[Respiratory and Facial Protection: Current Perspectives in the Context of the COVID-19 Pandemic].
The new SARS-CoV-2 pandemic is an example of an international public health emergency, which is associated with considerable social and economic challenges. At the healthcare level there is the risk that nosocomial outbreaks can be local amplifiers. Adequate infection control practices are of critical importance, which include proper use of personal protective equipment. This equipment must be appropriate to the pathogen transmission route that, in the case of SARS-CoV-2, occurs through droplet and contact routes. The infected individual, when talking, coughing or sneezing, spreads droplets containing the virus, directly contaminating other individuals within one to two meters of distance, as well as the surrounding environment. Airborne transmission may occur when aerosol-generating procedures are performed. Concerning respiratory protection, there is currently weak evidence that the use of respirators provides better protection than surgical masks for SARS-CoV-2 or other viruses (with the exception of aerosol-generating procedures, in which case the use of a respirator is recommended). Eye protection should be guaranteed whenever there is a risk of splashes, droplets or aerosols. The use of different, or higher than necessary, level of personal protective equipment, for the transmission route of the agent, is a form of misuse and can affect its supply for situations when it is clearly indicated. The adequate provision of protective equipment, as well as training of healthcare professionals in its correct use, is highly recommended to ensure safety of care.


Endothelium-dependent relaxations in canine coronary arteries are enhanced in early heart failure and persist in recovery.
In vitro coronary artery responsiveness to noradrenaline, phenylephrine, and BHT-920 together with functional relaxation to acetylcholine was assessed in dogs at the early onset of pacing-induced heart failure (1 week) and in dogs recovered from heart failure (3 weeks paced, followed by 4 weeks discontinued pacing). alpha-Adrenoceptor stimulation produced contractile responses that were unaltered in early congestive heart failure and recovery. Contractions to noradrenaline and BHT-920 were always less than those produced by phenylephrine. Endothelium-intact arteries demonstrated relaxations in response to noradrenaline and BHT-920, but not phenylephrine. Relaxations to noradrenaline were enhanced 24% in early heart failure and 47% following recovery from heart failure, compared with control. BHT-920 produced relaxations that were augmented 21 and 76% in early heart failure and recovery, respectively. Contractile sensitivity to noradrenaline increased 5-fold in early heart failure and was not different in recovery, compared with control. Contractile sensitivity to BHT-920 and phenylephrine was unaltered throughout. Acetylcholine produced relaxations that were increased 21% in early heart failure and 13% after recovery from congestive heart failure. Furthermore, acetylcholine sensitivity was significantly enhanced in early heart failure and recovery. The current study reveals a progressive adaptation of the coronary endothelium in congestive heart failure, possibly directed towards protection against excessive vasoconstriction due to circulating catecholamines.


Evaluation of a modular strategy for the construction of novel polydactyl zinc finger DNA-binding proteins.
In previous studies, we have developed a technology for the rapid construction of novel DNA-binding proteins with the potential to recognize any unique site in a given genome. This technology relies on the modular assembly of modified zinc finger DNA-binding domains, each of which recognizes a three bp subsite of DNA. A complete set of 64 domains would provide comprehensive recognition of any desired DNA sequence, and new proteins could be assembled by any laboratory in a matter of hours. However, a critical parameter for this approach is the extent to which each domain functions as an independent, modular unit, without influence or dependence on its neighboring domains. We therefore examined the detailed binding behavior of several modularly assembled polydactyl zinc finger proteins. We first demonstrated that 80 modularly assembled 3-finger proteins can recognize their DNA target with very high specificity using a multitarget ELISA-based specificity assay. A more detailed analysis of DNA binding specificity for eight 3-finger proteins and two 6-finger proteins was performed using a target site selection assay. Results showed that the specificity of these proteins was as good or better than that of zinc finger proteins constructed using methods that allow for interdependency. In some cases, near perfect specificity was achieved. Complications due to target site overlap were found to be restricted to only one particular amino acid interaction (involving an aspartate in position 2 of the alpha-helix) that occurs in a minority of cases. As this is the first report of target site selection for designed, well characterized 6-finger proteins, unique insights are discussed concerning the relationship of protein length and specificity. These results have important implications for the design of proteins that can recognize extended DNA sequences, as well as provide insights into the general rules of recognition for naturally occurring zinc finger proteins.


Influence of adsorption and deproteination on potential free thyroxine reference methods.
There is a need for consensus concerning reference methods to be used for calibration of commercial free-thyroxine (FT(4)) assays. Three different potential reference techniques were investigated for adsorption of T(4) to membrane materials, including any in vitro solid surfaces to which T(4) might adsorb, and for efficient separation of the T(4)-binding proteins from the free hormone fraction. We compared ultrafiltration with different commercial ultrafiltration units, ultrafiltration by dialysis tubing, equilibrium dialysis, and ultracentrifugation. We measured the adsorption to membranes and materials with L-[(125)I]T(4). Separation efficiency was determined by measuring the T(4)-binding protein albumin in the ultrafiltrate and the dialysate as well as in the supernatant from the ultracentrifugation with a double-antibody sandwich ELISA technique. We found a constant relationship between the amount of T(4) adsorbed to the dialysis or ultrafiltration membranes/materials and the initial T(4) concentration in HEPES buffer (protein-free medium). T(4) was considerably less adsorbed from serum than from HEPES buffer (P <0.001). Serum T(4) was less adsorbed upon ultracentrifugation than during dialysis and ultrafiltration (P <0.001). It was difficult to completely separate FT(4) from the binding proteins by ultrafiltration and ultracentrifugation. Separation by ultrafiltration depended on the material used. No investigated separation technique provides technically and theoretically correct separation of the free fraction of T(4) from the protein-bound fraction. Equilibrium dialysis seems to be the least compromised.


Heparin-binding EGF-like growth factor promotes intestinal anastomotic healing.
We have accumulated multiple lines of evidence supporting the ability of HB-EGF to protect the intestines from injury and to augment the healing of partial-thickness scald burns of the skin. The aim of the current study was to investigate the role of heparin-binding EGF-like growth factor (HB-EGF) in intestinal anastomotic wound healing. HB-EGF (-/-) knockout (KO) mice (n=42) and their HB-EGF (+/+) wild type (WT) counterparts (n=33), as well as HB-EGF transgenic (TG) mice (n=26) and their (WT) counterparts (n=27), underwent division and reanastomosis of the terminal ileum. In addition, WT mice (n=21) that received enteral HB-EGF (800 μg/kg) underwent the same operative procedure. Anastomotic bursting pressure was measured at 3 and 6 d postoperatively. Tissue sections were stained with hematoxylin and eosin to assess anastomotic healing, and Picrosirus red to assess collagen deposition. Immunohistochemistry using anti-von Willebrand factor antibodies was performed to assess angiogenesis. Complications and mortality were also recorded. HB-EGF KO mice had significantly lower bursting pressures, lower healing scores, higher mortality, and higher complication rates postoperatively compared with WT mice. Collagen deposition and angiogenesis were significantly decreased in KO mice compared with WT mice. Conversely, HB-EGF TG mice had increased anastomotic bursting pressure, higher healing scores, lower mortality, lower complication rates, increased collagen deposition, and increased angiogenesis postoperatively compared with WT mice. WT mice that received HB-EGF had increased bursting pressures compared with non-HB-EGF treated mice. Our results demonstrate that HB-EGF is an important factor involved in the healing of intestinal anastomoses.


Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.
Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.


Evidence for lactone formation during infrared multiple photon dissociation spectroscopy of bromoalkanoate doped salt clusters.
Reaction mechanisms of organic molecules in a salt environment are of fundamental interest and are potentially relevant for atmospheric chemistry, in particular sea-salt aerosols. Here, we found evidence for lactone formation upon infrared multiple photon dissociation (IRMPD) of non-covalent bromoalkanoate complexes as well as bromoalkanoate embedded in sodium iodide clusters. The mechanism of lactone formation from bromoalkanoates of different chain lengths is studied in the gas phase with and without salt environment by a combination of IRMPD and quantum chemical calculations. IRMPD spectra are recorded in the 833-3846 cm-1 range by irradiating the clusters with tunable laser systems while they are stored in the cell of a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The measurements of the binary complex Br(CH2)mCOOH·Br(CH2)mCOO- for m = 4 indicate valerolactone formation without salt environment while lactone formation is hindered for longer chain lengths. When embedded in sodium iodide clusters, butyrolactone formation from 4-bromobutyrate seems to take place already during formation of the doped clusters in the electrospray process, evidenced by the infrared (IR) signature of the lactone. In contrast, IRMPD spectra of sodium iodide clusters containing 5-bromovalerate contain signatures for both valerate as well as valerolactone. In both cases, however, a neutral fragment corresponding to the mass of valerolactone is eliminated, indicating that ring formation can be activated by IR light in the salt cluster. Quantum chemical calculations show that already complexation with one sodium ion significantly increases the barrier for lactone formation for all chain lengths. IRMPD of sodium iodide clusters doped with neutral bromoalkanoic acid molecules proceeds by elimination of HI or desorption of the intact acid molecule from the cluster.


Dietary habits in patients with ischemic stroke: a case-control study.
Diet appears to have some role in stroke development. The objective of our study was to describe the dietary habits in patients admitted with acute ischemic stroke and compare selected dietary components with healthy controls. Adherence to healthy diet behaviors was also assessed. A case-control study of consecutive patients with acute ischemic stroke admitted to the Neurology Department of Hospital del Mar from 2007 to 2010. Patients were matched by age and sex with control subjects. A previously validated nutritional survey was administered to patients and controls. Demographic data, vascular risk factors, caloric intake and dietary nutrients were evaluated. Intention to follow a healthy diet was also assessed in both groups. A total of 300 acute ischemic stroke patients and 300 controls with evaluation of dietary habits. No differences were observed in vascular risk factors, except smoking habit, diabetes and ischemic heart disease. Stroke patients reported a higher caloric intake: 2444.8(1736.8-3244.5) vs 2208.7(1753.1-2860.7) Kcal, p = 0.001. After adjusting for energy intake, patients had higher intake of proteins (p<0.001; OR 1.02), total cholesterol (p = 0.001; OR 1.04), and breaded foods (p = 0.001; OR 1.94) and lower consumption of probiotic yogurt (p = 0.002; OR 0.88). Compared to patients, control participants indicated greater intention to eat vegetables (p = 0.002; OR 1.5) and whole foods (p = 0.000; OR 2.4) and reduce their intake of salt (p = 0.002; OR 1.7), fat (p = 0.000; OR 3.7) and sweets (p = 0.004; OR 1.7) than patients. We observed different dietary patterns between stroke patients and controls. Stroke patients have a higher caloric intake and are less concerned about maintaining healthy nutritional habits.


Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome.
GH excess affects approximately 20% of the patients with McCune-Albright syndrome (MAS). MAS is caused by sporadic, postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, G(s)alpha (gsp oncogene). These same mutations are found in approximately one third of the sporadic cases of acromegaly. We examined efficacy of the GH receptor antagonist, pegvisomant, in controlling gsp oncogene-mediated GH excess and skeletal disease (fibrous dysplasia of bone) associated with MAS. Five MAS patients with GH excess were treated with 20 mg/d sc injection of pegvisomant for 12 wk in a randomized, double-blind, placebo-controlled crossover study at the National Institutes of Health. The primary measure of efficacy was normalization of IGF-I. Secondary outcome measures were reduction in serum IGF binding protein-3 (IGFBP-3), improvement of fatigue and sweating, and reduction in markers of bone metabolism and bone pain. Combined mean changes in serum IGF-I at 6 and 12 wk were -236.4 ng/ml (53%, P < 0.005) and -329.8 ng/ml (62%, P < 0.001), respectively. IGFBP-3 decreased by 0.8 mg/liter (24%, P < 0.01) and 2.9 mg/liter (37%, P < 0.005), respectively. There were no significant changes in signs and symptoms of acromegaly or markers of bone metabolism and bone pain, nor was there a significant change in pituitary size. Retrospective comparison of the degree of control achieved with pegvisomant vs. other medications (long-acting octreotide +/- dopamine agonist) in the same group showed that the two regimens were similarly effective. Pegvisomant effectively reduced IGF-I and IGFBP-3 levels in gsp-mediated GH excess but had no effect on fibrous dysplasia.


Optimal linear combination of facial regions for improving identification performance.
This paper presents a novel 3-D multiregion face recognition algorithm that consists of new geometric summation invariant features and an optimal linear feature fusion method. A summation invariant, which captures local characteristics of a facial surface, is extracted from multiple subregions of a 3-D range image as the discriminative features. Similarity scores between two range images are calculated from the selected subregions. A novel fusion method that is based on a linear discriminant analysis is developed to maximize the verification rate by a weighted combination of these similarity scores. Experiments on the Face Recognition Grand Challenge V2.0 dataset show that this new algorithm improves the recognition performance significantly in the presence of facial expressions.


Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection.
Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). As PGs play diverse biological roles in homeostasis and inflammatory responses, inhibiting PG production with NSAIDs could affect COVID-19 pathogenesis in multiple ways, including: (1) altering susceptibility to infection by modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; (2) regulating replication of SARS-CoV-2 in host cells; and (3) modulating the immune response to SARS-CoV-2. Here, we investigate these potential roles. We demonstrate that SARS-CoV-2 infection upregulates COX-2 in diverse human cell culture and mouse systems. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication. In contrast, in a mouse model of SARS-CoV-2 infection, NSAID treatment reduced production of pro-inflammatory cytokines and impaired the humoral immune response to SARS-CoV-2 as demonstrated by reduced neutralizing antibody titers. Our findings indicate that NSAID treatment may influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies rather than modifying susceptibility to infection or viral replication.ImportancePublic health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19). NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are critical for the generation of prostaglandins - lipid molecules with diverse roles in homeostasis and inflammation. Inhibition of prostaglandin production by NSAIDs could therefore have multiple effects on COVID-19 pathogenesis. Here, we demonstrate that NSAID treatment reduced both the antibody and pro-inflammatory cytokine response to SARS-CoV-2 infection. The ability of NSAIDs to modulate the immune response to SARS-CoV-2 infection has important implications for COVID-19 pathogenesis in patients. Whether this occurs in humans and whether it is beneficial or detrimental to the host remains an important area of future investigation. This also raises the possibility that NSAIDs may alter the immune response to SARS-CoV-2 vaccination.


Manifestations of diabetes mellitus on mouse preimplantation development: effect of elevated concentration of metabolic intermediates.
The metabolic derangements of pregnancies complicated by diabetes mellitus, specifically hyperglycaemia and hyperketonaemia, are known to be teratogenic during the period of organogenesis in animals. We have shown previously that poorly controlled diabetes mellitus impairs in-vivo and in-vitro mouse preimplantation embryo growth, and that culturing embryos in elevated glucose concentrations only partially recreates this developmental delay. To extend this observation we examined the effect on mouse preimplantation embryo growth of elevated concentrations of other metabolic intermediates, which may be deranged in diabetes mellitus, namely lipids, lactate, glycerol, amino acids, and ketones. Two-cell embryos from ovulation-induced B6C3F1 mice were cultured for 72 h in the presence of added lipids (250 mg/dl), lactate (5 mM), glycerol (160 microM) or mixed amino acids (8.5% travasol, 7 mM) and showed no significant difference in growth over 72 h versus their control groups. However, growth of preimplantation embryos in acetoacetate (10 mM) or in the racemic mixture of DL-beta-hydroxybutyrate (16 and 32 mM) revealed marked retardation versus controls when assessed either by distribution of developmental stages over time (24, 48, 72 h, P < 0.001) or by the difference in the average rank of sums indicating a delay in maturation (P < 0.0001). We conclude that elevated ketone concentrations adversely affect preimplantation embryo development. These findings extend previous studies which correlate uncontrolled diabetes mellitus as well as hyperglycaemia with abnormal organogenesis, and demonstrate that exposure to metabolic derangements may also hinder reproductive performance at even earlier stages in gestation.


Modeling and classifying human activities from trajectories using a class of space-varying parametric motion fields.
Many approaches to trajectory analysis, such as clustering or classification, use probabilistic generative models, thus not requiring trajectory alignment/registration. Switched linear dynamical models (e.g., HMMs) have been used in this context, due to their ability to describe different motion regimes. However, these models are not suitable for handling space-dependent dynamics that are more naturally captured by nonlinear models. As is well known, these are more difficult to identify. In this paper, we propose a new way of modeling trajectories, based on a mixture of parametric motion vector fields that depend on a small number of parameters. Switching among these fields follows a probabilistic mechanism, characterized by a field of stochastic matrices. This approach allows representing a wide variety of trajectories and modeling space-dependent behaviors without using global nonlinear dynamical models. Experimental evaluation is conducted in both synthetic and real scenarios. The latter concerning with human trajectory modeling for activity classification, a central task in video surveillance.


Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma.
This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma. Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady-state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional-hazards model. The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively. Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial.


Double-resonance and optical-pumping experiments on electromagnetically confined, laser-cooled ions.
Experiments illustrating advantages and unique features of double-resonance and optical pumping on electromagnetically confined, laser-cooled ions are discussed. In certain cases, scattered light from the cooling transition can be used as a monitor in double-resonance experiments to give nearly 100% detection efficiency. Nonradiative relaxation rates are extremely small for stored ions, permitting nearly complete optical pumping, even in extremely weak pumping schemes.


MemBrain: A deep learning-aided pipeline for detection of membrane proteins in Cryo-electron tomograms.
Cryo-electron tomography (cryo-ET) is an imaging technique that enables 3D visualization of the native cellular environment at sub-nanometer resolution, providing unpreceded insights into the molecular organization of cells. However, cryo-electron tomograms suffer from low signal-to-noise ratios and anisotropic resolution, which makes subsequent image analysis challenging. In particular, the efficient detection of membrane-embedded proteins is a problem still lacking satisfactory solutions. We present MemBrain - a new deep learning-aided pipeline that automatically detects membrane-bound protein complexes in cryo-electron tomograms. After subvolumes are sampled along a segmented membrane, each subvolume is assigned a score using a convolutional neural network (CNN), and protein positions are extracted by a clustering algorithm. Incorporating rotational subvolume normalization and using a tiny receptive field simplify the task of protein detection and thus facilitate the network training. MemBrain requires only a small quantity of training labels and achieves excellent performance with only a single annotated membrane (F1 score: 0.88). A detailed evaluation shows that our fully trained pipeline outperforms existing classical computer vision-based and CNN-based approaches by a large margin (F1 score: 0.92 vs. max. 0.63). Furthermore, in addition to protein center positions, MemBrain can determine protein orientations, which has not been implemented by any existing CNN-based method to date. We also show that a pre-trained MemBrain program generalizes to tomograms acquired using different cryo-ET methods and depicting different types of cells. MemBrain is a powerful and annotation-efficient tool for the detection of membrane protein complexes in cryo-ET data, with the potential to be used in a wide range of biological studies. It is generalizable to various kinds of tomograms, making it possible to use pretrained models for different tasks. Its efficiency in terms of required annotations also allows rapid training and fine-tuning of models. The corresponding code, pretrained models, and instructions for operating the MemBrain program can be found at: https://github.com/CellArchLab/MemBrain.


Death receptor 4 and bladder cancer risk.
Tumor necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptoticpathway by binding to death receptors 4 (DR4) and 5 (DR5). In DR4 exon 4, a C-->G polymorphism at amino acid 626 located immediately 3' to one of the main receptor ligand interface regions, results in a threonine-->arginine change. We found that the DR4 exon 4 G/G genotype was associated with an overall decreased risk of bladder cancer in Caucasians [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.38-0.88]. This protective effect was more apparent in younger individuals (OR = 0.42; 95% CI, 0.20-0.87) than in older individuals (OR = 0.60; 95% CI, 0.35-1.02) and in women (OR = 0.45; 95% CI, 0.20-0.99) than in men (OR = 0.60; 95% CI, 0.36-0.99). Moreover, the protective effect was greater for light smokers (OR = 0.19; 95% CI, 0.06-0.59) compared with heavy smokers (OR = 0.83; 95% CI, 0.41-1.69). These data provide the first large-scale molecular epidemiological evidence that the DR4 polymorphism is associated with environmental exposure and bladder cancer risk, possibly through modulating the capacity of the receptor ligand complex to engage the apoptotic pathway.


Validation of the multiple sensor mechanism of the Keap1-Nrf2 system.
The Keap1-Nrf2 system plays a critical role in cellular defense against electrophiles and reactive oxygen species. Keap1 possesses a number of cysteine residues, some of which are highly reactive and serves as sensors for these insults. Indeed, point mutation of Cys151 abrogates the response to certain electrophiles. However, this mutation does not affect the other set of electrophiles, suggesting that multiple sensor systems reside within the cysteine residues of Keap1. The precise contribution of each reactive cysteine to the sensor function of Keap1 remains to be clarified. To elucidate the contribution of Cys151 in vivo, in this study we adopted transgenic complementation rescue assays. Embryonic fibroblasts and primary peritoneal macrophages were prepared from mice expressing the Keap1-C151S mutant. These cells were challenged with various Nrf2 inducers. We found that some of the inducers triggered only marginal responses in Keap1-C151S-expressing cells, while others evoked responses in a comparable magnitude to those observed in the wild-type cells. We found that tert-butyl hydroquinone, diethylmaleate, sulforaphane, and dimethylfumarate were Cys151 preferable, whereas 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PG-J(2)), 2-cyano-3,12 dioxooleana-1,9 diene-28-imidazolide (CDDO-Im), ebselen, nitro-oleic acid, and cadmium chloride were Cys151 independent. Experiments with embryonic fibroblasts and primary macrophages yielded consistent results. Experiments testing protective effects against the cytotoxicity of 1-chloro-2,4-dinitrobenzene of sulforaphane and 15d-PG-J(2) in Keap1-C151S-expressing macrophages revealed that the former inducer was effective, while the latter was not. These results thus indicate that there exists distinct utilization of Keap1 cysteine residues by different chemicals that trigger the response of the Keap1-Nrf2 system, and further substantiate the notion that there are multiple sensing mechanisms within Keap1 cysteine residues.


Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics.
Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.


Patient Stratification for Antibiotic Prescriptions Based on the Bound-Free Phase Detection Immunoassay of C-Reactive Protein in Serum Samples.
C-reactive protein is a well-studied host response biomarker, whose diagnostic performance depends on its accurate classification into concentration zones defined by clinical scenario-specific cutoff values. We validated a newly developed, bead-based, bound-free phase detection immunoassay (BFPD-IA) versus a commercial CE-IVD enzyme-linked immunosorbent assay (ELISA) kit and a commercial CE-IVD immunoturbidimetric assay (ITA) kit. The latter was performed on a fully automated DPC Konelab 60i clinical analyzer used in routine diagnosis. We classified 53 samples into concentration zones derived from four different sets of cutoff values that are related to antibiotic prescription scenarios in the case of respiratory tract infections. The agreements between the methods were ELISA/ITA at 87.7%, ELISA/BFPD-IA at 87.3%, and ITA/-BFPD-IA at 93.9%, reaching 98-99% in all cases when considering the calculated relative combined uncertainty of the single measurement of each sample. In a subgroup of 37 samples, which were analyzed for absolute concentration quantification, the scatter plot slopes' correlations were as follows: ELISA/ITA 1.15, R2 = 0.97; BFPD-IA/ELISA 1.12, R2 = 0.95; BFPD-IA/ITA 0.95, R2 = 0.93. These very good performances and the agreement between BFPD-IA and ITA (routine diagnostic), combined with BFPD-IA's functional advantages over ITA (and ELISA)-such as quick time to result (~20 min), reduced consumed reagents (only one assay buffer and no washing), few and easy steps, and compatibility with nucleic-acid-amplification instruments-render it a potential approach for a reliable, cost-efficient, evidence-based point-of-care diagnostic test for guiding antibiotic prescriptions.


Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012.
It is estimated that over 700,000 new cases of cutaneous squamous cell carcinoma (CSCC) are diagnosed annually in the United States. However, CSCC has been excluded from national cancer registries. Thus the precise incidence of CSCC, along with metastases and deaths resulting from it, is unknown. We sought to estimate the 2012 incidence of invasive (non-in situ) CSCC and the number of nodal metastases and deaths arising from it in the US white population. US studies reporting incidence of CSCC, or the number of nodal metastases or deaths arising from it, were reviewed. Linear regression was used to estimate current CSCC incidence based on available incidence data adjusting for higher reported incidences in southern versus northern/central United States. Reported risks of nodal metastases and death from CSCC were averaged. Averages were used to estimate current metastasis and death rates based on incidence estimates. The number of estimated CSCC deaths was compared against deaths from other cancers. It is estimated that 186,157 to 419,543 whites were given a diagnosis of CSCC, 5604 to 12,572 developed nodal metastasis, and 3932 to 8791 died from CSCC in the United States in 2012. The estimates of the 2012 incidence, nodal metastasis, and death from invasive CSCC are based on previous estimates of incidence and outcomes of CSCC. CSCC is an underrecognized health issue. In the central and southern United States, deaths from CSCC may be as common as deaths from renal and oropharyngeal carcinomas, and melanoma. Population-based studies reporting CSCC incidence and outcomes are required to verify these estimates.


A comparison of lidocaine, fentanyl, and esmolol for attenuation of cardiovascular response to laryngoscopy and tracheal intubation.
Laryngoscopy and tracheal intubation are known to increase sympathetic activity that may be detrimental to patients with pre-existing ischemic or hypertensive heart diseases. In order to alter the hyperdynamic consequences resulting from intubation during induction of general anesthesia, we chose esmolol, an ultra-short acting cardioselective beta-adrenergic blocker, to attenuate the cardiovascular responses during tracheal intubation in patients undergoing elective surgery. The efficacy of esmolol in this regard was carefully evaluated. Eighty ASA physical status class I or II patients undergoing elective, non-cardiac procedures were included in a randomized, single-blinded study consisting of 4 groups with each group receiving a designated drug: group A received normal saline as control, while group B, group C and group D received lidocaine 2 mg/kg, fentanyl 3 micrograms/kg and esmolol 2 mg/kg, respectively. Monitoring included EKG, pulse oximetry, capnometry and arterial pressure. All patients were premedicated with diazepam 0.1 mg/kg 30 min before induction of general anesthesia. Each designated drug was given upon induction of anesthesia (time zero). Anesthesia was induced with thiopental 5 mg/kg and succinylcholine 1.5 mg/kg, and maintained with N2O, 1% isoflurane in 50% O2 and vecuronium. Intubation was carried out 3 min after the designated drug was given. Heart rate (HR) and systolic arterial blood pressure (SBP) were obtained every min for 10 min after induction. Either chi-square test or analysis of variances (ANOVA) was used for statistical comparison. A p value less than 0.05 was considered statistically significant. There was no difference in the demographic data among the four groups. After intubation, the incidence of tachycardia (HR > 100/min) was found in 3 of 20 (15%) patients in esmolol group, significantly lower than 17 of 20 (85%) patients in the control group, 15 of 20 (75%) patients in lidocaine group, and 11 of 20 (55%) patients in fentanyl group, respectively (p < 0.05). The incidence of hypertension (SBP > 180 mmHg) was found in 4 of 20 (20%) patients in esmolol group, significantly lower than 16 of 20 (80%) patients in control group and 14 of 20 (70%) patients in lidocaine group, respectively (p < 0.05), but not in 8 of 20 (40%) patients in fentanyl group. Besides, the incidence of hypertension in fentanyl group (40%) was significantly lower than control group (80%; p < 0.05), but not in lidocaine group (70%). Results of this study showed that only esmolol could reliably offer protection against the increase in both HR and SBP, low dose of fentanyl (3 micrograms/kg) prevented hypertension but not tachycardia, and 2 mg/kg lidocaine had no effect to blunt adverse hemodynamic responses during laryngoscopy and tracheal intubation.


Water dynamics within nanostructured amphiphilic statistical copolymers from quasielastic neutron scattering.
Understanding the properties of water under either soft or hard confinement has been an area of great interest, but nanostructured amphiphilic polymers that provide a secondary confinement have garnered significantly less attention. Here, a series of statistical copolymers of 2-hydroxyethyl acrylate (HEA) and 2-(N-ethylperfluorooctane sulfonamido)ethyl methacrylate (FOSM) are swollen to equilibrium in water to form nanostructured physically cross-linked hydrogels to probe the effect of soft confinement on the dynamics of water. Changing the composition of the copolymer from 10 to 21 mol. % FOSM decreases the average size of the assembled FOSM cross-link, but also the spacing between the cross-links in the hydrogels with the mean distance between the FOSM aggregates decreasing from 3.9 to 2.7 nm. The dynamics of water within the hydrogels were assessed with quasielastic neutron scattering. These hydrogels exhibit superior performance for inhibition of water crystallization on supercooling in comparison to analogous hydrogels with different hydrophilic copolymer chemistries. Despite the lower water crystallinity, the self-diffusion coefficient for these hydrogels from the copolymers of HEA and FOSM decreases precipitously below 260 K, which is a counter to the nearly temperature invariant water dynamics reported previously with an analogous hydrogel [Wiener et al., J. Phys. Chem. B 120, 5543 (2016)] that exhibits nearly temperature invariant dynamics to 220 K. These results point to chemistry dependent dynamics of water that is confined within amphiphilic hydrogels, where the interactions of water with the hydrophilic segments can qualitatively alter the temperature dependent dynamics of water in the supercooled state.


Selective adenylate cyclase increase in the limbic area of long-term imipramine-treated rats.
Long-term administration of imipramine to rats produced an increase in the Vmax of forskolin- or guanylylimidodiphosphate (Gpp(NH))p-activated adenylate cyclase only in the limbic area. This effect was prevented by the daily administration of alpha-methyl-p-tyrosine (alpha-MPT), given together with imipramine, at a dose (50 mg/kg) which had no effect on adenylate cyclase activity per se. The time course of the effects of chronic imipramine on dopaminergic transmission in the limbic area showed that the decrease in both D-1 receptor number and adenylate cyclase stimulation by dopamine (DA) reached significance on day 8 of treatment and were maximal on day 15. The Vmax of the enzyme started to increase on day 15 and was further increased on day 21. Possible mechanisms underlying these effects are discussed.


Routinely available antimicrobial susceptibility information can be used to increase the efficiency of screening for carbapenemase-producing Enterobacteriaceae.
Introduction. Increased carbapenem resistance is often caused by carbapenemase production.Aim. The objective of our study was to assess which antibiotic susceptibility patterns, as tested by automated systems, are highly associated with the absence of carbapenemase production in Enterobacteriaceae isolates, and could therefore be used as a screening tool.Methodology. Routine antibiotic susceptibility testing data from 42 medical microbiology laboratories in the Netherlands in the period between January 2011 and June 2017 were obtained from the national antimicrobial resistance surveillance programme. Data on Enterobacteriaceae isolates that had an elevated minimum inhibitory concentration (MIC) for carbapenems (meropenem >0.25 mg l-1 or imipenem >1.0 mg l-1) were selected and subjected to phenotypic or genotypic carbapenemase production testing. Routinely available amoxicillin/clavulanic acid, piperacillin/tazobactam, cefuroxime and ceftriaxone/cefotaxime susceptibilities were studied in relation to carbapenemase production by calculating the negative predictive value.Results. No evidence for carbapenemase-producing Enterobacteriaceae (CPE) was found in 767 of 1007 (76 %) isolates. The negative predictive value was highest for amoxicillin/clavulanic acid (99.6 %) and piperacillin/tazobactam (98.8 %).Conclusion. Enterobacteriaceae isolates with elevated carbapenem MICs that are susceptible to amoxicillin/clavulanic acid or piperacillin/tazobactam are unlikely to be carbapenemase producers. Preselection based on this susceptibility pattern may lead to increased laboratory efficiency and reduction of costs. Whether this is also true for countries with a different distribution of CPE species and types or a higher prevalence of CPE needs to be studied.


Cloning of the cryptochrome-encoding PeCRY1 gene from Populus euphratica and functional analysis in Arabidopsis.
Cryptochromes are photolyase-like blue/UV-A light receptors that evolved from photolyases. In plants, cryptochromes regulate various aspects of plant growth and development. Despite of their involvement in the control of important plant traits, however, most studies on cryptochromes have focused on lower plants and herbaceous crops, and no data on cryptochrome function are available for forest trees. In this study, we isolated a cryptochrome gene, PeCRY1, from Euphrates poplar (Populus euphratica), and analyzed its structure and function in detail. The deduced PeCRY1 amino acid sequence contained a conserved N-terminal photolyase-homologous region (PHR) domain as well as a C-terminal DQXVP-acidic-STAES (DAS) domain. Secondary and tertiary structure analysis showed that PeCRY1 shares high similarity with AtCRY1 from Arabidopsis thaliana. PeCRY1 expression was upregulated at the mRNA level by light. Using heterologous expression in Arabidopsis, we showed that PeCRY1 overexpression rescued the cry1 mutant phenotype. In addition, PeCRY1 overexpression inhibited hypocotyl elongation, promoted root growth, and enhanced anthocyanin accumulation in wild-type background seedlings grown under blue light. Furthermore, we examined the interaction between PeCRY1 and AtCOP1 using a bimolecular fluorescence complementation (BiFc) assay. Our data provide evidence for the involvement of PeCRY1 in the control of photomorphogenesis in poplar.


Discharge against medical advice from a Mission tertiary hospital, South-West, Nigeria.
The fiduciary duty of a managing physician makes paediatric discharges against medical advice (DAMA) particularly challenging as children lack the legal power or authority to make their health decisions. Aim: It is aimed in the present study to determine the prevalence of paediatric DAMA in a mission tertiary hospital. This was a prospective descriptive study carried out from June 2018 to May 2019 among paediatric inpatients at the Bowen University Teaching Hospital, Ogbomoso, Nigeria whose parent/ care giver signed DAMA, despite adequate counselling. Data was analysed using SPSS version 23. The prevalence of DAMA in the study was of 4.1%, and the neonatal group accounted for the largest bulk of DAMA. Birth asphyxia was the commonest diagnosis among this group. There was a slight female predominance among the patients whose parents signed DAMA. Financial constraint was the commonest reason [13(30.2%)] given for DAMA and none of the children whose parents signed DAMA was enrolled on the National Health Insurance Scheme (NHIS). Rate of DAMA in a private mission tertiary hospital was lower than previously reported from government tertiary hospitals in the present-day Nigeria.


The NOVEL trial: natural orifice versus laparoscopic cholecystectomy-a prospective, randomized evaluation.
The evolution of Natural Orifice Translumenal Endoscopic Surgery® (NOTES®) represents a case study in surgical procedural evolution. Beginning in 2004 with preclinical feasibility studies, and followed by the creation of the NOSCAR® collaboration between The Society of American Gastrointestinal and Endoscopic Surgeons and the American Society for Gastrointestinal Endoscopy, procedural development followed a stepwise incremental pathway. The work of this consortium has included white paper analyses, obtaining outside independent funding for basic science and procedural development, and, ultimately, the initiation of a prospective randomized clinical trial comparing NOTES® cholecystectomy as an alternative procedure to laparoscopic cholecystectomy. Ninety patients were randomized into a randomized clinical trial with the primary objective of demonstrating non-inferiority of the transvaginal and transgastric arms to the laparoscopic arm. In the original trial design, there were both transgastric and transvaginal groups to be compared to the laparoscopic control group. However, after enrollment and randomization of 6 laparoscopic controls and 4 transgastric cases into the transgastric group, this arm was ultimately deemed not practical due to lagging enrollment, and the arm was closed. Three transgastric via the transgastric approach were performed in total with 9 laparoscopic control cases enrolled through the TG arm. Overall a total of 41 transvaginal and their 39 laparoscopic cholecystectomy controls were randomized into the study with 37 transvaginal and 33 laparoscopic cholecystectomies being ultimately performed. Overall total operating time was statistically longer in the NOTES® group: 96.9 (64.97) minutes versus 52.1 (19.91) minutes. There were no major adverse events such as common bile duct injury or return to the operating room for hemorrhage. Intraoperative blood loss, length of stay, and total medication given in the PACU were not statistically different. There were no conversions in the NOTES® group to a laparoscopic or open procedure, nor were there any injuries, bile leaks, hemorrhagic complications, wound infections, or wound dehiscence in either group. There were no readmissions. Visual Analogue Scale (VAS) pain scores were 3.4 (CI 2.82) in the laparoscopic group and 2.9 (CI 1.96) in the transvaginal group (p = 0.41). The clinical assessment on cosmesis scores was not statistically different when recorded by clinical observers for most characteristics measured when the transvaginal group was compared to the laparoscopic group. Taken as a whole, the results slightly favor the transvaginal group. SF-12 scores were not statistically different at all postoperative time points except for the SF-12 mental component which was superior in the transvaginal group at all time points (p < 0.05). The safety profile for transvaginal cholecystectomy demonstrates that this approach is safe and produces at least non-inferior clinical results with superior cosmesis, with a transient reduction in discomfort. The transvaginal approach to cholecystectomy should no longer be considered experimental. As a model for intersociety collaboration, the study demonstrated the ultimate feasibility and success of partnership as a model for basic research, procedural development, fundraising, and clinical trial execution for novel interventional concepts, regardless of physician board certification.


Blood markers for early detection of colorectal cancer: a systematic review.
Despite different available methods for colorectal cancer (CRC) screening and their proven benefits, morbidity, and mortality of this malignancy are still high, partly due to low compliance with screening. Minimally invasive tests based on the analysis of blood specimens may overcome this problem. The purpose of this review was to give an overview of published studies on blood markers aimed at the early detection of CRC and to summarize their performance characteristics. The PUBMED database was searched for relevant studies published until June 2006. Only studies with more than 20 cases and more than 20 controls were included. Information on the markers under study, on the underlying study populations, and on performance characteristics was extracted. Special attention was given to performance characteristics by tumor stage. Overall, 93 studies evaluating 70 different markers were included. Most studies were done on protein markers, but DNA markers and RNA markers were also investigated. Performance characteristics varied widely between different markers, but also between different studies using the same marker. Promising results were reported for some novel assays, e.g., assays based on SELDI-TOF MS or MALDI-TOF MS, for some proteins (e.g., soluble CD26 and bone sialoprotein) and also for some genetic assays (e.g., L6 mRNA), but evidence thus far is restricted to single studies with limited sample size and without further external validation. Larger prospective studies using study populations representing a screening population are needed to verify promising results. In addition, future studies should pay increased attention to the potential of detecting precursor lesions.


Differential regulation of adrenergic receptor development by sympathetic innervation.
Rat sweat glands provide an interesting model system for a developmental study of adrenergic receptor expression because their sympathetic innervation undergoes a switch from a nonadrenergic to cholinergic and peptidergic phenotype. alpha 1B, alpha 2B, and beta 2 receptors are expressed in rat footpads; alpha 1 and beta 2 receptors are localized specifically to sweat glands, and alpha 2 receptors also are expressed in other tissues. alpha 1 and, to a lesser extent, beta 2 receptors decrease during development, whereas alpha 2 levels remain relatively constant. Decreased receptor expression is accompanied by the loss of alpha 1-stimulated inositol phosphate accumulation, but no change in beta-stimulated cAMP production. The number of alpha 1 and beta 2 receptors decreases after P21, when the sympathetic innervation no longer produces catecholamines. Neonatal sympathectomy causes a partial failure of alpha 1 downregulation, but has no effect on beta 2 or alpha 2 receptor levels. Therefore, at least two distinct mechanisms regulate development of adrenergic receptors in sweat glands. Innervation-independent processes control developmental expression of alpha 1, beta 2, and alpha 2 receptors, and an additional, innervation-dependent mechanism influences expression of alpha 1 receptors. Denervation at postnatal day 20, when the sympathetic innervation is cholinergic and peptidergic, results in retention of alpha 1 receptors, but cholinergic blockade begun at P20 does not. These results indicate that regulation of receptor expression in sweat glands is complex, and suggest that the innervation-dependent factors that decrease alpha 1 levels during development act through a nonadrenergic, noncholinergic mechanism.


The use of postpartum hemorrhage protocols in United States academic obstetric anesthesia units.
Postpartum hemorrhage (PPH) is the leading cause of severe maternal morbidity, cardiac arrest, and death during the hospitalization for childbirth. Protocol-driven care has been associated with improved outcomes in many settings; the National Partnership for Maternal Safety now recommends that PPH protocols be implemented in every labor and delivery unit in the United States. In this study, we sought to identify the level of PPH protocol availability in academic United States obstetric units. We hypothesized that the majority (>80%) of academic obstetric anesthesia units would have a PPH protocol in place. A survey was developed by an expert panel. Domains included hospital characteristics, availability of PPH protocol or plans to develop such a protocol, and protocol components included in the upcoming National Partnership for Maternal Safety obstetric hemorrhage safety bundle initiative. The electronic survey was emailed to the 104 directors of United States academic obstetric anesthesia units. Responses were stratified by PPH protocol availability as appropriate. Univariate statistics were used to characterize survey responses and the probability distribution for PPH protocol availability was estimated using the binomial distribution. The survey response rate was 58%. The percentage of responding units with a PPH protocol was lower than hypothesized (P = 0.03); there was a PPH protocol in 67% of responding units (N = 40, 95% confidence interval [CI]: 53%-78%). The median annual delivery volume for responding units with PPH protocol was 3900 vs 2300 for units without PPH protocol (P = 0.002), with no difference in cesarean delivery rate (P = 0.73) or observed PPH rate (P = 0.69). There was no difference in annual delivery volume between responding and nonresponding hospitals (P = 0.06), suggesting that academic centers with delivery volume >3200 births per year are more likely than smaller volume hospitals to have a PPH protocol in place (odds ratio 3.16 (95% CI: 1.01-9.90). Adjusting for delivery volume among nonresponding hospitals, we estimate that 67% (95% CI: 55%-77%) of all academic obstetric anesthesia units had a PPH protocol in place at the time of this survey. Institutional processes for escalation do not correlate with the presence of a PPH protocol. There was a massive transfusion protocol in 95% of units with a PPH protocol and in 90% of units without (95% CI of difference: -7% to 7%). A PPH code team or rapid response team was available in 57% of responding institutions, with no difference between units with or without a PPH protocol [mean difference 4%, 95% CI (-24% to 32%)]. Despite increasing emphasis on national quality improvement in patient safety, there are no PPH protocols in at least 20% of U.S. academic obstetric anesthesia units. Delivery volume is the most important variable predicting the presence of a PPH protocol. National efforts to ensure universal presence of a PPH protocol in all academic centers will achieve the greatest impact by focusing on small-volume facilities. Future work is needed to evaluate and facilitate PPH implementation in nonacademic obstetric units.


Household interventions for preventing domestic lead exposure in children.
Lead poisoning is associated with physical, cognitive and neurobehavioural impairment in children and trials have tested many household interventions to prevent lead exposure. This is an update of the original review by the same authors first published in 2008. To determine the effectiveness of household interventions in preventing or reducing lead exposure in children as measured by reductions in blood lead levels and/or improvements in cognitive development. We identified trials through electronic searches of CENTRAL (2012, Issue 1), MEDLINE (1948 to January Week 1 2012), EMBASE (1980 to Week 2 2012), CINAHL (1937 to January 2012), PsycINFO (1887 to January Week 2 2012), ERIC (1966 to January 2012), Sociological Abstracts (1952 to January 2012), Science Citation Index (1970 to 20 January 2012), ZETOC (20 January 2012), LILACS (20 January 2012), Dissertation Abstracts (late 1960s to January 2012), ClinicalTrials.gov (19 January 2012), Current Controlled Trials (19 January 2012), Australian New Zealand Clinical Trials Registry (19 January 2012) and the National Research Register Archive. We also contacted experts to find unpublished studies. Randomised and quasi-randomised controlled trials of household educational or environmental interventions to prevent lead exposure in children where at least one standardised outcome measure was reported. Two authors independently reviewed all eligible studies for inclusion, assessed risk of bias and extracted data. We contacted trialists to obtain missing information. We included 14 studies (involving 2656 children). All studies reported blood lead level outcomes and none reported on cognitive or neurobehavioural outcomes. We put studies into subgroups according to their intervention type. We performed meta-analysis of both continuous and dichotomous data for subgroups where appropriate. Educational interventions were not effective in reducing blood lead levels (continuous: mean difference (MD) 0.02, 95% confidence interval (CI) -0.09 to 0.12, I(2) = 0 (log transformed); dichotomous ≥ 10µg/dL (≥ 0.48 µmol/L): relative risk (RR) 1.02, 95% CI 0.79 to 1.30, I(2)=0; dichotomous ≥ 15µg/dL (≥ 0.72 µmol/L): RR 0.60, 95% CI 0.33 to 1.09, I(2) = 0). Meta-analysis for the dust control subgroup also found no evidence of effectiveness (continuous: MD -0.15, 95% CI -0.42 to 0.11, I(2) = 0.9 (log transformed); dichotomous ≥ 10µg/dL (≥ 0.48 µmol/L): RR 0.93, 95% CI 0.73 to 1.18, I(2) =0; dichotomous ≥ 15µg/dL (≥ 0.72 µmol/L): RR 0.86, 95% CI 0.35 to 2.07, I(2) = 0.56). When meta-analysis for the dust control subgroup was adjusted for clustering, no statistical significant benefit was incurred. The studies using soil abatement (removal and replacement) and combination intervention groups were not able to be meta-analysed due to substantial differences between studies. Based on current knowledge, household educational or dust control interventions are ineffective in reducing blood lead levels in children as a population health measure. There is currently insufficient evidence to draw conclusions about the effectiveness of soil abatement or combination interventions.Further trials are required to establish the most effective intervention for prevention of lead exposure. Key elements of these trials should include strategies to reduce multiple sources of lead exposure simultaneously using empirical dust clearance levels. It is also necessary for trials to be carried out in developing countries and in differing socioeconomic groups in developed countries.


Participatory action research intervention for improving sleep in inpatients with cancer.
To design and implement a plan to improve oncohaematological patients' sleep. The hospital environment can compromise inpatients' sleep, negatively impacting on health outcomes and patient satisfaction. The improvement plan was designed in collaboration with 18 professionals, 3 patients and 3 accompanying relatives. The study designed followed the SQUIRE 2.0 guidelines. Outcome variables were self-reported patient satisfaction regarding sleep, measured using a 30-item, ad hoc questionnaire and a 10-point visual analogue scale, completed by 318 oncohaematological inpatients (pre-intervention n = 120, post-intervention, n = 198) in a comprehensive cancer centre in Spain from 2017 to 2019. Overall, 61.5% (n = 190) of the inpatients reported sleep alterations, and 92.6% reported interruptions in their nightly sleep. Half slept less than 6 h/night, but 58.0% said they felt rested upon waking, despite the interruptions. These outcomes were similar before and after the intervention. The improvement plan identified four domains for work (professionals, care procedures, instruments/environment and patients/relatives), 10 areas for improvement and 35 actions for implementation. However, overall sleep worsened significantly, from 6.73 to 6.06 on the 10-point scale. The intervention significantly improved variables related to professionals' behaviour, including noise during the shift change, conversations at the control desk and the use of corridor lights. Sleep disturbances were mainly caused by pain/discomfort and infuser alarms, and collectively they decreased significantly after the intervention (p = .008). However, overall sleep worsened significantly, from 6.73 to 6.06 on the 10-point scale. Pain, clinical devices and noise made by professionals are the main causes of sleep disturbances. Involving professionals in decision-making to improve patients' sleep have a positive impact on noise levels. This study proposes new strategies for improving sleep by increasing staff awareness and changing attitudes towards patients' sleep. Nurses should be involved in addressing sleep disturbances during hospitalization.


Platelets as delivery vehicles for targeted enrichment of NO· to cerebral glioma for magnetic resonance imaging.
Using a magnetic resonance imaging (MRI) contrast agent, MRI has made substantial contributions to glioma diagnosis. Metal-free MRI agents, such as the nano free radical nitric oxide (NO·) micelle, can overcome the inherent toxicity of metal-based agents in certain patient populations. However, the low spatial resolution of nano NO· micelle in MRI limits its clinical development. In this study, we pretreated platelets (PLTs) and loaded them with nano NO· micelles to synthesize NO·@PLT, which can overcome the low contrast and poor in vivo stability of nitroxide-based MRI contrast agents. The PLTs can serve as potential drug carriers for targeting and delivering nano NO· micelles to gliomas and thus increase the contrast in T1-weighted imaging (T1WI) of MRI. This drug carrier system uses the unique tumor-targeting ability of PLTs and takes advantage of the high signal presentation of steady nano NO· micelles in T1WI, thereby ultimately achieving signal amplification of glioma in T1WI. With the effect of PLTs-tumor cell adhesion, NO·@PLT has per-nitroxide transverse relativities of approximately 2-fold greater than those of free NO· particles. These features allow a sufficient NO·@PLT concentration to accumulate in murine subcutaneous glioma tumors up from 5 min to 2.5 h (optimum at 1.5 h) after systemic administration. This results in MRI contrast comparable to that of metal-based agents. This study established a promising metal-free MRI contrast agent, NO·@PLT, for glioma diagnosis, because it has superior spatial resolution owing to its high glioma-targeting ability and has significant translational implications in the clinic.


Anti-polyethyleneglycol antibody response to PEGylated substances.
In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.


The present and future of withdrawal period calculations for milk in the European Union: focus on heterogeneous, nonmonotonic data.
Harmonization of the method for calculating the withdrawal period for milk dates from the 1990s. European harmonization has led to guidance with three accepted methods for determining the withdrawal period for milk that are currently applicable. These three methods can be used by marketing authorization holders, but, in some cases, their diversity can lead to very different withdrawal periods. This is particularly the case when concentrations in milk are nonmonotonic and heterogeneous, meaning that concentrations strictly increase and then strictly decrease with significant interindividual variability in the time to reach the maximal concentration. Here, we first describe the concepts associated with the different methods used in the harmonized approach currently applicable for the determination of milk withdrawal periods, and then, we propose the application of a modern pharmacometric tool. Finally, with a nonmonotonic heterogeneous dataset, we illustrate the usefulness of this tool in comparison with the three currently applicable methods and discuss the limitations and advantages of each method.


Health effects of lesion localization in multiple sclerosis: spatial registration and confounding adjustment.
Brain lesion localization in multiple sclerosis (MS) is thought to be associated with the type and severity of adverse health effects. However, several factors hinder statistical analyses of such associations using large MRI datasets: 1) spatial registration algorithms developed for healthy individuals may be less effective on diseased brains and lead to different spatial distributions of lesions; 2) interpretation of results requires the careful selection of confounders; and 3) most approaches have focused on voxel-wise regression approaches. In this paper, we evaluated the performance of five registration algorithms and observed that conclusions regarding lesion localization can vary substantially with the choice of registration algorithm. Methods for dealing with confounding factors due to differences in disease duration and local lesion volume are introduced. Voxel-wise regression is then extended by the introduction of a metric that measures the distance between a patient-specific lesion mask and the population prevalence map.


The plant host can affect the encapsidation of brome mosaic virus (BMV) RNA: BMV virions are surprisingly heterogeneous.
Brome mosaic virus (BMV) packages its genomic and subgenomic RNAs into three separate viral particles. BMV purified from barley, wheat, and tobacco have distinct relative abundances of the encapsidated RNAs. We seek to identify the basis for the host-dependent differences in viral RNA encapsidation. Sequencing of the viral RNAs revealed recombination events in the 3' untranslated region of RNA1 of BMV purified from barley and wheat, but not from tobacco. However, the relative amounts of the BMV RNAs that accumulated in barley and wheat are similar and RNA accumulation is not sufficient to account for the difference in RNA encapsidation. Virions purified from barley and wheat were found to differ in their isoelectric points, resistance to proteolysis, and contacts between the capsid residues and the RNA. Mass spectrometric analyses revealed that virions from the three hosts had different post-translational modifications that should impact the physiochemical properties of the virions. Another major source of variation in RNA encapsidation was due to the purification of BMV particles to homogeneity. Highly enriched BMV present in lysates had a surprising range of sizes, buoyant densities, and distinct relative amounts of encapsidated RNAs. These results show that the encapsidated BMV RNAs reflect a combination of host effects on the physiochemical properties of the viral capsids and the enrichment of a subset of virions. The previously unexpected heterogeneity in BMV should influence the timing of the infection and also the host innate immune responses.


Are trends in work and health conditions interrelated? A study of Swedish hospital employees in the 1990s.
Swedish hospital personnel were followed over an 8-year period, characterized by staff redundancies and restructuring processes. Self-rated and administrative data sets from 1994 to 2001 allowed for studying long-term consequences of organizational instability for staff health and work conditions. The aim was to identify, on a work-unit level, trends in work and health conditions and their interdependence. Regression analysis showed a downward trend in mental health and an upward trend in long-term sick leave. Increasing trends of work demands were accompanied by deteriorating mental health, and decreasing time to plan work showed the strongest association with increasing long-term sick leave. Job satisfaction and support were decreasing. A stable short-term sick leave rate over years related to lack of support.


The secreted peptide PIP1 amplifies immunity through receptor-like kinase 7.
In plants, innate immune responses are initiated by plasma membrane-located pattern recognition receptors (PRRs) upon recognition of elicitors, including exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Arabidopsis thaliana produces more than 1000 secreted peptide candidates, but it has yet to be established whether any of these act as elicitors. Here we identified an A. thaliana gene family encoding precursors of PAMP-induced secreted peptides (prePIPs) through an in-silico approach. The expression of some members of the family, including prePIP1 and prePIP2, is induced by a variety of pathogens and elicitors. Subcellular localization and proteolytic processing analyses demonstrated that the prePIP1 product is secreted into extracellular spaces where it is cleaved at the C-terminus. Overexpression of prePIP1 and prePIP2, or exogenous application of PIP1 and PIP2 synthetic peptides corresponding to the C-terminal conserved regions in prePIP1 and prePIP2, enhanced immune responses and pathogen resistance in A. thaliana. Genetic and biochemical analyses suggested that the receptor-like kinase 7 (RLK7) functions as a receptor of PIP1. Once perceived by RLK7, PIP1 initiates overlapping and distinct immune signaling responses together with the DAMP PEP1. PIP1 and PEP1 cooperate in amplifying the immune responses triggered by the PAMP flagellin. Collectively, these studies provide significant insights into immune modulation by Arabidopsis endogenous secreted peptides.


Comparison of the resistive indices obtained in the uterine artery and the ophthalmic artery in preeclamptic and normotensive patients in Doppler US.
Introduction: Preeclampsia is a medical condition characterized by hypertension and proteinuria during pregnancy, with the symptoms generally manifesting in the 3rd trimester. Hypertension brings hemodynamic changes; it is therefore expected that arterial blood flow velocity waveforms will be different in the uterine and ophthalmic arteries in preeclampsia. Vascular changes do occur in preeclampsia, which in turn induces hemodynamic changes. Aim: To compare mean values of the resistive index of the ophthalmic and uterine arteries in patients with preeclampsia and normotensive individuals in Doppler US. Methods: In this cross-sectional observational study, ultrasound of the uterine and ophthalmic arteries was performed in 60 pregnant women in the 2nd and 3rd trimester of pregnancy to compare the resistive index of these arteries in preeclamptic and normotensive individuals. All the patients, i.e. 30 preeclamptic and 30 normotensive pregnant women, took part in this study voluntarily. The study was approved by the institutional review board (IRB) of the University of Lahore. Results: The mean resistive index of the uterine artery was 0.50 ± 0.08 in normotensive participants and 0.64 ± 0.09 in preeclamptic women, with the p-value <0.001. The mean resistive index of the ophthalmic artery was 0.70 ± 0.05 in normotensive participants and 0.63 ± 0.04 in preeclamptic women, with the p-value <0.001. Conclusions: There was a significant negative correlation between the resistive index of the uterine and ophthalmic arteries among the patients with preeclampsia and a significant positive correlation among normotensive individuals. Preeclampsia could be easily diagnosed with Doppler ultrasound based on hemodynamic changes in response to vascular changes in the ophthalmic and uterine arteries. Introduction: Preeclampsia is a medical condition characterized by hypertension and proteinuria during pregnancy, with the symptoms generally manifesting in the 3rd trimester. Hypertension brings hemodynamic changes; it is therefore expected that arterial blood flow velocity waveforms will be different in the uterine and ophthalmic arteries in preeclampsia. Vascular changes do occur in preeclampsia, which in turn induces hemodynamic changes. Aim: To compare mean values of the resistive index of the ophthalmic and uterine arteries in patients with preeclampsia and normotensive individuals in Doppler US. Methods: In this cross-sectional observational study, ultrasound of the uterine and ophthalmic arteries was performed in 60 pregnant women in the 2nd and 3rd trimester of pregnancy to compare the resistive index of these arteries in preeclamptic and normotensive individuals. All the patients, i.e. 30 preeclamptic and 30 normotensive pregnant women, took part in this study voluntarily. The study was approved by the institutional review board (IRB) of the University of Lahore. Results: The mean resistive index of the uterine artery was 0.50 ± 0.08 in normotensive participants and 0.64 ± 0.09 in preeclamptic women, with the p-value <0.001. The mean resistive index of the ophthalmic artery was 0.70 ± 0.05 in normotensive participants and 0.63 ± 0.04 in preeclamptic women, with the p-value <0.001. Conclusions: There was a significant negative correlation between the resistive index of the uterine and ophthalmic arteries among the patients with preeclampsia and a significant positive correlation among normotensive individuals. Preeclampsia could be easily diagnosed with Doppler ultrasound based on hemodynamic changes in response to vascular changes in the ophthalmic and uterine arteries.


Sn(20.5) square(3.5)As(22)I(8): a largely disordered cationic clathrate with a new type of superstructure and abnormally low thermal conductivity.
Sn(20.5)As(22)I(8), a new cationic clathrate, has been prepared by using an ampoule technique. According to the X-ray powder diffraction data, it crystallizes in the face-centered cubic space group F23 or Fm(-)3 with a unit-cell parameter of a=22.1837(4) A. Single-crystal X-ray data allowed solution of the crystal structure in the subcell with a unit-cell parameter of a(0)=11.092(1) A and the space group Pm(-)3n (R=5.7 %). Sn(20.5)As(22)I(8) (or Sn(20.5) square(3.5)As(22)I(8), accounting for the vacancies in the framework) possesses the clathrate-I type crystal structure, with iodine atoms occupying the cages of the cationic framework composed of tin and arsenic atoms. The crystal structure is strongly disordered. The main features are a random distribution of vacancies, and shifts of the tin and arsenic atoms away from their ideal positions. The coordination of the tin atoms has been confirmed by using (119)Sn Mössbauer spectroscopy. Electron diffraction and high-resolution electron microscopy (HREM) analyses have confirmed the presence of the superstructure ordering, which results in a doubling of the unit-cell parameter and a change of the space group from Pm(-)3n to either F23 or Fm(-)3. Analysis of the crystal structure has led to the construction of four ordering models for the superstructure, which have been corroborated by HREM, and has also led to the identification of disordered regions originating from overlap of the different types of ordered domains. Sn(20.5)As(22)I(8) is a diamagnetic semiconductor with an estimated band gap of 0.45 eV; it displays abnormally low thermal conductivity, with the room temperature value being just 0.5 W m(-1) K(-1).


Causes of blindness in rural Myanmar (Burma): Mount Popa Taung-Kalat Blindness Prevention Project.
This study is a review of the major causes of visual impairment (VI) and severe visual impairment/blindness (SVI/BL) in Mount Popa Taung-Kalat, a rural region in Myanmar (Burma). A review of our clinical records of consecutive patients attending clinics was conducted. Participants of all ages (n = 650) of the population of Mount Popa Taung-Kalat and villages in its vicinity underwent ophthalmic interview and a detailed dilated ocular evaluation by trained Australian ophthalmologists and ophthalmic nurses. This evaluation included anterior segment examination with a slit lamp, intraocular pressure recording, and direct or indirect ophthalmoscopy. VI and SVI/BL were defined by the World Health Organization (WHO) criteria. Six hundred fifty subjects were screened, with a mean age of 49.0 +/- 20.6 years (range, 1-99). One hundred five patients (16.2%) were children (ages 1-18). Five hundred thirty-one eyes of the total 1,300 eyes (39.5%) had VI/SVI/BL, and 40 eyes of the children (38.1%) (average age 15.3 +/- 13.3) had VI/SVI/BL. The leading causes of VI/SVI/BL were cataract with 288 cases (54.2%), glaucoma with 84 cases (15.8%), and corneal pathology with 78 cases (14.7%). Of all the VI/SVI/BL cases, 8.4% were preventable, 81.9% were treatable, and total of 90.5% were avoidable. In the current study, cataracts were the major cause of blindness and visual impairment, and most of the ophthalmic pathology causing blindness is avoidable. These results highlight the lack of basic ophthalmologist eye care and optician resources in rural regions in Myanmar.


Aluminum chloride hexahydrate in a salicylic acid gel base: a case series of combination therapy with botulinum toxin type A for moderate to severe hyperhidrosis.
Hyperhidrosis is a common condition that has a tremendous impact on the quality of life of patients. For moderate to severe hyperhidrosis, topical aluminum chloride hexahydrate (AC), iontophoresis, and botulinum toxin type A injections are first-line therapies. Botulinum toxin type A has been a useful addition to the hyperhidrosis armamentarium and typically is utilized when topical therapy or iontophoresis have failed. Although highly effective for most patients, there remains a subset of patients who do not completely respond to botulinum toxin type A injections. For these patients, combination therapy with AC can greatly improve patient response. We present a case series of 10 patients with hyperhidrosis and a history of partial response to botulinum toxin type A monotherapy. With the addition of AC 15% in a salicylic acid 2% gel base, 5 patients achieved 75% to 100% reduction in sweating and 5 patients achieved 100% reduction in sweating. Aluminum chloride hexahydrate in a salicylic acid gel base offers a novel and effective topical therapy in combination with botulinum toxin type A for patients with moderate to severe hyperhidrosis.


Poly(ethylene glycol) based nanotubes for tuneable drug delivery to glioblastoma multiforme.
Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumour, which is associated with a poor two-year survival rate and a high rate of fatal recurrence near the original tumour. Focal/local drug delivery devices hold promise for improving therapeutic outcomes for GBM by increasing drug concentrations locally at the tumour site, or by facilitating the use of potent anti-cancer drugs that are poorly permeable across the blood brain barrier (BBB). For inoperable tumours, stereotactic delivery to the tumour necessitates the development of nanoscale/microscale injectable drug delivery devices. Herein we assess the ability of a novel class of polymer nanotube (based on poly(ethylene glycol) (PEG)) to load doxorubicin (a mainstay breast cancer therapeutic with poor BBB permeability) and release it slowly. The drug loading properties of the PEG nanotubes could be tuned by varying the degree of carboxylic acid functionalisation and hence the capacity of the nanotubes to electrostatically bind and load doxorubicin. 70% of the drug was released over the first seven days followed by sustained drug release for the remaining two weeks tested. Unloaded PEG nanotubes showed no toxicity to any of the cell types analysed, whereas doxorubicin loaded nanotubes decreased GBM cell viability (C6, U-87 and U-251) in a dose dependent manner in 2D in vitro culture. Finally, doxorubicin loaded PEG nanotubes significantly reduced the viability of in vitro 3D GBM models whilst unloaded nanotubes showed no cytotoxicity. Taken together, these findings show that polymer nanotubes could be used to deliver alternative anti-cancer drugs for local therapeutic strategies against brain cancers.


Paranucleospora theridion n. gen., n. sp. (Microsporidia, Enterocytozoonidae) with a Life Cycle in the Salmon Louse (Lepeophtheirus salmonis, Copepoda) and Atlantic Salmon (Salmo salar).
Paranucleospora theridion n. gen, n. sp., infecting both Atlantic salmon (Salmo salar) and its copepod parasite Lepeophtheirus salmonis is described. The microsporidian exhibits nuclei in diplokaryotic arrangement during all known life-cycle stages in salmon, but only in the merogonal stages and early sporogonal stage in salmon lice. All developmental stages of P. theridion are in direct contact with the host cell cytoplasm or nucleoplasm. In salmon, two developmental cycles were observed, producing spores in the cytoplasm of phagocytes or epidermal cells (Cycle-I) and in the nuclei of epidermal cells (Cycle-II), respectively. Cycle-I spores are small and thin walled with a short polar tube, and are believed to be autoinfective. The larger oval intranuclear Cycle-II spores have a thick endospore and a longer polar tube, and are probably responsible for transmission from salmon to L. salmonis. Parasite development in the salmon louse occurs in several different cell types that may be extremely hypertrophied due to P. theridion proliferation. Diplokaryotic merogony precedes monokaryotic sporogony. The rounded spores produced are comparable to the intranuclear spores in the salmon in most aspects, and likely transmit the infection to salmon. Phylogenetic analysis of P. theridion partial rDNA sequences place the parasite in a position between Nucleospora salmonis and Enterocytozoon bieneusi. Based on characteristics of the morphology, unique development involving a vertebrate fish as well as a crustacean ectoparasite host, and the results of the phylogenetic analyses it is suggested that P. theridion should be given status as a new species in a new genus.


Characterization of Desmoglein 3 (DSG3) as a Sensitive and Specific Marker for Esophageal Squamous Cell Carcinoma.
Although P40 and P63 are both sensitive and specific for routine esophageal squamous cell carcinoma (SCC) diagnosis, we recently showed that P40 and P63 immunoreactivities were significantly lower in well-differentiated SCC than those in higher grade tumors. Therefore, a novel esophageal SCC marker, ideally performing better in well-differentiated SCC, is still needed. We characterized desmoglein 3 (DSG3) immunohistochemistry in esophageal SCC, esophageal adenocarcinoma, small-cell lung carcinoma, and large B-cell lymphoma, alongside P40 and CK5/6. The World Health Organization classification was used to grade tumors as well-differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD). There were 20 WD, 26 MD, and 17 PD components among 39 esophageal SCC cases. All esophageal SCC components showed significant DSG3 immunoreactivity (mean, 80%; range, 30%-100%), and the proportions of DSG3 immunoreactive cells were higher in the WD and MD components than in the PD components. No esophageal adenocarcinoma cases showed more than 10% DSG3 immunoreactivity with only weak cytoplasmic staining. With a 5% immunoreactivity cutoff, DSG3 positivity was 100% in all 63 SCC components, 18% in adenocarcinoma cases, and 0% in small-cell lung carcinoma or large B-cell lymphoma cases. The overall DSG3 specificity was 94%. To the best of our knowledge, this is the first study to characterize DSG3 as a sensitive and specific marker for esophageal SCC.


de Haas-van Alphen study of the Fermi surfaces of superconducting LiFeP and LiFeAs.
We report a de Haas-van Alphen oscillation study of the 111 iron pnictide superconductors LiFeAs with T(c) ≈ 18 K and LiFeP with T(c) ≈ 5 K. We find that for both compounds the Fermi surface topology is in good agreement with density functional band-structure calculations and has almost nested electron and hole bands. The effective masses generally show significant enhancement, up to ~3 for LiFeP and ~5 for LiFeAs. However, one hole Fermi surface in LiFeP shows a very small enhancement, as compared with its other sheets. This difference probably results from k-dependent coupling to spin fluctuations and may be the origin of the different nodal and nodeless superconducting gap structures in LiFeP and LiFeAs, respectively.


Impact of coffee biochar on carbon, microbial biomass and enzyme activities of a sandy soil cultivated with bean.
Biochar has been used to reuse the agro-industrial wastes and improve soil quality. Several studies have been carried out to show the impact of biochar on physical and chemical soil attributes. However, there are still gaps regarding the effects on as microbial biomass and enzymatic activities that are important to determine sensitive indicators to evaluate changes in management practices. The objective of this study was to assess the effect of two biochars on the chemical, microbial biomass carbon, and the enzymatic activities in an Entisol cultivated with bean. We evaluate two types of coffee biochar: ground and husks, four doses (4, 8, 12, and 16 Mg ha-1) and control. All treatments received organic fertilization with cow manure. Husks biochar increase the soil pH, Ca, and K, also contributing to the reduction of toxic aluminum contents and raising the concentrations of P labile. The treatments that received ground biochar showed higher soil organic carbon, microbial biomass, β-glucosidase, and fluorescein diacetate. Biochar produced from coffee residues increased sandy soil quality. We showed the first report on the beneficial impact of coffee biochar on enzymatic and microbiological quality of sandy soil cultivated with the bean.


WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer.
The Wilms' tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer. WT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment. WT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score. Expression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.


Collision cross section predictions using 2-dimensional molecular descriptors.
Traditional methods for deriving computationally-generated collision cross sections for comparisons with ion mobility-mass spectrometry data require 3-dimensional energy-minimized structures and are often time consuming, preventing high throughput implementation. Here, we introduce a method to predict ion mobility collision cross sections of lipids and peptide analogs important in prebiotic chemistry and other fields. Using less than 100 2-D molecular descriptors this approach resulted in prediction errors of less than 2%.


[Diagnostic and therapeutic pitfalls in benign vocal fold diseases].
More than half of patients who present with the symptom of hoarseness show benign vocal fold changes. The clinician should be familiar with modern diagnostic and therapeutic possibilities of benign vocal fold changes in order to ensure an optimal and individualized attention to voice patients. Basic knowledge of the etiology are provided for targeted phonosurgical or conservative therapy. This review article focuses on the diagnostic and therapeutic limitations and difficulties of treatment of benign vocal fold tumors, the management and prophylaxis of scarred vocal fold changes and the issue of unilateral vocal fold paralysis.


Treatment of Experimental Cerebral Malaria by Slow Release of Artemisone From Injectable Pasty Formulation.
Malaria caused by Plasmodium falciparum causes numerous cases of morbidity with about 400,000 deaths yearly owing, mainly, to inflammation leading to cerebral malaria (CM). CM conventionally is treated by repetitive administration of anti-plasmodial drugs and supportive non-specific drugs, for about a week. A mouse model of CM caused by Plasmodium berghei ANKA, in which brain and systemic clinical pathologies occur followed by sudden death within about a week, was used to study the effect of artemisone, a relatively new artemisinin, within an injectable pasty polymer formulated for its controlled release. The parasites were exposed to the drug over several days at a non-toxic concentrations for the mice but high enough to affect the parasites. Artemisone was also tested in cultures of bacteria, cancer cells and P. falciparum to evaluate the specificity and suitability of these cells for examining the release of artemisone from its carrier. Cultures of P. falciparum were the most suitable. Artemisone released from subcutaneous injected poly(sebacic acid-ricinoleic acid) (PSARA) pasty polymer, reduced parasitemias in infected mice, prolonged survival and prevented death in most of the infected mice. Successful prophylactic treatment before infection proved that there was a slow release of the drug for about a week, which contrasts with the three hour half-life that occurs after injection of just the drug. Treatment with artemisone within the polymer, even at a late stage of the disease, helped to prevent or, at least, delay accompanying severe symptoms. In some cases, treatment prevented death of CM and the mice died later of anemia. Postponing the severe clinical symptoms is also beneficial in cases of human malaria, giving more time for an appropriate diagnosis and treatment before severe symptoms appear. The method presented here may also be useful for combination therapy of anti-plasmodial and immunomodulatory drugs.


Chitosan-Urea Nanocomposite for Improved Fertilizer Applications: The Effect on the Soil Enzymatic Activities and Microflora Dynamics in N Cycle of Potatoes (Solanum tuberosum L.).
The impact of polymer-based slow-release urea formulations on soil microbial N dynamics in potatoes has been sparingly deciphered. The present study investigated the effect of a biodegradable nano-polymer urea formulation on soil enzymatic activities and microflora involved in the N cycling of potato (Solanum tuberosum L.). The nano-chitosan-urea composite (NCUC) treatment significantly increased the soil dehydrogenase activity, organic carbon content and available potassium compared to the conventional urea (CU) treatment. The soil ammonical nitrogen (NH4+-N) and nitrate nitrogen (NO3--N) contents and urease activity were significantly decreased in the NCUC-amended soil. The slow urea hydrolysis rate led to low concentrations of NH4+-N and NO3--N in the tested potato soil. Furthermore, these results corroborate the low count of ammonia oxidizer and nitrate reducer populations. Quantitative PCR (q-PCR) studies revealed that the relative abundance of eubacterial (AOB) and archaeal ammonia-oxidizing (AOA) populations was reduced in the NCUC-treated soil compared to CU. The abundance of AOA was particularly lower than AOB, probably due to the more neutral and alkaline conditions of the tested soil. Our results suggest that the biodegradable polymer urea composite had a significant effect on the microbiota associated with soil N dynamics. Therefore, the developed NCUC could be used as a slow N-release fertilizer for enhanced growth and crop yields of potato.


Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation.
Gaucher disease is an inherited lysosomal storage disease in which the loss in functional activity of glucocerebrosidase (GC) results in the storage of its lipid substrate in cells of the macrophage lineage. A gene therapy approach involving retroviral transduction of autologous bone marrow (BM) followed by transplantation has been recently approved for clinical trial. Amelioration of the disease symptoms may depend on the replacement of diseased macrophages with incoming cells expressing human GC; however, the processes of donor cell engraftment and vector gene expression have not been addressed at the cellular level in relevant tissues. Therefore, we undertook a comprehensive immunohistologic study of macrophage and microglia replacement after murine BM transplantation with retrovirus-marked BM. Serial quantitative PCR analyses were employed to provide an overview of the time course of engraftment of vector-marked cells in a panel of tissues. Following reconstitution of hematopoietic tissues with vector-marked donor cells at early stages, GC+ cells began to infiltrate the liver, lung, brain, and spinal cord by 3 months after transplant. Immunohistochemical analyses of PCR+ tissues using the 8E4 monoclonal antibody specific for human GC revealed that macrophages expressing human GC had partially reconstituted the Mac-1+ population in all tissues in a manner characteristic to each tissue type. In the brain, 20% of the total microglia had been replaced with donor cells expressing GC by 3 to 4 months after transplant. The finding that significant numbers of donor cells expressing a retroviral gene product immigrate to the central nervous system suggests that gene therapy for neuronopathic forms of lysosomal storage diseases as well as antiviral gene therapy for AIDS may be feasible.


[Indices characterizing the expression of hyperesthesia of the hard dental tissues in patients with periodontitis].
Clinical examinations of 226 patients with periodontitis have revealed in 61% of them hyperesthesia of the hard dental tissues, that was mostly generalized, characterized by a marked reaction to thermal, chemical, and tactile stimulants. Study of the mineral metabolism has demonstrated that growing bone tissue loss in dental biopsy specimens and gingival fluid is associated with reducing levels of P, Ca, and Mg. Combination of clinical manifestations of periodontitis and hyperesthesia necessitate search for combined therapy aimed at simultaneous elimination of hyperesthesia and inflammation.


A H2O2-activatable nanoprobe for diagnosing interstitial cystitis and liver ischemia-reperfusion injury via multispectral optoacoustic tomography and NIR-II fluorescent imaging.
Developing high-quality NIR-II fluorophores (emission in 1000-1700 nm) for in vivo imaging is of great significance. Benzothiadiazole-core fluorophores are an important class of NIR-II dyes, yet ongoing limitations such as aggregation-caused quenching in aqueous milieu and non-activatable response are still major obstacles for their biological applications. Here, we devise an activatable nanoprobe to address these limitations. A molecular probe named BTPE-NO2 is synthesized by linking a benzothiadiazole core with two tetraphenylene groups serving as hydrophobic molecular rotors, followed by incorporating two nitrophenyloxoacetamide units at both ends of the core as recognition moieties and fluorescence quenchers. An FDA-approved amphiphilic polymer Pluronic F127 is then employed to encapsulate the molecular BTPE-NO2 to render the nanoprobe BTPE-NO2@F127. The pathological levels of H2O2 in the disease sites cleave the nitrophenyloxoacetamide groups and activate the probe, thereby generating strong fluorescent emission (950~1200 nm) and ultrasound signal for multi-mode imaging of inflammatory diseases. The nanoprobe can therefore function as a robust tool for detecting and imaging the disease sites with NIR-II fluorescent and multispectral optoacoustic tomography (MSOT) imaging. Moreover, the three-dimensional MSOT images can be obtained for visualizing and locating the disease foci.