Prevalence and proliferation of antibiotic resistance genes in two municipal wastewater treatment plants.
The propagation of antibiotic resistance genes (ARGs) is an emerging health concern worldwide. Thus, it is important to understand and mitigate their occurrence in different systems. In this study, 30 ARGs that confer resistance to tetracyclines, sulfonamides, quinolones or macrolides were detected in two activated sludge wastewater treatment plants (WWTPs) in northern China. Bacteria harboring ARGs persisted through all treatment units, and survived disinfection by chlorination in greater percentages than total Bacteria (assessed by 16S rRNA genes). Although the absolute abundances of ARGs were reduced from the raw influent to the effluent by 89.0%-99.8%, considerable ARG levels [(1.0 ± 0.2) × 10(3) to (9.5 ± 1.8) × 10(5) copies/mL)] were found in WWTP effluent samples. ARGs were concentrated in the waste sludge (through settling of bacteria and sludge dewatering) at (1.5 ± 2.3) × 10(9) to (2.2 ± 2.8) × 10(11) copies/g dry weight. Twelve ARGs (tetA, tetB, tetE, tetG, tetH, tetS, tetT, tetX, sul1, sul2, qnrB, ermC) were discharged through the dewatered sludge and plant effluent at higher rates than influent values, indicating overall proliferation of resistant bacteria. Significant antibiotic concentrations (2%-50% of raw influent concentrations) remained throughout all treatment units. This apparently contributed selective pressure for ARG replication since the relative abundance of resistant bacteria (assessed by ARG/16S rRNA gene ratios) was significantly correlated to the corresponding effluent antibiotic concentrations. Similarly, the concentrations of various heavy metals (which induce a similar bacterial resistance mechanism as antibiotics - efflux pumps) were also correlated to the enrichment of some ARGs. Thus, curtailing the release of antibiotics and heavy metals to sewage systems (or enhancing their removal in pre-treatment units) may alleviate their selective pressure and mitigate ARG proliferation in WWTPs.


Murine typhus in Tunisia: a neglected cause of fever as a single symptom.
We had for aim to describe the epidemiologic and clinic characteristics of murine typhus in a series of 43 serologically confirmed cases, in our region. Serologic screening for IgG and IgM against Rickettsia typhi was performed in 1024 patients during three years (2006-2008). The characteristics of patients with a positive serology were examined retrospectively. One hundred and seventy sera obtained from blood donors were tested to detect IgG against R. typhi to determine the seroprevalence of the infection. There was evidence of recent R. typhi infection in 43 patients (4.2%) during the study period, and 3.7% of blood donors had IgG against R. typhi. The mean age of patients was 43.1 years and the sex-ratio was 1.04. Among the patients, 58.1% were from rural areas. No patient reported any exposure to rats or rat-fleas. There were more cases during the summer and fall. The most frequent complaint was fever as a single symptom (67.5%). A cutaneous rash was reported in 44.1% and headache in 60.5% of patients. Among the patients, 44.1% presented with thrombopenia and 47.2% with elevated liver enzymes. Murine typhus seems to be frequent in Tunisia. This infection could be a threat for travellers. Serology should be performed systematically in patients with fever as a single symptom since its clinical presentation is non-specific.


Exploring the feasibility of biotransforming salted soy whey into a soy sauce-like condiment using wine yeast Torulaspora delbrueckii and soy sauce yeasts Zygosaccharomyces rouxii and Candida versatilis as single starter cultures.
Salted soy whey, a liquid by-product from salted tofu processing, is a source of valuable nutrients. However, it is often under-utilized due to its high salt content. The objective of this study was to investigate the feasibility of using different species of yeast to transform salted soy whey into a soy sauce-like condiment. Three yeasts were used for salted soy whey biotransformation: Zygosaccharomyces rouxii NCYC 1682, Candida versatilis NCYC 1433, and Torulaspora delbrueckii Biodiva. This study focused on the growth of the yeasts in soy whey added with different levels of NaCl and the physicochemical changes of salted soy whey after fermentation. The soy sauce yeasts (Z. rouxii and C. versatilis) grew by approximately 2 log CFU/mL in soy whey with 2% and 10% salt while the cell count of wine yeast T. delbrueckii increased by around 1.5 log CFU/mL at 10% salt and 1.78 log CFU/mL at 2% salt after 14 days of fermentation. Candida versatilis grew better at 10% salt with less glucose consumption (consumed 68.49% at 10% versus 94.05% at 2% salt) than at 2% salt. It was also found that all three yeasts converted isoflavone glycosides (bound isoflavones) into aglycones (free isoflavones), the latter having better bioavailability. C. versatilis showed the greatest ability to transform isoflavone glycosides in salted soy whey into higher amounts of aglycones (conversion efficiency of 23.04% at 2% salt and 15.05% at 10% salt). Salted soy whey fermented with different yeasts had different volatile profiles. Soy sauce yeasts produced more isobutyl alcohol, isoamyl alcohol and volatile phenols while T. delbrueckii generated a substantial amount of ethanol and esters. This study revealed the growth and flavour modulating potential of yeasts in salted soy whey fermentation, which provides a possible avenue to develop a soy sauce-like condiment using salted soy whey as a substrate.


Light response characteristics of net CO2 exchange in brackish wetland plant communities.
Photosynthetic responses to incident photon flux density (400-700 nm; PPFD) was studied in a grass community consisting of Spartina patens and Distichlis spicata and a mixed community having the two grasses and a sedge, Scirpus Olneyi. Net community CO2 exchange and incident PPFD were monitored from dawn to dusk in a large open gas exchange system, and a hyperbolic light response model was fit to the data for each day. Light response curves from five growing seasons were evaluated for seasonal trends in the compensation value, initial slope, and maximum net CO2 exchange rate calculated from the model at PPFD=1670 μmol m-2s-1.All response curves were curvilinear. Data from approximately 30% of the 113 days studied fit saturation curves which occurred primarily in spring and fall. Approximately 5% of all curves constructed required a different response curve for the morning and afternoon. These occurred during mid-summer and were interpreted to be evidence of water stress.The compensation flux density was very high early in the growing season, but rapidly decreased and during the months June, July and August, it averaged near 100 and 120 μmol m-2s-1 in the mixed and grass communities. The initial slope and maximum net CO2 exchange rate increased from early May to maxima in July and declined thereafter. Mid-summer mean values for the mixed and grass communities respectively were 34.3±10.3 mmol mol-1 and 39.1±9.1 mmol mol-1 for the initial slope and 20.3±4.2 μmol m-2s-1 and 23.0±3.8 μmol m-2s-1 for maximum net CO2 exchange. Daytime respiration accounted for approximately 20% of maximum gross photosynthesis in both communities.Photosynthetic efficiency, CO2 assimilated per unit total incident solar radiation, was approximately 4.1% and 4.7% at dawn or dusk and 2.3% and 2.6% at midday for the mixed and grass community. Gross photosynthesis, maximum photosynthesis plus midday respiration, accounted for 2.7% and 3.0% of total incident solar radiation in the mixed and grass communities.


Physico-chemical and functional properties of Resistant starch prepared from red kidney beans (Phaseolus vulgaris.L) starch by enzymatic method.
The objective of this study was to evaluate the production, physico-chemical and functional properties of Resistant starch (RS) from red kidney bean starch by enzymatic method. Native and gelatinized starch were subjected to enzymatic hydrolysis (pullulanase, 40 U/g/10 h), autoclaved (121 °C/30 min), stored under refrigeration (4 °C/24 h), and lyophilized. The enzymatic hydrolysis and thermal treatment of starch increased the formation of RS which showed an increase in water absorption and water solubility indexes and a decrease in swelling power due to hydrolytic and thermal process. The process for obtaining RS changed the crystallinity pattern from C to B and increased the crystallinity due to the retrogradation process. RS obtained from hydrolysis showed a reduction in viscosity, indicating the rupture of starch molecules. The viscosity was found to be inversely proportional to the RS content in the sample. The thermal properties of RS increased due to the retrogradation and recrystallization (P<0.05).


[The catheterembolisation for permanent occlusion of the renal artery--anaesthesiologic views (author's transl)].
Experiences with a new radiological technique, namely embolisation of the renal artery with a spiral from Gianturco, are reported. Continuous epidural block has been found to be the best method of anaesthetic management. The technique of embolisation was used in 17 patients. As a preoperative measure it facilitates tumournephrectomy, saves blood and reduces the danger of dissemination of tumour-cells during operation.


The Vodder School: the Vodder method.
The history and development of manual lymphatic drainage (MLD) from Winiwarter to Vodder and the Vodder School of today are discussed. The Vodder technique differs in the use of adapted pressure and its application. The constant change in pressure optimizes results, moving fluid in the skin, increasing lymphomotoricity, and softening fibrosis, with the positive side effects of reducing pain and relaxing tense muscles. Another difference from other methods is the technique of stretching skin, not sliding it. Because of the fluid content in lymphedema, which is different from all other edemas, the combination of MLD with compression treatment is the only solution for this pathology. Depending of it severity, each case requires individualized treatment. Phase 1 (intensive treatment) consists of daily treatment with up to two sessions per day for up to 2 hours. This phase is combined with special, individual skin care and remedial exercise. In phase 2, the goal of treatment is to maintain the results achieved in phase 1. The frequency of treatment is changed, but there is still the need for permanent, continued therapy. In phase 1, an average reduction of more than 40% of edema volume is achieved. In phase 2, the results are maintained and, with repetitions of phase 1, further improvement is possible. Thus, long term results with permanent improvement are possible. Because of the complexity of the technique, no one can learn MLD in 1 week. Students require a great deal of correction, and the technique must be checked constantly. To become a certified Vodder therapy, a 4-week education program must be completed, and reviews must be attended every 2 years to maintain certification. The best education produces the best results for patients as long as patients are compliant. Therefore, the Vodder School also includes a patient education program as part of its curriculum.


Effect of CPP-ACP on Streptococcus mutans in saliva of high caries-risk preschool children: a randomized clinical trial.
The aim of this study was to assess the efficacy of CPP-ACP in reducing salivary S. mutans levels and compare its effect as a dentifrice to use of a fluoride dentifrice alone, or with the sequential use of a combination of both agents (fluoride, then CPP-ACP) in three groups of preschool children over a 6-month period. This was a double-blinded clinical trial, the sample (n = 127, age 4.6 ± 0.47 years), with high caries risk, was randomized into three groups which applied different agents twice daily; fluoride toothpaste (500 ppm, n = 50), CPP-ACP (10% w/v, n = 38), and combination group (n = 39) applied fluoride, then CPP-ACP. S. mutans salivary levels were measured by GC Saliva-Check Mutans™. Within groups, a significant decrease in S. mutans-positive children (SMPC) occurred in fluoride and combination groups at 3-months, (P < 0.05), and in all groups at 6-months, (P < 0.05). The highest reduction in SMPC occurred in the CPP-ACP group, however, there were no significant differences in SMPC between groups at all study intervals, (P > 0.05). Although all agents were effective, CPP-ACP showed the highest reduction in SMPC over 6-months.


Safe delivery and newborn care practices in Sindh, Pakistan: a community-based investigation of mothers and health workers.
to determine the prevalence of specific intrapartum practices in Sindh province, Pakistan. a cross-sectional, questionnaire based study. 6 health clinics in Mirpurkhas, Sindh province, rural Pakistan. 225 mothers and 82 health workers. outcome measures were indicators of safe delivery practices and referral following an obstetric complication. Prevalence of unhygienic and unsafe practices in deliveries attended by Traditional Birth Attendants (TBAs) was common. Deliveries by skilled attendants were significantly safer but with some failures in hygienic practices. 29% of women who had experienced an obstetric complication had not received emergency obstetric care. safe delivery practices and newborn care needs to be improved in rural Pakistan. This may be achieved by training health workers and TBAs in safe delivery practices, using safe delivery kits and with an effective referral system.


Hamiltonian Monte Carlo acceleration using surrogate functions with random bases.
For big data analysis, high computational cost for Bayesian methods often limits their applications in practice. In recent years, there have been many attempts to improve computational efficiency of Bayesian inference. Here we propose an efficient and scalable computational technique for a state-of-the-art Markov chain Monte Carlo methods, namely, Hamiltonian Monte Carlo. The key idea is to explore and exploit the structure and regularity in parameter space for the underlying probabilistic model to construct an effective approximation of its geometric properties. To this end, we build a surrogate function to approximate the target distribution using properly chosen random bases and an efficient optimization process. The resulting method provides a flexible, scalable, and efficient sampling algorithm, which converges to the correct target distribution. We show that by choosing the basis functions and optimization process differently, our method can be related to other approaches for the construction of surrogate functions such as generalized additive models or Gaussian process models. Experiments based on simulated and real data show that our approach leads to substantially more efficient sampling algorithms compared to existing state-of-the-art methods.


A new HLA-B*44 variant, B*4453, identified by haplotype-specific extraction and sequencing-based typing.
We report the identification of a novel HLA B*44 allele, officially named B*4453, found in an Austrian patient and his two sisters.


Pharmacokinetics of three formulations of diphenylhydantoin in the dog.
The pharmacokinetics of the sodium salt of diphenylhydantoin was studied in three healthy dogs, using three formulations, a capsule, a tablet and a suspension. The results were essentially the same for all three formulations. The serum half life after intravenous injection ranged from 3.1 to 3.6 hours before and 1.3 to 1.6 hours after a two-week period of oral treatment. The bioavailability of the formulations varied from 43 to 54 per cent. Serum levels likely to be required for canine therapy could not be maintained with any of the formulations used in this experiment.


Breakage and binding of DNA by reaction products of hypochlorous acid with aniline, 1-naphthylamine, or 1-naphthol.
Hypochlorous acid (HOCl) is a chemically reactive oxidant and a potent microbicidal agent that is synthesized in phagosomes of inflammatory neutrophils and released into extracellular spaces. Besides reducing pathogenicity by reacting with phagocytized infectious agents, HOCl may damage tissues and yield toxic products upon reaction with various other molecules, including xenobiotics. As model xenobiotics, the substituted aryl compounds aniline, 1-naphthylamine, and 1-naphthol (1-NOH) were investigated herein for their potential to react with HOCl and the transformed into genotoxic products. The compounds were first exposed to HOCl (25-150 microM) in phosphate buffer and afterward used to treat human fibroblasts or purified DNA. DNA single-strand breaks in cells and the binding of HOCl-reacted 1-[14C]NOH to purified DNA were assessed by DNA alkaline elution and scintillation spectrometry, respectively. It was found that neither HOCl nor compounds alone could break cellular DNA. But HOCl-reacted compounds produced up to 400 rad equivalents of DNA breaks. HOCl reaction products of aniline and the model bicyclic aryl compounds differed in their DNA-breaking characteristics. HOCl-reacted 1-[14C]NOH was stable and bound to DNA at up to 124 pmol/mg DNA. Sodium thiosulfate, glutathione, and taurine inhibited the transformation reactions; but only the former two blocked binding of HOCl-reacted 1-NOH to DNA. Ultraviolet spectra showed that HOCl reacted rapidly (less than 1 min) and equally well with 1-NOH at pH 7.2 or at an intraphagosomal pH of 5.0. Reaction concentrations of HOCl in this study were 2- to 11-fold lower than levels generated in vitro by stimulated neutrophils. These results show that certain aryl compounds can react readily with approximated physiological levels of HOCl (-OCl) to form relatively long-lived products that bind DNA and are genotoxic to human cells.


Radio-Immune Response Modelling for Spatially Fractionated Radiotherapy.
Radiation-induced cell death is a complex process influenced by physical, chemical and biological phenomena. Strong dose gradient may intensify the complexity and reportedly creates significantly more cell death known as bystander effect. Although consensus on the nature and the mechanism of the bystander effect were not yet made, the immune process presumably plays an important role in many aspects of the radiotherapy including the bystander effect. Immune response of host body and immune suppression of tumor cells are modelled with four compartments in this study; viable tumor cells, T cell lymphocytes, immune triggering cells, and doomed cells. The growth of tumor was analyzed in two distinctive modes of tumor status (immune limited and immune escape) and its bifurcation condition. Tumors in the immune limited mode can grow only up to a finite size, named as terminal tumor volume analytically calculated from the model. The dynamics of the tumor growth in the immune escape mode is much more complex than the tumors in the immune limited mode especially when the status of tumor is close to the bifurcation condition. Radiation can kill tumor cells not only by radiation damage but also by boosting immune reaction. The model demonstrated that the highly heterogeneous dose distribution in spatially fractionated radiotherapy (SFRT) can make a drastic difference in tumor cell killing compared to the homogeneous dose distribution. SFRT can not only enhance but also moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics. The model was applied to the lifted data of 67NR tumors on mice and a sarcoma patient treated multiple times over 1200 days for the treatment of tumor recurrence as a demonstration.


Implications of the DSM's emphasis on sadness and anhedonia in major depressive disorder.
At least five symptoms must occur for a DSM diagnosis of major depressive disorder (MDD), one of which must be sadness or anhedonia. The present study is the first known investigation of the implications of the presence or absence of these prioritized symptoms on symptom expression and clinical characteristics among 564 young adults with MDD. Differences in symptom expression and clinical characteristics occurred among MDD participants with sadness relative to those without sadness as well as among MDD participants with anhedonia relative to those without anhedonia. Differential symptom expression could have important implications for the etiology, prevention, and treatment of MDD.


An integrated approach to quantify ecological and human health risks of soil heavy metal contamination around coal mining area.
Soil heavy metals harm ecological biodiversity and human health, and quantifying the risks more accurately is still obscure. In this study, a network environ analysis was applied to quantify risks between ecological communities based on control allocation and human health risk models to calculate human health exposure risks from soil heavy metals around Greenside coal mining in South Africa. Ecological and human health risks were apportioned using PMF model. Results showed assessed heavy metals (mean) exceeded local background content with a cumulative of moderately polluted using pollution load index (PLI). Total initial risk (Ri), the risk to biological organisms from direct soil exposure, was 0.656 to vegetation and 1.093 to soil microorganisms. Risk enters the food web via vegetation and harms the whole system. Integrated risks (initial, direct, and indirect) to vegetation, herbivores, soil microorganisms, and carnivores were 0.656, 0.125, 1.750, and 0.081, respectively, revealing that soil microorganisms are the most risk receptors. Total Hazard Index (HIT) was <1 for adults (0.574) whereas >1 for children (4.690), signifying severe non-cancer effects to children. Total cancer risk (TCR) to children and adults surpassed the unacceptable limit (1.00E-04). Comparatively, Cr is a high-risk metal accounted for 63.24% (adults) and 65.88% (children) of the HIT and 92.98% (adults) and 91.31% (children) of the TCR. Four sources were apportioned. Contributions to Ri (soil microorganisms and vegetation) from F3 (industrial), F4 (atmospheric), F2 (coal mining), and F1 (natural) were 42.20%, 24.56%, 23.55%, and 9.68%, respectively. The non-cancer risk from F3 (37.67% to adults and 38.40% to children) was dominant, and TCR to children from the sources except F1 surpassed the unacceptable limit. An integrated approach of risk quantification is helpful in managing risks and reducing high-risk pollution sources to better protect the environment and human health.


Reconstructed hydrotalcite as a highly active heterogeneous base catalyst for carbon-carbon bond formations in the presence of water.
The aldol reaction of carbonyl compounds is efficiently catalyzed by reconstructed hydrotalcites, obtained by treating the Mg-Al mixed oxide with water, as solid base catalysts in the presence of water. The catalysis of the reconstructed hydrotalcites is attributable to the surface base sites, created during the organization of the layered structure, with uniformly distributed strength. Furthermore, the reconstructed hydrotalcites provide a unique acid-base bifunctional surface capable of promoting the Knoevenagel and Michael reactions of nitriles with carbonyl compounds.


Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2+ γδ T cell can be a promising complement.
In hepatocellular carcinoma (HCC), γδ T cells participate in mediating the anti-tumour response and are linked with a positive prognosis. However, these cells can become pro-tumoural in the tumour microenvironment (TME). We aimed to decipher the immune landscape and functional states of HCC-infiltrating γδ T cells to provide fundamental evidence for the adoptive transfer of allogeneic Vδ2+ γδ T cells in HCC immunotherapy. We performed single-cell RNA sequencing (scRNA-seq) on γδ T cells derived from HCC tumours and healthy donor livers. Confocal microscopy, flow cytometry and a Luminex assay were applied to validate the scRNA-seq findings. The γδ T cells in the HCC TME entered G2/M cell cycle arrest, and expressed cytotoxic molecules such as interferon-gamma and granzyme B, but were functionally exhausted as indicated by upregulated gene and protein LAG3 expression. The γδ T cells in the HCC TME were dominated by the LAG3+ Vδ1+ population, whereas the Vδ2+ γδ T population was greatly depleted. Moreover, glutamine metabolism of γδ T cells was markedly upregulated in the glutamine-deficient TME. Both in vitro and in vivo experiments showed that glutamine deficiency upregulated LAG3 expression. Finally, our results indicated that ex vivo-expanded Vδ2+ γδ T cells from healthy donor could complement the loss of T cell receptor clonality and effector functions of HCC-derived γδ T cells. This work deciphered the dysfunctional signatures of HCC-infiltrating γδ T cells in the HCC TME, providing scientific support for the use of allogeneic Vδ2+ γδ T cells in HCC cellular therapy.


Hyperstriatal-tectal projections in the pigeon (Columba livia) as demonstrated by the retrograde double-label fluorescence technique.
Hyperstriatal-tectal connections were investigated in the pigeon by mapping retrogradely labeled neurons in the hyperstriatum following the injection of different fluorescent tracers (Fast Blue, Nuclear Yellow, Evans Blue) either bilaterally or unilaterally into distinct portions of the tectum. The projections were found to arise from the hyperstriatum accessorium (HA) of the Wulst, were essentially ipsilateral and topographically organized with respect to the dorsoventral and lateromedial plane of HA. No double-labeled neurons which would indicate bilateral axon branching via collaterals were observed. Some interspecies differences in the organization of the avian hyperstriatal-tectal pathways are discussed.


Thiophene anchored coumarin derivative as a turn-on fluorescent probe for Cr3+: cell imaging and speciation studies.
A thiophene-coumarin hybrid molecule, (6E)-6-((thiophen-2-yl)methyleneamino)-2H-chromen-2-one (TMC) has been prepared and its single crystal X-ray structure is reported. TMC can selectively detect Cr(3+) in presence of other common cations. Both TMC and its Cr(3+) complex are well characterized by different spectroscopic techniques like (1)H NMR, QTOF-MS ES(+), FTIR and elemental analysis as well. TMC exhibits fluorescence enhancement upon binding Cr(3+) in CH(3)CN-HEPES buffer (0.02 M, pH 7.4) (4:6, v/v) medium. Detection limit of the method is 1 × 10(-6)M. Binding constant is estimated with the Benesi-Hildebrand method and the value 8 × 10(4) indicates a fairly strong interaction between TMC and Cr(3+). Speciation studies have been performed in a fast and environment friendly way using least sample volume, less hazardous chemicals and solvents. Cr(3+) assisted restricted rotation around the imine bond and inhibited photo-induced electron transfer from the N,S-donor sites to the coumarin unit are responsible for fluorescence enhancement. TMC is capable to detect intracellular Cr(3+) in living cells.


Ultrasound-assisted carbon ion dosimetry and range measurement using injectable polymer-shelled phase-change nanodroplets: in vitro study.
Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets' response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification.


Baseline predictors of placebo response in exercise-induced bronchoconstriction (EIB): pooled regression analysis >from three studies of montelukast in EIB.
Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient-related factors driving placebo response could facilitate more efficient clinical trials for EIB. Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15-45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV₁) ≥20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5-12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV₁ while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the "best" model. Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV₁ % predicted (p <.001), smaller maximum % fall in FEV₁ in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011). Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients.


Impact of the nature of the temporalis fascia graft on the outcome of type I underlay tympanoplasty.
Temporalis fascia has become the most widely used graft for tympanoplasty, as it is strong, durable, and easy to procure and handle. However, the type of temporalis fascia graft to use (i.e. dry or wet) remains controversial. The present review aimed to evaluate the success rates of dry and wet temporalis fascia grafts in type I underlay tympanoplasty. A literature search was performed, using PubMed up to August 2016, to identify all studies of dry and wet temporalis fascia grafts in type I underlay tympanoplasty. The initial search using the key words 'temporalis fascia' and 'tympanoplasty' identified 130 articles; these were screened by reviewing the titles or abstracts based on the inclusion and exclusion criteria. Ultimately, this review included seven articles. A dry or wet temporalis fascia graft did not affect the outcome of type I underlay tympanoplasty. However, using wet temporalis fascia could shorten the duration of surgery in type I underlay tympanoplasty. Concerns that the fibroblast count of temporalis fascia may beneficially affect success rate have not been substantiated in clinical reports thus far.


[Inclination of crown and tooth longitudinal axis in cephalometric analysis of normal occlusions].
We measured and analyzed the angle between the longitudinal axis of incisor crown and tooth to provide a reference for orthodontists for selecting orthodontic methods and evaluating treatment results. A total of 120 participants were included according to the criteria of Andrews' six keys, and cephalometric radiograph under the instructions of modified natural head position acquirement method was performed. The angles of maxillary incisor crown longitudinal axis, tooth longitudinal axis, occlusion plane (OP), and true vertical (TV) plane were measured, as well as mandibular incisors. As for maxillary incisors, the angle between crown longitudinal axis and TV plane, OP, and tooth longitudinal axis were 11.72°±4.71°, 73.29°±5.69°, and 20.04°±3.71°, respectively. For mandibular incisors, the angle between crown longitudinal axis and TV plane, OP, and tooth longitudinal axis were 16.03°±5.40°, 81.76°±4.81°, and 14.82°±4.01°, respectively. For the maxillary incisor, the angles between crown longitudinal axis and tooth longitudinal axis were mainly within 15° to 25°, whereas those for mandibular incisors were within 10° to 20°. The longitudinal axis inclinations of the maxillary and mandibular incisor crown and of the incisor tooth need to be considered when cephalometric radiographs are used for treatment planning or for evaluating the treatment result.


[Immunological Aspects in Oncology--Circulating γδ T Cells].
γδ T cells present a minor population of the T cell family which basically differs in construction of their T cell receptor (TCR). Thanks to the features of γδ TCR, these cells can acquire unique effector functions and play a specific role (not only) in antitumor immune response. In this article, we describe the basic characteristics of this cell population and their connection to cancer. In the experimental part we performed exploratory analysis of circulating γδ T cells in reference population and comparison with melanoma and breast carcinoma patients. The median percentage of γδ T cells from all lymphocytes was 2.9% (interquartile range-IQR 1.7-4%). The median absolute numbers of γδ cells per liter of blood was 5.05×10(7) (IQR 2.9-7.84×10(7)). The median percentage of γδ cells between all CD3 T cells was 3.9% (IQR 2.3-5.6%). No correlation between γδ T cells levels and gender or age was observed in reference population. Detailed immunophenotyping was also conducted describing representation of memory subsets (using CD45RO and CD27 markers) and presence of surface markers HLADr, CD69, CD25, CD28, CCR7, CTLA 4, ICOS, PD 1L and PD 1 between γδ T cells of the controls and breast carcinoma patients. From this analysis, it is evident that γδ T cells do not represent a uniform population but they differ in surface markers as well as in their effector functions.


Current treatment methods for combination antiretroviral therapy-induced lipoatrophy of the face.
Combination antiretroviral therapy (CART) reduces the mortality and morbidity in HIV-infected patients. However, facial lipoatrophy (FLA) is one of the well-known side-effects of this treatment and subsequently imposes major problems for HIV-infected patients. In the last decade, ample experience has been obtained with both local therapeutic options as well as possible systemic treatment options. Soft tissue fillers are a relatively simple and efficient treatment option for FLA. Especially, the biodegradable semi-permanent fillers combine a good effect with durability and an acceptable safety profile. The best way to prevent or restrict the development of FLA remains the exclusion of thymidine analogue nucleoside reverse-transcriptase inhibitors from the CART schedule.


Local minima and plateaus in hierarchical structures of multilayer perceptrons.
Local minima and plateaus pose a serious problem in learning of neural networks. We investigate the hierarchical geometric structure of the parameter space of three-layer perceptrons in order to show the existence of local minima and plateaus. It is proved that a critical point of the model with H - 1 hidden units always gives many critical points of the model with H hidden units. These critical points consist of many lines in the parameter space, which can cause plateaus in learning of neural networks. Based on this result, we prove that a point in the critical lines corresponding to the global minimum of the smaller model can be a local minimum or a saddle point of the larger model. We give a necessary and sufficient condition for this, and show that this kind of local minima exist as a line segment if any. The results are universal in the sense that they do not require special properties of the target, loss functions and activation functions, but only use the hierarchical structure of the model.


Saccades of video head impulse test in Meniere's disease and Vestibular Migraine: What can we learn from?
Saccades are often observed on video head impulse tests (vHIT) in patients with Meniere's Disease (MD) and Vestibular Migraine (VM). However, their saccadic features are not fully described. This study aims to identify the saccades characteristics of MD and VM. 75 VM patients and 103 definite unilateral MD patients were enrolled in this study. First raw saccades were exported and analyzed. The VM patients were divided into left and right based on their ears, while the MD patients were separated into affected and unaffected subgroups based on their audiograms and symptoms. The MD patients have more saccades on the affected side (85% vs. 69%), and saccade velocity is more consistent than the contralateral side (shown by the coefficient of variation). The saccades occurrence rates on both sides are similar in VM (77% vs. 76%), as are other saccadic parameters. The MD patients have more significant inter-aural differences than the VM patients, manifested in higher velocity (p-value 0.000), earlier arriving (p-value 0.010), and more time-domain gathered (p-value 0.003) on the affected side. Bilateral saccades are commonly observed in MD and VM. In contrast to MD, saccades on VM are subtle, scattered, and late-arrived. Furthermore, the MD patients showed inconsistent saccadic distribution with more velocity-uniform saccades on the affected side.


Evaluation of subclinical cardiovascular disease by carotid intima media thickness, epicardial adipose tissue thickness, serum endocan, and nesfatin-1 levels in patients with primary hyperparathyroidism.
Data on the presence and extent of cardiovascular disease (CVD) risk in primary hyperparathyroidism (PHPT) are conflicting. In our study, we aimed to investigate the increased CVD risk in patients with PHPT by carotid intima-media thickness (CIMT), epicardial adipose tissue (EAT) thickness, and serum levels of endocan and nesfatin-1. Patients with PHPT (n = 44) and age- and sex-matched healthy control subjects (n = 40) were enrolled in this study. Demographic data of the participants were questioned. Serum endocan and nesfatin-1 concentrations were assessed using commercially available ELISA kits. Noninvasive measurements of CIMT and EAT thickness were made with high-resolution ultrasonography and B-mode echocardiography. There was no statistically significant difference in serum endocan and nesfatin-1 levels and EAT thickness in the PHPT group compared to controls. CIMT was statistically significantly higher in the PHPT group compared to controls (p = 0.001). A negative correlation was found between PTH and low-density lipoprotein cholesterol level (p = 0.001) but no significant relationship was found between other parameters. We found that CIMT is increased in patients with PHPT and consequently, CVD risk is high in these patients. More comprehensive studies are needed to identify other markers that predict increased CVD risk in patients with PHPT.


A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder.
The efficacy of fluoxetine was evaluated in depressed patients in double-blind imipramine- and placebo-controlled clinical trials. Fluoxetine produced greater improvement than placebo on all major efficacy parameters and was comparable to imipramine with respect to the primary indicators of depression. Fluoxetine had significantly less associated anticholinergic effects, dizziness, drowsiness, somatosensory disturbance, and excessive sweating than imipramine. Although nausea occurred more frequently in fluoxetine patients, it was generally mild and well tolerated. A significantly smaller percentage of fluoxetine than imipramine patients terminated therapy because of adverse experiences.


Extensive search for discriminative features of alternative splicing.
Alternative pre-mRNA splicing events can be classified into various types, including cassette, mutually exclusive, alternative 3' splice site, alternative 5' splice site, retained intron. The detection of features of a particular type of alternative splicing events is an important and challenging problem in understanding the mechanism of alternative splicing. In this paper, we consider the problem of finding regulatory sequence patterns, which are specific to a particular type of alternative splicing events, on alternative exons and their flanking introns. For this problem, we have designed various pattern features and evaluated them on the alternative splicing data compiled in Lee's ASAP (Alternative Splicing Annotation Project) database. Through our work, we have succeeded in finding features with practically high accuracies.


Probabilistic risk assessment of exposure to multiple metals and pesticides through consumption of fruit juice samples collected from Iranian market.
The current study assessed the risk posed to Iranian consumers by oral exposure to a mixture of 20 pesticides and six metals in 96 fruit juice (FJ) samples (3 batches × 4 brands × 8 types of FJs) collected from Iran market. Concentrations of metals and pesticides in FJs were quantified by inductively coupled plasma-optical emission spectrometry (ICP-OES) and chromatography-mass spectrometry (GC-MS), respectively. The mean concentration of all pesticides was below the maximum residue limits (MRLs) set by the European Union (EU). The calculated target hazard quotients (THQs) and total hazard index (HI) were <1.0 for all pesticides residue, indicating no risk. For the carcinogenic metals (As, Ni, and Pb), estimated incremental lifetime cancer risks (ILCRs) at the 50th and 95th centiles were respectively 4.25 × 10-5 and 5.30 × 10-5 (for As), 2.85 × 10-5 and 3.71 × 10-5 (for Ni), and 2.84 × 10-8, and 3.97 × 10-8 (for Pb), indicating no risk. At the 50th and 95th centiles, HI for non-carcinogenic metals (Cd, Hg, and Cr) was <1.0, indicating no risk. Based on sensitivity analyses of the input variables, the concentration of metals and pesticides, and the FJs ingestion rate had significant influential impacts on the calculated THQ and HI.


Epilepsy-associated neurocognitive disorders (EAND) in an onchocerciasis-endemic rural community in Cameroon: A population-based case-control study.
Epilepsy affects at least 50 million individuals worldwide, especially in sub-Saharan Africa (sSA). Cognitive impairment is common in people with epilepsy (PWE) yet, little is known on the burden of cognitive impairment in people with epilepsy in sSA. This study was thus designed to assess cognitive impairment in PWE or epilepsy-associated neurocognitive disorders (EAND) in a rural population in Cameroon. This was a case-control study including PWE and age/sex-matched healthy controls from July to September 2017 in Bilomo, a village in the Mbam and Kim Division. The Montreal Cognitive Assessment (MoCA), International HIV Dementia Scale (IHDS), Dubois' Five Word testing, Frontal Assessment Battery (FAB), Isaac's Set Test and the Clock drawing test were administered to the study participants to evaluate global and specific cognitive functions. Eighty participants were included (40 cases and 40 controls) with a mean age of 25.78 years. Using the MoCA, 87.5% of cases had cognitive impairment, against 37.5% of controls (p < 0.001; OR 11.67; CI 3.40-45.09). Using the IHDS, the prevalence of global cognitive impairment was 84.6% among the cases against 40% for the controls (p = <0.001; OR 7.07; CI 2.29-29.19). Specifically, executive function deficits (92.5% of cases vs 40.0% of controls p = <0.001 OR = 18.50 CI; 4.48-105.08) and decreased verbal fluency (100% of cases against 45% of controls p < 0.001) were the most affected cognitive domains. Longer duration of epilepsy and higher seizure frequency were associated with global cognitive impairment. Low level of education was associated with both decreased verbal fluency and executive dysfunction while a longer stay in Bilomo correlated with poor results on the Isaac's Set Test. The prevalence of cognitive impairment appears to be much higher in PWE in the Mbam valley, particularly decreased executive function and verbal fluency, than in people without epilepsy. Longer disease duration, higher seizure frequency, low level of education and length of stay in Bilomo are associated with poorer cognitive performance. More studies are needed to refine evaluation tools to better characterize and manage EAND in sSA.


Nebulised hypertonic saline (3%) among children with mild to moderately severe bronchiolitis--a double blind randomized controlled trial.
To Assess the efficacy of nebulised hypertonic saline (HS) (3%) among children with mild to moderately severe bronchiolitis. Infants aged 6 weeks to 24 months, with a first episode of wheezing and Clinical Severity scores (Arch Dis Child 67:289-93, 1992) between 1 and 8, were enrolled over 4 months duration. Those with severe disease, co-morbidities, prior wheezing, recent bronchodilator and steroid use were excluded. Patients were randomized in a double-blind fashion, to receive two doses of nebulized 3% HS (Group 1) or 0.9% normal saline (Group 2) with 1.5 mg of L-Epineprine, delivered 30 min apart. Parents were contacted at 24 h and 7 days. The principal outcome measure was the mean change in clinical severity score at the end of 2 h of observation. A total of 100 infants (mean age 9.6 months, range 2-23 months; 61 % males) were enrolled. Patients in both groups had mild to moderately severe disease at presentation. On an intention-to-treat basis, the infants in the HS group had a significant reduction (3.57 ± 1.41) in the mean clinical severity score compared to those in the NS group (2.26 ± 1.15); [p < 0.001; CI: 0.78-1.82]. More children in the HS group (n = 35/50; 70.0%) were eligible for ER/OPD discharge at the end of 2 h than those in the NS group (n = 15/50; 30%; p < 0.001), and less likely to need a hospital re-visit (n = 5/50; 10.0%) in the next 24 h as compared to the NS group (n = 15/50, 30.0%; p < 0.001). The treatment was well tolerated, with no adverse effects. Nebulized 3% HS is effective, safe and superior to normal saline for outpatient management of infants with mild to moderately severe viral bronchiolitis in improving Clinical Severity Scores, facilitating early Out-Patient Department discharge and preventing hospital re-visits and admissions in the 24 h of presentation. Clinicaltrials.gov NCTID012766821. Registered on January 12, 2011.


Imidazolium Chloride: An Efficient Catalyst for Transamidation of Primary Amines.
A highly efficient and convenient protocol of imidazolium chloride (30 mol %) catalyzed amidation of amines with moderate to excellent yields was reported. The protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic primary amines.


Estuarine dissolved speciation and partitioning of trace metals: a novel approach to study biogeochemical processes.
Estuaries are complex systems involving numerous biogeochemical gradients and processes that influence the behavior of trace metals. Lead (Pb), cadmium (Cd), and copper (Cu) speciation and partitioning were studied in the Gironde Estuary (SW France), using a multi-method approach in which data from innovative sensors and laboratory-based techniques were combined. For the first time in this system, the so-called dynamic fractions of the target metals (dissolved forms that are potentially bioavailable) were recorded on-board through voltammetry using unique antifouling gel-integrated microelectrode arrays (GIME) incorporated in a submersible sensing probe (TracMetal). Trace metals in the operationally defined dissolved <0.2 μm and <0.02 μm fractions, as well as complexed with suspended particles (collected after centrifugation) were quantified through sampling/laboratory-based techniques. High spatial resolution trace metal concentrations were monitored along the salinity gradient (S = 0.10 to S = 34.0) together with master bio-physicochemical parameters providing robust cruise-specific information on how well-known abiotic and biotic processes control the Gironde estuarine trace element partitioning, (i.e. conservative behavior, addition/removal). Combining conventional methods with GIME measurements showed: (i) the dominance of Cd dynamic species in the intra-estuarine total dissolved fraction (up to 90%), (ii) the importance of small colloids as trace metal carrier phases, desorbing and complexing dynamic fractions of Pb and Cu, and (iii) the potential influence of photo-redox processes remobilizing Pb under their dynamic forms (up to 80%). Data also suggest trace metal release/sorption by phytoplankton with an increase of dissolved Cu concentrations in the riverine branch, as well as Cu and Cd particulate concentrations showing higher levels towards productive coastal waters. This complete approach allowed to monitor key estuarine biogeochemical processes and highlighted the valuable use of the TracMetal to record subtle variations of potentially bioavailable dissolved metal fractions.


Peripheral blood eosinophilia in dogs: Prevalence and associated diseases.
Canine eosinophilia has not been evaluated over the last two decades. As in human local differences, changes in the prevalence and associated diseases over time can be expected. This study aims to determine the prevalence and causes of marked blood eosinophilia in dogs. Retrospective study. A total of 317 clinical histories of dogs with an eosinophil concentration > 1.5 × 109 /L (marked eosinophilia) between 2013 and 2017 were evaluated. Patients were allocated to 10 groups according to their major clinical findings. Eosinophilia was present in 1,592 of 10,829 dogs (14.7%); it was mild (0.8-1.49 × 109 /L) in 78.4%, moderate (1.5 - 4.9 × 109 /L) in 20.5% and severe (> 5 × 109 /L) in 1.1% of cases. Rottweilers were overrepresented (16.1%). Of 317 cases with marked eosinophilia, 19.6% had neoplasia, 19.1% gastrointestinal disorders, 13.6% health check, 10.4% endoparasites, 6% respiratory, 5.4% neurologic, 5.4% dermatologic, 4.8% urogenital, 3.2% endocrine disorders and 12.6% miscellaneous. Lymphomas (29%) and mast cell tumours (12.9%) were the most frequent tumours in the neoplasia group. A total of 72.6% of tumour-bearing dogs were older than 8 years, while 63.6% of dogs had endoparasites, and 86% of apparently healthy dogs were younger than 5 years. Eosinophilia was significantly higher in patients with respiratory disorders (p < 0.0146). Leukocytosis was found in 50.2% of cases. Malignancy was the most common cause of marked blood eosinophilia in older dogs and endoparasitism in younger dogs. Eosinophilia was common in apparently healthy young dogs and may be related to undiagnosed parasitic infestations.


Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide.
Vasoactive intestinal polypeptide (VIP), a 28 amino acid peptide hormone, plays many physiological roles in the peripheral and central nerve systems. A functional cDNA clone of the VIP receptor was isolated from a rat lung cDNA library by cross-hybridization with the secretin receptor cDNA. VIP bound the cloned VIP receptor expressed in mouse COP cells and stimulated adenylate cyclase through the cloned receptor. The rat VIP receptor consists of 459 amino acids with a calculated Mr of 52,054 and contains seven transmembrane segments. It is structurally related to the secretin, calcitonin, and parathyroid hormone receptors, suggesting that they constitute a new subfamily of the Gs protein-coupled receptors. VIP receptor mRNA was detected in various rat tissues including liver, lung, intestines, and brain. In situ hybridization revealed that VIP receptor mRNA is widely distributed in neuronal cells of the adult rat brain, with a relatively high expression in the cerebral cortex and hippocampus.


Zinc increases EGF-stimulated DNA synthesis in primary mouse hepatocytes. Studies in tumor promoter-treated cell cultures.
To investigate factors influencing cell proliferation, cells are often cultured in serum-free medium. In the present study it is shown that addition of zinc chloride (40 microM) to primary mouse hepatocytes, cultured in Dulbecco's minimal essential medium, markedly enhanced growth factor (EGF)-stimulated [3H]thymidine incorporation into DNA. Treatment of cell cultures with phenobarbital or 3,4,3',4'-tetrachlorobiphenyl (enzyme inducers and tumor promoters in vivo) or with 12-O-tetradecanoylphorbol-13-acetate (the classical skin tumor promoter) further increased EGF-stimulated DNA synthesis. The results emphasize the need to adequately substitute zinc in serum-free cultured cells.


Detection of antibody against extractable nuclear antigen by an enzyme-linked immuno-sorbent assay. Results from patients with rheumatic and internal medical diseases.
Anti-ENA antibody determination by ELISA technique may offer a valuable diagnostic help in the discrimination of patients with mixed connective tissue disease (MCTD) from those with other chronic inflammatory connective tissue diseases. Determination of this antibody was performed in a prospective designed investigation among 101 blood donors, 154 patients with various non-rheumatic internal medical diseases, and 229 patients with chronic inflammatory connective tissue diseases, including five patients with MCTD. A positive titre of anti-ENA antibody was found in approximately 10% of blood donors and patients with various internal medical disorders. A highly positive anti-ribonucleoprotein (RNP) titre was found in the patients with MCTD, but was also observed in patients with other chronic inflammatory connective tissue diseases, giving a predictive value of 56% for MCTD. We conclude that highly positive anti-RNP antibody values do not automatically indicate the diagnosis MCTD. Other diagnostic possibilities should still be considered.


Nascent RNA cleavage by purified ternary complexes of vaccinia RNA polymerase.
Ternary complexes of vaccinia virus RNA polymerase containing 3'-OMeGMP-arrested transcripts were purified by native gel electrophoresis. These complexes resumed elongation in situ when gel slices were incubated with magnesium and NTPs. Elongation occurred in the absence of pyrophosphate, suggesting that the blocking 3'-OMeGMP residue was removed via a novel pathway. We show that purified elongation complexes contain an intrinsic nuclease activity that shortens nascent RNA from the 3'-end. RNA cleavage was absolutely dependent on a divalent cation and was stimulated by CTP. The initial 5' cleavage product remained associated with the ternary complex and could be elongated in the presence of NTPs. Multiple stepwise cleavages generated progressively shorter chains. Purified ternary complexes containing 3'-OH-terminated RNAs also displayed nuclease activity. Involvement of the vaccinia RNA polymerase subunit rpo30 in the transcript-shortening reaction is suggested based on sequence similarity of rpo30 to mammalian protein SII (TFIIS), an extrinsic transcription factor required for nascent RNA cleavage by RNA polymerase II (Reines, D. (1991) J. Biol. Chem. 267, 3795-3800).


Robotic single-site versus laparo-endoscopic single-site surgery for adnexal tumours: a propensity score-matching analysis.
The aim of this study was to compare the surgical outcomes of robotic single-site (RSS) and laparo-endoscopic single-site (LESS) surgery for adnexal tumours and evaluate the feasibility of RSS surgery. RSS surgery was performed using the da Vinci Single-Site® surgical platform and LESS surgery using a single multi-channel port system. Surgical outcomes were compared between RSS (n = 20) and LESS (n = 228) after 1:4 propensity score matching. After the propensity score matching, the RSS group showed longer operating times than the LESS (91.1 vs 66.1 min; p = 0.001). While the LESS showed 1.3% of major complication rates, the RSS group had no perioperative complication. For the LESS, 2.5% of patients needed additional port insertion. The RSS surgery for adnexal tumours could be performed safely without complications or additional port insertion. Although it showed a longer operating time, further experience and technical refinements will continue to improve operative results. Copyright © 2015 John Wiley & Sons, Ltd.


Adenoid cystic carcinoma of the parotid gland with temporal bone invasion.
To present our series of 16 patients with adenoid cystic carcinoma (ACC) of the parotid gland with temporal bone invasion. All patients treated at our institution between July 1988 and July 2004 with parotid gland ACC with temporal bone invasion. Preoperative radiographic assessment with combined surgical and radiation therapy treatment. Postoperative- or radiation-related complications and overall 2-, 5-, and 10-year survival. The most common surgically related complications were new-onset cranial nerve deficits, whereas osteoradionecrosis of the bony external auditory canal was the most frequently noted complication associated with radiation therapy. The overall survival rates at 2, 5, and 10 years were 94, 75, and 60%, respectively. Lateral cranial base access should be used in the extirpation of ACC of the parotid gland with temporal bone involvement.


Recurrent neural network based prediction of number of COVID-19 cases in India.
COVID-19 has become the most devastating disease of the current century and is pandemic. As per WHO report, there are globally 31,174,627 confirmed cases including 962,613 deaths as of 22nd September,2020. The disease is spreading through outbreaks despite the availability of latest technologies for treatment of patients. In this paper, we proposed a neural network-based prediction of number of cases in India due to COVID-19. Recurrent neural network (RNN) based LSTM is applied on India dataset for prediction. LSTM networks are a type of RNN capable of learning order dependence in sequence forecasting problems. We analyze the performance of the network and then compare it with two parameter reduced variants of LSTM, obtained by elimination of hidden unit signals, bias and input signal. For performance evaluation, we used the MSE measure.


Polybrominated diphenyl ethers and decabromodiphenylethane in sediments from twelve lakes in China.
Sediment cores from 12 Chinese lakes were analyzed to investigate the historical inputs of polybrominated diphenyl ethers (PBDEs) and decabromodiphenylethane (DBDPE) during the past few decades. Concentrations of ΣPBDE(1) (sum of tri- to hepta-BDEs), ΣPBDE(2) (sum of nona- to deca-BDEs) and DBDPE in the surface sediments were 0.02-0.29 ng g(-1), 0.46-46.6 ng g(-1) and 1.02-3.64 ng g(-1), respectively. The temporal trends of PBDEs and DBDPE followed a general increase from the bottom to the surface. The calculated fluxes for ΣPBDE(1), ΣPBDE(2) and DBDPE were 0.001-0.09, 0.03-4.24, and 0.05-0.31 ng cm(-2) yr(-1), and the inventories were 0.09-7.86, 0.91-461, and 3.83-24.6 ng cm(-2), respectively. The urbanization and industrialization are highly related to the contamination of PBDEs and DBDPE in sediments. The DBDPE input in recent years was still lower than ΣPBDE(2) but the temporal trends indicated that the contamination would increase with the increasing usage of DBDPE in the future.


The effect of pH on the viability of hypothermically stored rat hepatocytes.
Hepatocytes isolated from the rat liver were stored for up to 72 hr at 4 degrees C in a tissue culture medium (Liebovitz-15) at different pH values to determine how pH affects hepatocyte viability. This is a model to simulate cold storage of livers for transplantation and determine the optimal pH for maintenance of liver cell function. The cells were stored in the absence of oxygen. At the end of cold storage the percentage of the total cellular LDH released into the extracellular medium was used as a measure of hepatocyte viability. Also, lactate dehydrogenase (LDH) release was determined in hepatocytes incubated at normothermia (37 degrees C) for 90 min following 72 hr of cold storage. The results demonstrate that hepatocytes tolerate a wide range of pH values in the storage medium and that only about 10% of the total LDH was released from hepatocytes stored up to 72 hr at pH's from 5.0 to 8.0. Normothermic incubation, however, demonstrated that the pH of the storage medium affected viability. After 48 hr of storage only hepatocytes stored at pH values from 7.0 to 8.0 remained viable (LDH release similar to that of freshly incubated hepatocytes = 28 +/- 7.2%). After 72 hr of storage and 90 min of normothermic incubation, hepatocytes incubated at all pH values studied were nonviable (greater than 60% release of LDH). These results suggest that the optimal pH for storage of hepatocytes at 4 degrees C is near neutrality (7.0 to 7.4).


Delay or deficit? Spelling processes in children with specific language impairment.
Few studies have explored the phonological, morphological and orthographic spellings skills of children with specific language impairment (SLI) simultaneously. Fifteen children with SLI (mean age=113.07 months, SD=8.61) completed language and spelling tasks alongside chronological-age controls and spelling-age controls. While the children with SLI showed a deficit in phonological spelling, they performed comparably to spelling-age controls on morphological spelling skills, and there were no differences between the three groups in producing orthographically legal spellings. The results also highlighted the potential importance of adequate non-word repetition skills in relation to effective spelling skills, and demonstrated that not all children with spoken language impairments show marked spelling difficulties. Findings are discussed in relation to theory, educational assessment and practice. As a result of this activity, readers will describe components of spoken language that predict children's morphological and phonological spelling performance. As a result of this activity, readers will describe how the spelling skills of children with SLI compare to age-matched and spelling age-matched control children. Readers will be able to interpret the variability in spelling performance seen in children with SLI.


Exposure and vulnerability estimation for modelling flood losses to commercial assets in Europe.
Commercial assets comprise buildings, machinery and equipment, which are susceptible to floods. Existing damage models and exposure estimation methods for this sector have limited transferability between flood events and therefore limited potential for pan-European applications. In this study we introduce two methodologies aiming at improving commercial flood damage modelling: (1) disaggregation of economic statistics to obtain detailed building-level estimates of replacement costs of commercial assets; (2) a Bayesian Network (BN) damage model based primarily on post-disaster company surveys carried out in Germany. The BN model is probabilistic and provides probability distributions of estimated losses, and as such quantitative uncertainty information. The BN shows good accuracy of predictions of building losses, though overestimates machinery/equipment loss. To test its suitability for pan-European flood modelling, the BN was applied to three case studies, comprising a coastal flood in France (2010) and fluvial floods in Saxony (2013) and Italy (2014). Overall difference between modelled and reported average loss per company was only 2-19% depending on the case study. Additionally, the BN model achieved better results than six alternative damage models in those case studies (except for one model in the Italian case study). Further, our exposure estimates mostly resulted in better predictions of the damage models compared to previously published pan-European exposure data, which tend to overestimate exposure. All in all, the methods allow easy modelling of commercial flood losses in the whole of Europe, since they are applicable even if only publicly-available datasets are obtainable. The methods achieve a higher accuracy than alternative approaches, and inherently provide confidence intervals, which is particularly valuable for decision making under high uncertainty.


Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.
Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD), and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L-CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 - 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype-phenotype correlations.


Utility of Items of Baseline National Institutes of Health Stroke Scale as Predictors of Functional Outcomes at Three Months after Mild Ischemic Stroke.
Predicting outcomes of acute stroke patients initially presenting with mild neurologic deficits is crucial in decision making regarding thrombolytic therapy. We examined the utility of individual National Institutes of Health Stroke Scale (NIHSS) score items or clusters of items as predictors of functional outcomes at 3 months after mild stroke. Using a multicenter stroke registry database, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had baseline NIHSS scores less than or equal to 5. Functional outcomes at 3 months were dichotomized as favorable (modified RankinScale [mRS] score 0 or 1) or unfavorable (mRS 2-6). Individual NIHSS items, clusters of items, and the total score were tested for their ability to predict outcomes in multivariable models. Area under the receiver operating characteristic curve (AUC) was used to assess model performance. Of the 2209 patients who met eligibility criteria, 588 (26.6%) exhibited unfavorable functional outcomes at 3 months. Of the 15 items of the NIHSS, all except item 8 (sensory) and item 11 (extinction) were significantly associated with unfavorable functional outcomes in bivariate analysis (P's < .05). Among the multivariable models, the model with the total NIHSS score exhibited an AUC similar to that of the model with all NIHSS items in predicting functional outcomes (.758 [95% confidence interval .739-.775] versus .759 [.740-.776]; P = .75 for pairwise comparison). Simply using the total NIHSS score was as effective as using all individual items in predicting outcomes of mild stroke patients.


Life-cycle assessment of municipal solid wastes: development of the WASTED model.
This paper describes the development of the Waste Analysis Software Tool for Environmental Decisions (WASTED) model. This model provides a comprehensive view of the environmental impacts of municipal solid waste management systems. The model consists of a number of separate submodels that describe a typical waste management process: waste collection, material recovery, composting, energy recovery from waste and landfilling. These submodels are combined to represent a complete waste management system. WASTED uses compensatory systems to account for the avoided environmental impacts derived from energy recovery and material recycling. The model is designed to provide solid waste decision-makers and environmental researchers with a tool to evaluate waste management plans and to improve the environmental performance of solid waste management strategies. The model is user-friendly and compares favourably with other earlier models.


FDG PET scan strategies and long-term outcomes after first-line therapy in Hodgkin's disease.
The use of positron emission tomography with fluoro-deoxy-glucose (FDG PET) in Hodgkin's disease (HD) is continuing to expand worldwide, with response assessment after completion of therapy being its most widely utilized application. A positive scan has been associated with high relapse rates and disease progression. A decision analysis was performed to determine the long-term impact of FDG PET restaging both with and without computed tomography (CT) in terms of the 5-year progression-free survival (5yrPFS). Outcomes and utilities were based on published data. The first strategy involved CT restaging after first-line therapy, with or without subsequent FDG PET, while the second strategy used FDG PET scan alone. All positive test required histological examination. Upon histological confirmation of active lymphoma, patients were considered candidates for autologous transplantation and long-term outcomes were retrieved. The expected clinical benefit of the two strategies was calculated and depicted, along with the mean costs. One-way and two-way sensitivity analyses were performed to ensure the validity of the results. CT restaging plus FDG PET when residual mass is detected, results in a 2% benefit at 5yrPFS at baseline compared to FDG PET-alone restaging and remains positive for a wide range of probabilities. This strategy reduces the average cost by euro 1863 per patient, including costs of biopsy and autologous transplantation. A more conservative approach that includes CT restaging after first-line therapy and FDG PET scan only on residual mass, is the preferred strategy in HD. Furthermore it appears to confer the maximal diagnostic yield along with a substantial reduction in the mean cost.


Review: The Next Steps in Crop Improvement: Adoption of Emerging Strategies to Identify Bottlenecks in Sugar Flux.
Sugar allocation in plants is the fundamental process that transports sugar from source to sink tissues and has a dramatic impact on crop yields. Controlling sugar allocation is required to increase crop yields, as well as biomass for biofuel production. Successful examples have demonstrated that genetic engineering of sugar partitioning offers a promising strategy to achieve this goal. However, improvement has thus far been limited by gaps in understanding of the underlying mechanisms controlling the allocation of sugars. The dynamics of sugar partitioning are minimally predictable under different conditions, between species, or in response to abiotic stresses. Here, we discuss four methodologies that have not been sufficiently exploited for the identification of bottlenecks in sugar flux. Furthermore, we suggest how these strategies can be used and combined to provide the insight needed to maximize crop yields or biomass, especially under conditions of environmental stress.


Pulmonary Circulation Under Pressure: Pathophysiological and Therapeutic Implications of BK Channel.
The large-conductance Ca2+-activated K+ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca+2 concentration, and chronic hypoxia, resulting in massive K+ efflux, membrane hyperpolarization, decreased L-type Ca+2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.


Valuing Protected Area Tourism Ecosystem Services Using Big Data.
Economic value from protected areas informs decisions for biodiversity conservation and visitor benefits. Calculating these benefits assists governments to allocate limited budget resources. This study estimated tourism ecosystem service expenditure values for a regional protected area network in South Australia (57 parks) using direct transactional data, travel costs and economic multipliers. The big dataset came from a comprehensive booking system, which helped overcome common limitations associated with survey data (e.g., key areas rather than full network and high zero-value observations). Protected areas returned AU$373.8 million in the 2018-19 base year to the South Australian economy. The results indicate that combined estimation methods coupled to big data sets provide information on baseline expenditure to engage with critical conservation and tourism sites (e.g., Kangaroo Island). In this case they offer a unique full area network expenditure estimate which is an improvement on typical survey approaches, highlighting the advantage of protected area managers investing in big data. Finally, as South Australian protected areas exceed that in many other contexts the study offers important inputs to funding narratives and protected area expansion in line with global assessment targets.


The emerging role of cardiac computed tomography for the assessment of coronary perfusion: a systematic review and meta-analysis.
Computed tomography perfusion (CTP) is an emerging method which, coupled with the anatomical detail afforded by cardiac computed tomographic angiography (CCTA), may allow for determination of both structural and physiologic significance of coronary stenoses with a single imaging modality. This study was designed to execute a systematic review/meta-analysis to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CTP as compared with reference standards for detection of significant coronary artery stenoses and impaired perfusion. A systematic review identified 13 out of 4368 studies allowing a calculation of sensitivity, specificity, PPV, and NPV on a per patient or per vessel or per segment basis using radionuclide myocardial perfusion imaging (MPI), conventional coronary angiography (CCA), magnetic resonance perfusion imaging (MRPI), or fractional flow reserve (FFR) as the reference standard. Meta-analyses of results were carried out using random effects modelling. Most studies used a maximal vasodilator stress protocol with adenosine, provided information mainly on a per vessel basis, and used myocardial perfusion imaging or CCA as the reference standard. Of the studies comparing combinations of both anatomical and functional imaging, the most rigourous standard was CCA/FFR. Compared with the latter, CCTA/CTP had sensitivity, specificity, PPV, and NPV of 81%, 93%, 87%, and 88%, respectively. CTP shows promise as an adjunct to CCTA, potentially allowing determination of both structural and physiologic significance with a single imaging modality.


Fetal hyperechogenic kidney with normal amniotic fluid volume: a diagnostic dilemma.
To determine the prognostic value of sonographically detected fetal hyperechogenic kidneys with normal amniotic fluid volume. Seven cases of hyperechogenic fetal kidneys were identified by sonography over a 7-year period (1996--2002). Increased renal echogenicity was diagnosed when the renal parenchyma was of greater echogenicity than adjacent liver tissue. Amniotic fluid volume was measured by the semiquantitative sonographic technique known as the amniotic fluid index (AFI). Three of the live-born infants had autosomal dominant polycystic kidney disease and one had autosomal recessive polycystic kidney. In the remainder, autopsy study revealed multifocal renal dysplasia in two cases and normal kidneys in one. Increased renal echogenicity with normal amniotic fluid volume in a fetus without other anomalies is a difficult diagnostic dilemma. Although it is usually indicative of renal parenchymal disease with possible renal failure after birth or in early childhood, in some cases, it represents a normal variant. .


Red cell transfusion strategies in the ICU. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group.
Transfusion of red blood cells continues to be an important therapy for treatment of anemia in intensive care settings. The critically ill are a population predisposed to the adverse outcomes of anemia and, as such, the risks imposed on them by transfusion therapy is one of great interest. Over the past decade there has been a shift in transfusion practice with guidelines being developed that promote more conservative and safer use of blood. The Transfusion Requirements in Critical Care (TRICC) trial clearly established the safety of a restrictive transfusion strategy, suggesting that physicians could easily minimize exposure to allogeneic RBCs by lowering their transfusion threshold. Further research will add to the generalizability of this study as well as explore the possible mechanism to explain why red cell transfusions did not improve outcomes in the critically ill.


Asymptomatic detection of SARS-CoV-2 among cancer patients receiving infusional anti-cancer therapy.
Little is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS-CoV-2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high-risk cohort. Retrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti-cancer therapy to undergo a symptom/exposure screen and SARS-CoV-2 PCR testing 24-96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS-CoV-2 infection. Secondary outcomes included the rate of COVID-19-related hospitalization and mortality and delays in oncologic therapy. Among a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS-CoV-2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID-19-related symptoms. Four patients required hospitalization for complications of COVID-19 infection. No patient died from COVID-related complications. 97.7% (N = 42/43) had their anti-cancer therapy delayed or deferred with a median delay of 21 days (range: 7-77 days). Overall, among a cohort of active cancer patients receiving anti-cancer therapy, an asymptomatic SARS-CoV2 PCR-based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long-term follow-up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID-19 infection.


Bilateral renal mass suggestive of cancer.
We present the case of a 44-year old man, presenting with acute left flank pain and gross haematuria, affected by bilateral renal mass and massive para-aortic and mediastinic lymphadenopathy, highly suspicious for metastatic renal cancer.


Direct stenting for stable angina pectoris is associated with reduced periprocedural microcirculatory injury compared with stenting after pre-dilation.
We conducted a randomized study to compare the effect of direct stenting (DS) and conventional stenting (CS) on post-procedural index of microcirculatory resistance (IMR) values. Direct stenting has been suggested to reduce periprocedural microcirculatory injury compared with stenting that follows pre-dilation (CS). The index of microcirculatory resistance is a sensitive invasive marker of coronary microvascular resistance. Fifty patients admitted for elective percutaneous coronary intervention (PCI) were included. All patients had stable angina (Canadian Cardiovascular Society class <IV) related to a lesion suitable for DS and were randomized to DS (n = 25) or CS (n = 25). Baseline demographics and clinical and procedural data were comparable in both groups. An intracoronary pressure/temperature sensor-tipped guide wire was used. Thermodilution curves were obtained at baseline and during maximal hyperemia achieved by infusion of intravenous adenosine. The index of microcirculatory resistance was calculated from the ratio of the mean distal coronary pressure at maximal hyperemia to the inverse of mean hyperemic transit time. After otherwise-uneventful PCI, patients treated with CS had significantly greater IMR (DS 13 +/- 3, CS 24 +/- 14; p < 0.01) and tended to have greater post-PCI troponin T values (DS 0.035 +/- 0.04, CS 0.17 +/- 0.02; p = 0.07). In the whole sample, 20% of patients had post-PCI troponin release (troponin T >0.03 ng/ml). Patients with troponin elevation had significantly greater post-PCI IMR values than patients without troponin elevation: 24.7 +/- 13.2 versus 16.9 +/- 10.2; p = 0.04. In patients undergoing successful coronary stenting for stable angina, DS is associated with reduced microvascular dysfunction induced by PCI as compared with CS.


Proteomic techniques identify urine proteins that differentiate patients with interstitial cystitis from asymptomatic control subjects.
The purpose of this study was to identify differences in urine proteins between patients with interstitial cystitis (IC) and asymptomatic control (AC) subjects with the use of proteomic techniques. Nine patients with IC and their age-, race-, and sex-matched AC subjects volunteered a urine specimen. Urine proteins were separated with the use of 2-dimensional polyacrylamide gels. Differing proteins underwent digestion and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Computer-assisted data analysis was used to identify the corresponding protein. Differences in urine protein responses between patients with IC and AC subjects were evaluated by the Mann-Whitney U test to account for the nonnormal frequency distribution of the parameter estimate or chi-square when data were bimodal. Four proteins differed significantly between patients with IC and AC subjects. The AC subjects had a greater concentration of a uromodulin (P = .019) and two kininogens (P = .023, .046). The patients with IC had a greater concentration of inter-alpha-trypsin inhibitor heavy chain H4 (P = .019). These urine protein isoforms may be biomarkers for IC.


Identification of dysarthria types based on perceptual analysis.
This study was conducted to investigate the degree of accuracy with which three groups of listeners could use perceptual analysis alone for identification of specific dysarthria types. The dysarthria types to be identified in this study were identical to those described by Darley, Aronson, and Brown (1969a): Flaccid, Spastic, Ataxic, Hypokinetic, Hyperkinetic Chorea, Hyperkinetic Dystonia, and Mixed. Each group demonstrated minimal success in the accurate identification of specific dysarthria types. Factors that possibly contributed to this poor success and potential implications are discussed.


A New Approach to the Rayleigh-Taylor Instability.
In this article we consider the inhomogeneous incompressible Euler equations describing two fluids with different constant densities under the influence of gravity as a differential inclusion. By considering the relaxation of the constitutive laws we formulate a general criterion for the existence of infinitely many weak solutions which reflect the turbulent mixing of the two fluids. Our criterion can be verified in the case that initially the fluids are at rest and separated by a flat interface with the heavier one being above the lighter one-the classical configuration giving rise to the Rayleigh-Taylor instability. We construct specific examples when the Atwood number is in the ultra high range, for which the zone in which the mixing occurs grows quadratically in time.


The biomechanical variables involved in the aetiology of iliotibial band syndrome in distance runners - A systematic review of the literature.
The aim of this literature review was to identify the biomechanical variables involved in the aetiology of iliotibial band syndrome (ITBS) in distance runners. An electronic search was conducted using the terms "iliotibial band" and "iliotibial tract". The results showed that runners with a history of ITBS appear to display decreased rear foot eversion, tibial internal rotation and hip adduction angles at heel strike while having greater maximum internal rotation angles at the knee and decreased total abduction and adduction range of motion at the hip during stance phase. They further appear to experience greater invertor moments at their feet, decreased abduction and flexion velocities at their hips and to reach maximum hip flexion angles earlier than healthy controls. Maximum normalised braking forces seem to be decreased in these athletes. The literature is inconclusive with regards to muscle strength deficits in runners with a history of ITBS. Prospective research suggested that greater internal rotation at the knee joint and increased adduction angles of the hip may play a role in the aetiology of ITBS and that the strain rate in the iliotibial bands of these runners may be increased compared to healthy controls. A clear biomechanical cause for ITBS could not be devised due to the lack of prospective research.


Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts.
To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2-11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by -9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody (p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (-6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (-9.8 ± 7.6, p < 0.001) and pain intensity during attacks (-1.2 ± 2.0, numerical rating scale (NRS) [0-10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was -8.0 ± 8.4 (p = 0.004) and -9.1 ± 10.0 (p = 0.024), respectively. Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.


Inhibitory effects of Dioscin on atherosclerosis and foam cell formation in hyperlipidemia rats.
Macrophage-derived foam cells are well known for their key role in development of atherosclerosis (AS). The present study aimed to examine whether dioscin exerts anti-atherosclerotic activity and inhibits foam cell formation. A high-fat induced AS model and ox-LDL treated macrophages were established and received treatment of dioscin. Anti-atherosclerotic activity in vivo was assessed by atherosclerotic lesions size and aortic lipid contents. Macrophage formed foam cells were positively identified by oil red o staining. Moreover, the expression of LOX-1 and NF-κB in aorta tissue and macrophages was examined by western blotting assay. Our results showed that dioscin not only reduced the levels of plasma lipid, TNF-a, IL-1β and IL-6, but also inhibited atherosclerotic development in AS rats, as evidenced by decreased atherosclerotic lesions size and aortic lipid level. In vitro study revealed dioscin directly reduced foam cell formation, decreased intracellular cholesterol accumulation and lowered TNF-a, IL-1β and IL-6 secretion in ox-LDL treated macrophages. Interestingly, further work found dioscin significantly reduced expression of LOX-1 and NF-κB in the aortic tissue and ox-LDL treated macrophages. In summary, our study was the first to confirm anti-atherosclerotic activity of dioscin in vivo and vitro. Moreover, the other important finding is dioscin mediated ox-LDL/LOX-1/NF-κB regulated contributions to the attenuate macrophage ox-LDL uptake and AS.


p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis.
The transcription factor p63, member of the p53 family, is crucial for epithelial development. An RNAi screening identified the apoptotic gene Procaspase-8 as a target activated by p63. The caspase-8 inhibitor FLIP is also under p63 control. We analysed and detailed the direct transactivation through the use of RNAi, reporter assays, ChIPs, western blots, confocal studies in HaCat, as well as in primary human keratinocytes. The direct DeltaNp63 regulation of these targets was confirmed in vivo using transgenic DeltaNp63 mice under the K5 promoter, as compared with p63 knockout mice, and in vitro in normal human primary keratinocytes following UV irradiation. Lowering the steady state of p63 protein levels changes the relative ratio of FLIP isoforms, causing the activation of the expressed, inactive Procaspase-8, into the active isoform thus triggering the proapoptotic cascade. Therefore, p63 fine-tunes the Procaspase-8-FLIP pro- and antiapoptotic pathway in keratinocytes.


Oxidation of the N-containing phosphonate antiscalants NTMP and DTPMP in reverse osmosis concentrates: Reaction kinetics and degradation rate.
N-containing organophosphonate antiscalants such as Aminotris (methylene phosphonic acid) (NTMP/ATMP) and Diethylenetriamine penta(methylene phosphonic acid) (DTPMP) are commonly used in reverse osmosis (RO) to prevent scaling, as well as to increase permeate yields. However, the concentrate in RO still contains antiscalants which can cause adverse effects in the environment such as mobilization of heavy metals. The abatement of antiscalants from RO concentrate can promote the precipitation of oversaturated scale-forming substances and reduce the risk of adverse environmental effects. In the present study, the degradation of NTMP and DTPMP as representatives for N-containing organophosphonate by ozone, hydroxyl radicals (•OH), and sulfate radicals (SO4•-) are studied regarding reaction kinetics and degradation in different matrices. The results show that NTMP and DTPMP react fast with ozone and sulfate radicals (formed in UV/persulfate). Reaction rate constants of ozone showed a strong pH dependency due to the dissociation of the amine. The apparent reaction rates for pH 7 have been determined to be kapp(NTMP + ozone) = 1.44 × 105 M-1 s-1 and kapp(DTPMP + ozone) = 1.16 × 106 M-1 s-1. Reaction kinetics of •OH and SO4•- did not play a distinctive pH dependency (k(•OH) = 109-1010 M-1 s-1 and k(SO4•-) = 107-108 M-1 s-1). Furthermore, real water experiments have shown that ozonation and UV/persulfate are effective tools to abate organophosphonates in RO concentrates. The formation of carcinogenic bromate in ozonation is minimized by the presence of N-containing organophosphonates presumably due to enhanced ozone consumption and scavenging of free bromine.


Antiviral activity of limitin against encephalomyocarditis virus, herpes simplex virus, and mouse hepatitis virus: diverse requirements by limitin and alpha interferon for interferon regulatory factor 1.
Limitin has sequence homology with alpha interferon (IFN-alpha) and IFN-beta and utilizes the IFN-alpha/beta receptor. However, it has no influence on the proliferation of normal myeloid and erythroid progenitors. In this study, we show that limitin has antiviral activity in vitro as well as in vivo. Limitin inhibited not only cytopathic effects in encephalomyocarditis virus- or herpes simplex virus (HSV) type 1-infected L929 cells, but also plaque formation in mouse hepatitis virus (MHV) type 2-infected DBT cells. In addition, administration of limitin to mice suppressed MHV-induced hepatitis and HSV-induced death. The antiviral activity may be mediated in part by 2',5'-oligoadenylate synthetase, RNA-dependent protein kinase, and Mx protein, which inhibit viral replication or degrade viral components, because limitin induced their mRNA expression and enzyme activity. While limitin has antiviral activity as strong as that of IFN-alpha in vitro (the concentration that provided 50% inhibition of cytopathic effect is approximately 30 pg/ml), IFN regulatory factor 1 (IRF-1) dependencies for induction of an antiviral state were different for limitin and IFN-alpha. In IRF-1-deficient fibroblasts, a higher concentration of limitin than of IFN-alpha was required for the induction of antiviral activity and the transcription of proteins from IFN-stimulated response element. The unique signals and the fewer properties of myelosuppression suggest that a human homolog of limitin may be used as a new antiviral drug.


How does reorganization energy change upon protein unfolding? Monitoring the structural perturbations in the heme cavity of cytochrome c.
In several classes of proteins the redox center provides an additional intrinsic biophysical probe that could be used to study the protein structure and function. In present report reorganization energy (lambda, as a parameter describing electron transfer properties) was used to study the protein structural changes around the heme prosthetic group in cytochrome c (cyt c). We attempted to monitor the value of this parameter upon the unfolding process of cyt c by urea, during which it was increased sigmoidally from about 0.52 to 0.82 eV for native and unfold protein, respectively. Results indicate that by structural changes in the heme site, lambda provides a complementary tool for following the unfolding process. Assuming a reversible two-state model for cyt c unfolding, Delta G(H2O), Cm and m values were determined to be 8.32+/-0.7 kcal mol(-1), 1.53+/-0.19 kcalmol(-1)M(-1) and 5.03 M, respectively.


Root and leaf metabolite profiles analysis reveals the adaptive strategies to low potassium stress in barley.
Potassium (K) deficiency in arable land is one of the most important factors affecting crop productivity. Development of low K (LK) tolerant crop cultivars is regarded as a best economic and effective approach for solving the issue of LK. In previous studies, we found a wider variation of LK tolerance in the Tibetan wild barley accessions than cultivated barley. However, the mechanism of LK tolerance in wild barley is still elusive. In this study, two wild barley genotypes (XZ153, LK tolerant and XZ141, LK sensitive) and one cultivar (LuDaoMai, LK tolerant) was used to investigate metabolome changes in response to LK stress. Totally 57 kinds of metabolites were identified in roots and leaves of three genotypes at 16 d after LK treatment. In general, accumulation of amino acids and sugars was enhanced in both roots and leaves, while organic acids were reduced under LK stress compared to the control. Meanwhile, the concentrations of the negatively charged amino acids (Asp and Glu) and most organic acids was reduced in both roots and leaves, but more positively charged amino acids (Lys and Gln) were increased in three genotypes under LK. XZ153 had less reduction than other two genotypes in biomass and chlorophyll content under LK stress and showed greater antioxidant capacity as reflected by more synthesis of active oxygen scavengers. Higher LK tolerance of XZ153 may also be attributed to its less carbohydrate consumption and more storage of glucose and other sugars, thus providing more energy for plant growth under LK stress. Moreover, phenylpropanoid metabolic pathway mediated by PAL differed among three genotypes, which is closely associated with the genotypic difference in LK tolerance. LK tolerance in the wild barley is attributed to more active phenylpropanoid metabolic pathway mediated by PAL, energy use economy by reducing carbohydrate consumption and storage of glucose and other sugars, and higher antioxidant defense ability under LK stress.