i) MTL deep neural networks, which share several hidden layers but have final layers unique to each task; ii) Multi-task Multi-Kernel learning, which feeds information across tasks through kernel weights on feature types; and iii) a Hierarchical Bayesian model in which tasks share a common Dirichlet Process prior. We offer the code for this work in open source. These techniques are investigated in the context of predicting future mood, stress, and health using data collected from surveys, wearable sensors, smartphone logs, and the weather. Empirical results demonstrate that using MTL to account for individual differences provides large performance improvements over traditional machine learning methods and provides personalized, actionable insights.


"Wisdom, bias, and balance: Toward a process-sensitive measurement of wisdom-related cognition": Correction to Brienza et al. (2017).
Reports an error in "Wisdom, bias, and balance: Toward a process-sensitive measurement of wisdom-related cognition" by Justin P. Brienza, Franki Y. H. Kung, Henri C. Santos, D. Ramona Bobocel and Igor Grossmann (Journal of Personality and Social Psychology, Advanced Online Publication, Sep 21, 2017, np). In the article, the original supplemental material has been revised to include a clarifying note to the Tests of model fit over larger sample (Samples C-G) section and post-peer review analyses added to the Post-peer review Factor Analytic Tests section. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2017-42043-001.) Philosophers and behavioral scientists refer to wisdom as unbiased reasoning that guides one toward a balance of interests and promotes a good life. However, major instruments developed to test wisdom appear biased, and it is unclear whether they capture balance-related tendencies. We examined whether shifting from global, de-contextualized reports to state-level reports about concrete situations provides a less biased method to assess wise reasoning (e.g., intellectual humility, recognition of uncertainty and change, consideration of the broader context at hand and perspectives of others, integration of these perspectives or compromise), which may be aligned with the notion of balancing interests. Results of a large-scale psychometric investigation (N = 4,463) revealed that the novel Situated WIse Reasoning Scale (SWIS) is reliable and appears independent of psychological biases (attribution bias, bias blind spot, self-deception, and impression management), whereas global wisdom reports are subject to such biases. Moreover, SWIS scores were positively related to indices of living well (e.g., adaptive emotion regulation, mindfulness), and balancing of cooperative and self-protective interests, goals (influence-vs.-adjustment), and causal inferences about conflict (attribution to the self-vs.-other party). In contrast, global wisdom reports were unrelated or negatively related to balance-related measures. Notably, people showed modest within-person consistency in wise reasoning across situations or over time, suggesting that a single-shot measurement may be insufficient for whole understanding of trait-level wisdom. We discuss theoretical and practical implications for research on wisdom, judgment and decision making, well-being, and prosociality. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


[Combination of pegfilgrastim and plerixafor as an effective regimen of hematopoietic stem cells mobilization in cancer patients: own experience].
The method of high-dose chemotherapy is limited quantity and quality of hematopoietic material used in transplantation. In this article on own material (56 apheresis procedures) there was performed a comparative analysis of the efficacy of several mobilization regimens. In 35 patients (63%) apheresis was initiated with using DHAP ([D]examethasone; [H]igh-dose [A] ra-C; [P]latinol) + G-CSF (group No 1); in 9 patients (16%) apheresis was initiated with regimen of HDCyc ([H]igh [D] ose [Cyc]lophosphamide) + G-CSF (group No 2); in 12 patients (21%) apheresis was performed using a combination of plerixafor and pegfilgrastim (group No 3). It was shown that all three of the proposed regimens were found to be as effective. In all groups, patients failed to receive an enough amount of CD34 + cells. At the same time using new mobilizing agent plerixafor in combination with prolonged action G-CSF pegfilgrastim showed some advantages: low toxicity of this combination, which does not needs to additional blood components, antibacterial and antifungal agents, and the possibility of its use in the outpatient setting.


Measuring myosin cross-bridge attachment time in activated muscle fibers using stochastic vs. sinusoidal length perturbation analysis.
The average time myosin cross bridges remain bound to actin (t(on)) can be measured by sinusoidal length perturbations (sinusoidal analysis) of striated muscle fibers using recently developed analytic methods. This approach allows measurements of t(on) in preparations possessing a physiologically relevant myofilament lattice. In this study, we developed an approach to measure t(on) in 5-10% of the time required for sinusoidal analysis by using stochastic length perturbations (white noise analysis). To compare these methods, we measured the influence of MgATP concentration ([MgATP]) on t(on) in demembranated myocardial strips from mice, sampling muscle behavior from 0.125 to 200 Hz with a 20-s burst of white noise vs. a 300-s series of sinusoids. Both methods detected a similar >300% increase in t(on) as [MgATP] decreased from 5 to 0.25 mM, differing by only 3-14% at any [MgATP]. Additional experiments with Drosophila indirect flight muscle fibers demonstrated that faster cross-bridge cycling kinetics permit further reducing of the perturbation time required to measure t(on). This reduced sampling time allowed strain-dependent measurements of t(on) in flight muscle fibers by combining 10-s bursts of white noise during periods of linear shortening and lengthening. Analyses revealed longer t(on) values during shortening and shorter t(on) values during lengthening. This asymmetry may provide a mechanism that contributes to oscillatory energy transfer between the flight muscles and thoracic cuticle to power flight. This study demonstrates that white noise analysis can detect underlying molecular processes associated with dynamic muscle contraction comparable to sinusoidal analysis, but in a fraction of the time.


Device to monitor sock use in people using prosthetic limbs: technical report.
A device using radio frequency identification (RFID) technology was developed to continuously monitor sock use in people who use prosthetic limbs. RFID tags were placed on prosthetic socks worn by subjects with transtibial limb loss, and a high-frequency RFID reader and antenna were placed in a portable unit mounted to the outside of the prosthetic socket. Bench testing showed the device to have a maximum read range between 5.6 cm and 12.7 cm, depending on the RFID tag used. Testing in a laboratory setting on three participants with transtibial amputation showed that the device correctly monitored sock presence during sitting, standing, and walking activity when one or two socks were worn but was less reliable when more socks were used. Accurate detection was sensitive to orientation of the tag relative to the reader, presence of carbon fiber in the prosthetic socket, pistoning of the limb in the socket, and overlap among the tags. Use of ultra-high-frequency RFID may overcome these limitations. With improvements, the technology may prove useful to practitioners prescribing volume accommodation strategies for patients by providing information about sock use between clinical visits, including timing and consistency of daily sock-ply changes.


Postoperative sleep disturbance: influences of opioids and pain in humans.
To test the hypothesis that opioids and pain contribute independently to postoperative sleep disturbance, 10 women undergoing surgery requiring a low abdominal incision for treatment of benign gynecologic conditions were randomized to receive either epidural opioid (fentanyl) (n=6) or epidural local anesthetic (bupivacaine) (n=4) for intraoperative and postoperative analgesia. N/A. N/A. N/A. N/A. Polysomnography was performed in a standard patient room on the preoperative and first three postoperative nights. Pain at rest and with coughing was evaluated using a visual-analogue pain scale each evening and morning. On the first postoperative night, rapid eye movement (REM) sleep was abolished in all patients. On the third postoperative night, the mean +/- SE REM sleep time increased significantly (p=.003) to 9.8% +/- 3.1% in the fentanyl group, and 12.9% +/- 3.8% in the bupivacaine group. Conversely, light non-REM (NREM) sleep (%stage 1 + %stage 2) was higher on the first postoperative night and significantly lower on the third postoperative night (p=0.011). Between group comparison revealed only that the mean % slow-wave sleep (SWS) in the fentanyl group (6.0%, 2.0%, and 14.7%) was different from the bupivacaine group (7.8%, 9.1%, and 10.6%) in the postoperative period after adjusting for the preoperative night % SWS (p=0.021). Pain was well controlled in all patients, but was slightly better controlled in the fentanyl group than in the bupivacaine group on postoperative night 2 (p=0.024). There was no statistically significant association between pain score and any polysomnographically defined stage. Postoperative patients suffer a profound sleep disturbance even when opioids are avoided and pain is well controlled.


Peripheral nervous system progenitors can be reprogrammed to produce myelinating oligodendrocytes and repair brain lesions.
Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combining in vitro culture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC-derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency in shiverer mice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy.


Regulation of Ca2+ handling by phosphorylation status in mouse fast- and slow-twitch skeletal muscle fibers.
The effects of phosphorylation status on Ca2+ release and Ca2+ removal were studied in fast-twitch flexor digitorum brevis and slow-twitch soleus skeletal muscle fibers enzymatically isolated from wild-type and phospholamban knockout (PLBko) mice. In all fibers the adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) inhibitor H-89 decreased the peak amplitude of the intracellular Ca2+ concentration ([Ca2+]) transient for a single action potential, and the PKA activator dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) reversed this effect, indicating modulation of Ca2+ release by phosphorylation status in all fibers. H-89 decreased the decay rate constant of the [Ca2+] transient and DBcAMP reversed this effect only in phospholamban-expressing fibers (wild-type soleus), indicating modulation of Ca2+ removal only in the presence of phospholamban. A high basal level of PKA phosphorylation in soleus fibers maintained under our control conditions was indicated by the lack of effect of direct application of DBcAMP on Ca2+ release or Ca2+ removal in wild-type or PLBko soleus fibers and was confirmed by analysis of phospholamban from wild-type soleus fibers.


The macroecology of airborne pollen in Australian and New Zealand urban areas.
The composition and relative abundance of airborne pollen in urban areas of Australia and New Zealand are strongly influenced by geographical location, climate and land use. There is mounting evidence that the diversity and quality of airborne pollen is substantially modified by climate change and land-use yet there are insufficient data to project the future nature of these changes. Our study highlights the need for long-term aerobiological monitoring in Australian and New Zealand urban areas in a systematic, standardised, and sustained way, and provides a framework for targeting the most clinically significant taxa in terms of abundance, allergenic effects and public health burden.