Groundwater exploitation management under land subsidence constraint: empirical evidence from the Hangzhou-Jiaxing-Huzhou Plain, China.
Land subsidence caused by extensive groundwater pumping has become a factor which cannot be ignored in the sustainable exploitation of groundwater resources. The Hangzhou-Jiaxing-Huzhou Plain is one of the locations with China's most severe land subsidence problems; the region has experienced dramatic land subsidence since the 1960s. Historical records of groundwater extraction, hydraulic head, and land subsidence show the latter to be the result of continual and excessive extraction of groundwater from deep confined aquifers. This study reconstructs land subsidence using an integrated regional groundwater flow and land subsidence model. The model is calibrated using land subsidence and groundwater level measurements from 1996 to 2007. Simulation results reproduce the cones of depression for groundwater heads and nadirs of land subsidence reasonably well. The calibrated model is used to evaluate the efficacy of land subsidence prevention plans from 2008 to 2010, and to predict future land subsidence over the next decade considering several groundwater exploitation scenarios. The results show the main cause of land subsidence to be inelastic compaction of the aquifer system resulting from continuously declining water levels. The model reveals that while the area of land subsidence will continue to extend, the rate of this extension may be significantly decreased by reduction of groundwater extraction. If the current land subsidence prevention and reclamation plans are continued and surface water diversion projects implemented, though land subsidence cannot be halted, the rate at which it is occurring can be effectively reduced.


Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel.
To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa = 0.26) and within the groups considered. The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality.


Poly[[diaquabis(μ(2)-4,4'-bipyridyl)iron(II)] bis{2-[(3-carboxypyridin-2-yl)disulfanyl]nicotinate}].
In the title compound, {[Fe(C(10)H(8)N(2))(2)(H(2)O)(2)](C(12)H(7)N(2)O(4)S(2))(2)}(n), synthesized by hydro-thermal reaction, the 4,4'-bipyridyl ligands (one with symmetry 2, one with symmetry [Formula: see text]) connect Fe(2+) cations, forming a cationic layer parallel to (001). The coordination of the Fe(2+) cation (site symmetry 2) is octahedral, with four N atoms from four 4,4'-bipyridyl ligands and O atoms from two trans water molecules. Adjacent layers are linked with each other by inter-molecular O-H⋯O hydrogen bonds, forming a three-dimensional supra-molecular structure. Parts of the nicotinic acid derivative are equally disordered over two sets of sites.


Theoretical insight on the optical centred electrical properties of guanidinium isophthalate NLO crystal for electro-optic Q switches.
Guanidinium isophthalate single crystals with dimensions 16 × 4 x 2 mm3 were prepared by the low temperature solvent evaporation method and growth kinetics with interfacial tension was discussed to bring out the growth parameters of guanidinium isophthalate single crystals. The harvested single crystals were utilized for various characterization studies like powder X-ray diffraction, optical transmission, photoluminescence, laser damage study and optical limiting studies. The visualization of varying potential regions on the surfaces to quantify short contacts were generated by Hirshfeld surface analysis. 2D fingerprint plots were analyzed, in which H ….H contact was found to be the most significant with 54.1%. Growth kinetics of the crystalline material was studied to reveal the nucleation process. Crystal samples prepared with reference to the solubility data were found to be free of inclusions and cracks and had maximum transmittance in the complete visible region. The electronic disorder of the crystal sample was reported in the form of Urbach energy. The PL spectra with the emission intensity provide the emission characteristic of the title compound. The major fundamental optical limit for a crystal material is experimentally measured and presented in the picosecond regime. Thus the present work contributes to the understanding of growth, structural, optical and electronic characteristics of the title guanidinium isophthalate single crystals for the fabrication of electro-optic devices in photonic industry.


Probabilistic models of genome shuffling.
The comparison of entire genomes in evolutionary studies gives rise to alignments characterized by many intersections, or inversions in the order of two fragments in different genomes. To model this, we suggest a random migration process for fragments, and discuss its equilibrium distribution in the case of linear and circular genomes. Simulations are carried out to explore "cut-off" behavior as the process approaches equilibrium. We define a new process to take into account the indistinguishability of two fragments which are adjacent in both genomes being compared. Questions of applicability of these models are discussed.


Helminthic infections rates and malaria in HIV-infected pregnant women on anti-retroviral therapy in Rwanda.
Within sub-Saharan Africa, helminth and malaria infections cause considerable morbidity in HIV-positive pregnant women and their offspring. Helminth infections are also associated with a higher risk of mother-to-child HIV transmission. The aim of this study was to determine the prevalence of, and the protective and risk factors for helminth and malaria infections in pregnant HIV-positive Rwandan women receiving anti-retroviral therapy (ART). Pregnant females (n = 980) were recruited from health centres in rural and peri-urban locations in the central and eastern provinces of Rwanda. Helminth infection was diagnosed using the Kato Katz method whilst the presence of Plasmodium falciparum was identified from blood smears. The prevalence of helminth infections was 34.3%; of malaria 13.3%, and of co-infections 6.6%. Helminth infections were more common in rural (43.1%) than peri-urban (18.0%; p<0.0005) sites. A CD4 count ≤ 350 cells/mm(3) was associated with a higher risk of helminth infections (odds ratio, 3.39; 95% CIs, 2.16-5.33; p<0.0005) and malaria (3.37 [2.11-5.38]; p<0.0005) whilst helminth infection was a risk factor for malaria infection and vice versa. Education and employment reduced the risk of all types of infection whilst hand washing protected against helminth infection (0.29 [0.19-0.46]; p<0.0005);). The TDF-3TC-NVP (3.47 [2.21-5.45]; p<0.0005), D4T-3TC-NVP (2.47 [1.27-4.80]; p<0.05) and AZT-NVP (2.60 [1.33-5.08]; p<0.05) regimens each yielded higher helminth infection rates than the AZT-3TC-NVP regimen. Anti-retroviral therapy had no effect on the risk of malaria. HIV-positive pregnant women would benefit from the scaling up of de-worming programs alongside health education and hygiene interventions. The differential effect of certain ART combinations (as observed here most strongly with AZT-3TC-NVP) possibly protecting against helminth infection warrants further investigation.


Interacting hands draw attention during scene observation.
In this study I examined the role of the hands in scene perception. In Experiment 1, eye movements during free observation of natural scenes were analyzed. Fixations to faces and hands were compared under several conditions, including scenes with and without faces, with and without hands, and without a person. The hands were either resting (e.g., lying on the knees) or interacting with objects (e.g., holding a bottle). Faces held an absolute attentional advantage, regardless of hand presence. Importantly, fixations to interacting hands were faster and more frequent than those to resting hands, suggesting attentional priority to interacting hands. The interacting-hand advantage could not be attributed to perceptual saliency or to the hand-owner (i.e., the depicted person) gaze being directed at the interacting hand. Experiment 2 confirmed the interacting-hand advantage in a visual search paradigm with more controlled stimuli. The present results indicate that the key to understanding the role of attention in person perception is the competitive interaction among objects such as faces, hands, and objects interacting with the person.


Isolated IgG4-related sclerosing cholangitis with normal serum IgG4 levels-A case report.
The isolated IgG4-SC that absent from AIP is quite rare and difficult to diagnose. We presented a case of isolated IgG4-SC with the normal serum IgG4 which was hard to differentiate with cholangiocarcinoma. Under such circumstances, liver pathology has a pivotal role in the diagnosis.


Venom characteristics as an indicator of hybridization between Crotalus viridis viridis and Crotalus scutulatus scutulatus in New Mexico.
One hundred and thirteen venoms from 46 populations of Crotalus viridis viridis were screened by immunodiffusion for protein toxins antigenically similar to the phospholipase A2 (PLA) toxin 'Mojave toxin', using a polyclonal antibody to it's basic PLA subunit. Venom i.p. LD50 values in mice were recorded from 22 of the 46 populations. The venoms of three of 14 specimens from southwest (S.W.) New Mexico and one specimen from northern Arizona were immunologically positive by the immunodiffusion tests and produced low LD50 values (0.38-0.65 mg/kg) compared to all immunologically negative venoms (0.9-5.5 mg/kg). These four specimens were morphologically typical for C. v. viridis and their venoms were the only samples of 15 southern New Mexico specimens examined by reverse phase HPLC to exhibit peaks corresponding to the acidic and basic subunits of Mojave toxin. Alkaline polyacrylamide gel electrophoresis (PAGE) analysis of the recombined subunit peaks from the C.v. viridis venom from the S.W. New Mexico specimens showed more similarity to Mojave toxin from C.s. scutulatus venom than to similar toxins in C.v. concolor venom. The combined results of the immunodiffusion, lethal toxicity tests, HPLC profiles and PAGE analysis strongly suggest that the venoms of the three New Mexico specimens contain Mojave toxin(s), as a result of some previous hybridization with C.s. scutulatus. The northern Arizona specimen likely contains 'concolor toxin' through integration with C.v. concolor in its' genetic background.


Comparison of the therapeutic efficacy of linezolid and vancomycin and correlation of serum and tissue malondialdehyde and myeloperoxidase in an experimental mediastinitis model.
We aimed to investigate the therapeutic efficacy of linezolid in an experimental mediastinitis model and to compare it with vancomycin, which is commonly used. The objective of this study was also to evaluate the role of the immune system in mediastinitis. Fifty adult Wistar rats were randomly divided into five groups: an uncontaminated and contaminated untreated control groups; a group that received sefazolin prophylaxis; and two groups treated with vancomycin or linezolid. Median sternotomy without access to pleural spaces was performed on all rats. All groups, except the uncontaminated one, were inoculated with 0.5 mL 10(8) colony-forming units/mL methicillin-resistant Staphylococcus aureus in the mediastinal and sternal layers. Postoperatively, vancomycin and linezolid groups were given antibiotic treatment for 7 d, starting 24 h after the end of the procedure. After 7-d treatment tissue samples from the upper ends of the sternotomy line and mediastinum were obtained and evaluated microbiologically. Additionally, serum, heart, lung, liver, kidney, and mediastinal tissues samples were obtained to determine malondialdehyde (MDA) and myeloperoxidase (MPO). The study showed that either vancomycin or linezolid successfully reduced bacterial counts in mediastinum and sternotomy line. MDA and MPO levels were found to be decreased in the treated groups. There was a positive correlation between serum and tissues MDA and MPO in all of the groups. Our study showed that linezolid appears to be a promising option for treating mediastinitis due to methicillin-resistant S. aureus. Additionally, it was demonstrated that a wide inflammatory process occurred after mediastinitis.


Beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1)-mediated changes of endogenous amyloid beta in wild-type and transgenic mice in vivo.
Beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates generation of amyloid beta (Abeta), a pathological hallmark of Alzheimer's disease. We investigated the impact of BACE1 protein level on endogenous Abeta. Endogenous Abeta and BACE1 protein levels were concurrently and significantly reduced during early life. However, Abeta levels were similar between BACE1 transgenic and wildtype mice. This suggests that BACE1 protein level has a minimal effect on the level of endogenous Abeta. Consequently, other factors must be involved in modulation of Abeta production in adult and ageing brain and investigation of such factors may yield therapeutic targets. Further, these results suggest that substantial inhibition of BACE1 in brain may be required for clinical benefit in Alzheimer's disease.


A randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis.
Onychomycosis accounts for up to 50% of all onychopathies. To evaluate the efficacy of four posaconazole regimens compared with placebo in the treatment of toenail onychomycosis, to assess the safety and tolerability of posaconazole, and to estimate the relative efficacy of posaconazole against terbinafine. A phase 2B, randomized, placebo- and active-controlled, parallel-group, multicentre, investigator-blinded (double blind for placebo) study (ClinicalTrials.gov identifier: NCT00491764). Onychomycosis patients aged 18-75years (n=218) were randomized equally to one of six treatment regimens: posaconazole (oral suspension) 100, 200 or 400mg once daily (24weeks); posaconazole 400 mg once daily (12weeks); terbinafine (tablets) 250mg once daily (12weeks); or placebo (24weeks). The primary efficacy variable was complete cure (negative mycology and 0% nail involvement) at week 48. All posaconazole treatment arms had a significantly (P≤0·012) greater proportion of patients with complete cure at week 48 compared with placebo. The proportions of patients with complete cure were numerically higher for posaconazole 200mg/24weeks (54·1%) and 400mg/24weeks (45·5%), but lower for 400mg/12weeks (20%) compared with terbinafine (37%; differences were not statistically significant). Posaconazole was well tolerated. Seven patients receiving posaconazole withdrew because of asymptomatic liver enzyme increases, as mandated by protocol discontinuation criteria. The efficacy and favourable safety profile of posaconazole suggest a potential new treatment for onychomycosis. The availability of low-cost generic terbinafine may limit posaconazole use to second-line treatment of infections refractory to, or patients intolerant of, terbinafine, or nondermatophyte mould infections.


Prolactin acts on the extreme 5' portion of MMTV LTR involving a mammary cell-specific enhancer.
We have previously shown that a human mammotropic polypeptide hormone, prolactin (PRL) can act synergistically with steroid hormones to regulate gene expression directed by the long terminal repeat of mouse mammary tumor virus (MMTV LTR) in a human ductal carcinoma cell line T47D cells using a chloramphenicol acetyltransferase reporter gene system and gene transfection methods. In the present study, using various recombinant plasmids we analyzed functional elements in the MMTV LTR that is essential for the PRL responses. We show that the PRL-responsive elements are located in the extreme 5' end of the MMTV LTR, a region previously described by others to be a mammary cell-specific enhancer.


HAprog: A New Prognostic Application to Assist Oncologists in Routine Care.
More patients are seeing palliative care (PC) earlier in the disease trajectory. The Barretos Prognostic Nomogram (BPN) was designed to fill the gap of survival prognostication for patients with advanced cancer and months of life expectancy. However, its routine use is limited by the common need for a ruler and calculator. Additionally, the BPN requires blood tests. The aim is to refine the BPN and to create a prognostic application (App) for use on smartphones. This is a reanalysis of the two cohorts of advanced cancer patients (development, n=215 and validation, n=276). The variable 'metastasis' was revised (volume-site combinations) and 'KPS' replaced by 'ECOG-PS'. Prognostic variables were selected for multivariable Cox and Log-logistic parametric regression analyses; the most accurate final models were identified by backward variable elimination. Calibration and discrimination properties were evaluated in the validation sample. The 'full version' model is composed of 6 parameters: sex, locoregional disease, sites of metastasis, ECOG-PS, WBC and albumin. In the 'clinical version' model (5 variables), the variable 'antineoplastic treatment' was included and the laboratory variables were excluded. At validation, both models were well calibrated and presented adequate c-Index values (0.778 and 0.739). HAprog is a freely downloadable offline App that is used by clinicians to calculate prognosis in less than 1 minute. The new models that integrate HAprog are refined prognostic tools with adequate calibration and discrimination properties. It has potential practical impact for the oncologist dealing with outpatients with advanced cancer during the decision-making process.


Sedimentation equilibrium analysis of protein interactions with global implicit mass conservation constraints and systematic noise decomposition.
Sedimentation equilibrium is a powerful tool for the characterization of protein self-association and heterogeneous protein interactions. Frequently, it is applied in a configuration with relatively long solution columns and with equilibrium profiles being acquired sequentially at several rotor speeds. The present study proposes computational tools, implemented in the software SEDPHAT, for the global analysis of equilibrium data at multiple rotor speeds with multiple concentrations and multiple optical detection methods. The detailed global modeling of such equilibrium data can be a nontrivial computational problem. It was shown previously that mass conservation constraints can significantly improve and extend the analysis of heterogeneous protein interactions. Here, a method for using conservation of mass constraints for the macromolecular redistribution is proposed in which the effective loading concentrations are calculated from the sedimentation equilibrium profiles. The approach is similar to that described by Roark (Biophys. Chem. 5 (1976) 185-196), but its utility is extended by determining the bottom position of the solution columns from the macromolecular redistribution. For analyzing heterogeneous associations at multiple protein concentrations, additional constraints that relate the effective loading concentrations of the different components or their molar ratio in the global analysis are introduced. Equilibrium profiles at multiple rotor speeds also permit the algebraic determination of radial-dependent baseline profiles, which can govern interference optical ultracentrifugation data, but usually also occur, to a smaller extent, in absorbance optical data. Finally, the global analysis of equilibrium profiles at multiple rotor speeds with implicit mass conservation and computation of the bottom of the solution column provides an unbiased scale for determining molar mass distributions of noninteracting species. The properties of these tools are studied with theoretical and experimental data sets.


An Editor's farewell.
At the end of his mandate as Breathe Chief Editor, James Paton reflects on the previous 3 years http://ow.ly/RctU8.


Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits.
Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11-13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT1A receptor agonist 8OH-DPAT treatment from postnatal day 7 (PD7) to PD21 ameliorated social abnormality in the three-chamber social interaction test in adult 15q dup mice. The effect of 8OH-DPAT was inhibited by blockade of OXT receptors in 15q dup mice. Thus, serotonin-OXT interaction via 5-HT1A receptors plays a critical role in the normal development of social behavior in 15q dup mice. Therefore, targeting serotonin-OXT interaction may provide a novel therapeutic strategy for treatment of ASD.


Endodontic treatment of the maxillary first molar with palatal canal variations: A case report and review of literature.
Root canal variations frequently occur in maxillary first molars, which greatly affects the success of its treatment. The second mesiobuccal (MB) root canal is the most common root canal variation. However, only a few studies have been conducted on palatal root canal variations. Herein, we report the presence of two separate root canals in a palatal root of the maxillary first molar. A 39-year-old woman complained of pain in the maxillary right region for 1 year, which recently worsened. Clinical examination revealed a poorly restored right maxillary first molar and caries detected at the filling marginal. Cold and heat test results indicated severe pain in the right maxillary first molar. The patient was diagnosed with irreversible pulpitis, and subsequently, root canal treatment (RCT) was performed. In total, five root canals were found in the maxillary first molar, including two separate root canals in the palatal root. RCT was successfully performed using an endodontic microscope and cone-beam computed tomography (CBCT). The CBCT image revealed a vertucci type I canal morphology in the distobuccal root, while the MB and palatal root canals were type Ⅳ. At the 1-mo follow-up, the maxillary first molar was completely asymptomatic, and the X-ray results indicated a successful RCT. Finally, the ceramic crown restoration was performed. An endodontic microscope and CBCT are useful in effectively identifying and treating root canal variations.


Speed of clinical improvement in the real-world setting from patient-reported Psoriasis Symptoms and Signs Diary: Secondary outcomes from the Psoriasis Study of Health Outcomes through 12 weeks.
Rapid skin improvement is a key treatment goal of patients with moderate-to-severe psoriasis (PsO). To compare the speed of clinical improvement of approved biologics on the symptoms and signs of psoriasis assessed by patients using the validated Psoriasis Symptoms and Signs Diary (PSSD) through 12 weeks. Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional study that compares the effectiveness of anti-interleukin (IL)-17A biologics versus other biologics, together with pairwise comparisons of ixekizumab versus five individual biologics in patients with PsO. Using the PSSD 7-day recall period, patients assessed the symptoms (itch, skin tightness, burning, stinging and pain) and signs (dryness, cracking, scaling, shedding/flaking, redness and bleeding) of their psoriasis (0-10). Symptom and sign summary scores (0-100) are derived from the average of individual scores. Percentage change in summary scores and proportion of patients with clinically meaningful improvements (CMI) in PSSD summary and individual scores are evaluated weekly. Longitudinal PSSD data are reported as observed with treatment comparisons analysed using mixed model for repeated measures (MMRM) and generalized linear mixed models (GLMM). Across cohorts and treatments, eligible patients (n = 1654) had comparable baseline PSSD scores. From Week 1, the anti-IL-17A cohort achieved significantly larger score improvements in PSSD summary scores and a higher proportion of patients showed CMIs compared to the other biologics cohort through 12 weeks. Lower PSSD scores were associated with a greater proportion of patients reporting their psoriasis as no longer impacting their quality-of-life (DLQI 0,1) and a high level of clinical response (PASI100). Results also indicate a relationship between an early CMI in PSSD score at Week 2 and PASI100 score at Week 12. Treatment with anti-IL-17A biologics, particularly ixekizumab, resulted in rapid and sustained patient-reported improvements in psoriasis symptoms and signs compared with other biologics in a real-world setting.


Laminin-immunoreactive sites are induced by growth-associated triggering factors in injured rabbit optic nerve.
We have previously demonstrated that application of soluble growth-associated triggering factors (GATFs) from regenerating fish optic nerve or neonatal rabbit optic nerve to a non-regenerative crushed adult rabbit optic nerve provokes regeneration-like changes in the adult rabbit. In this study we show that the responses initiated by GATFs also include a change in pattern of appearance of an extracellular matrix component, laminin, known to play a role in neurite outgrowth and elongation. These findings suggest a mechanism whereby GATFs activate the adult rabbit glial cells to produce or to accumulate laminin and thereby allow partial compensation for the low inherent regenerative ability of the adult rabbit optic nerve.


Schools as Drivers of Capitalist Accumulation Conditional Socialized Reproduction in Shenzhen.
Based on fieldwork in an urbanized village of Shenzhen, this paper analyzes the place of schools in the reproduction of Chinese state capitalism. It retraces the circuit of socialized capital that allows for the social reproduction of the native elite and the exclusion of many migrant workers in the context of Shenzhen's development as a special economic zone and its efforts to upgrade the economy. The native villagers, now forming an urban upper-class of rentiers, have capitalized on their overseas connections and capital accumulation to finance their school, allowing for their elite's upward social mobility after, but also already under Mao. After China's transition to capitalism, this school has served as an asset in generating value in the context of redevelopment and the real estate-driven upgrading of Shenzhen's economy. Property ownership is now a major criterion in points-based systems for accessing school places. I make two interrelated arguments. First, there is a closer relationship between the secondary circuit of socialized capital and the larger circuit of capital than what the literature on social reproduction implies. Second, the conditionality of quality education upon value generation amounts to separating the population deemed worthy of socialized reproduction and the surplus population that is left out. The paper connects diverse strands of social reproduction theory, Althusser's interpellation and ideological state apparatuses, feminist agentive social reproduction theories, and Bourdieu's capital conversion recuperated within a Marxian framework, to provide an integrated approach to social reproduction within capitalism.


Prevalence and risk factors for Giardia spp. infection in a large national sample of pet dogs visiting veterinary hospitals in the United States (2003-2009).
Estimates of the prevalence of intestinal infection of dogs with Giardia spp. in the United States vary widely. Risk factors for infection in a large sample of dogs over an extended period of time have not been well characterized. A national, electronic database of medical records was used to estimate the prevalence and identify risk factors for Giardia spp. infection among dogs visiting Banfield Pet Hospital™ located in 43 states in the United States. The overall prevalence of Giardia spp. Infection was 0.44% (95% CI: 0.43-0.45%) in approximately 2.5 million owned dogs who had a fecal flotation test performed from January 2003 to December 2009. A steady decrease in annual prevalence was observed, from a high of 0.61% in 2003 to 0.27% in 2009. Seasonal increases in prevalence were noted during the winter and summer months. Giardia spp. prevalence was highest in the Mountain region, especially Colorado (2.63%; 95% CI: 2.53-2.73%), and in puppies ≤0.5 year of age (0.63%; 95% CI: 0.61-0.64%). It was lowest for dogs of mixed breeding compared with pure breeds. Infection risk was 25-30% greater in sexually intact dogs compared to spayed and neutered dogs.


Relationship Between Clinicopathological Features and Prognosis in Appendicular Osteosarcoma in Dogs.
Osteosarcoma is the most common primary bone neoplasm in dogs and often involves the appendicular skeleton. We report the clinicopathological and prognostic features of appendicular osteosarcomas diagnosed in 153 dogs from 2008 to 2018. The survival data for 22 dogs that underwent surgery and chemotherapy were statistically compared with the clinical, histopathological and immunohistochemical data for correlation with prognosis. The affected dogs had a mean age of 9.1 years and a mean body weight of 33.4 kg. No sex predilection was detected, although the incidence was slightly higher in females (52%). Large mixed and purebred dogs were most commonly affected. Long bones were affected in 124 cases (92.5%; 124/134). The extremities affected within long bones were the metaphysis of the proximal humerus (29%), distal radius (17.7%), distal femur (15.3%) and proximal tibia (7.2%). Histologically, osteoblastic osteosarcoma was most commonly detected (56.9%), followed by chondroblastic (13.7%), telangiectatic (11.8%), fibroblastic (7.8%), giant cell-rich (5.2%) and poorly differentiated neoplasms (4.6%). Regional lymph nodes were available for analysis in 28 out of 70 excisional biopsies from amputated entire limbs. Metastases to regional lymph nodes were observed in 14.3% (4/28) of these cases. Distant metastases were found in 75% (39/52) of cases in which diagnostic imaging or necropsy was carried out. The lungs were the most common site of metastasis (87.2%; 34/39 cases). Weight, age, sex, affected limb or bone, histological classification, mitotic count or histological grade did not influence survival (P >0.05). Neoplasms located at proximal extremities (n = 7) of affected limbs had a tendency for a poorer prognosis than those at distal extremities (n = 15) (P = 0.06). For these cases, the 1-year survival rate was 14.3% compared with 40% for neoplasms at distal extremities. There was no significant difference in the survival rate when amputation (n = 16) or limb preservation (n = 6) techniques were employed with chemotherapy (P = 0.20). The survival period of dogs that had undergone limb amputation, or limb preservation surgery, and chemotherapy was 73-1,185 days, with a mean and median of 376 and 256 days, respectively. Mild to marked cytoplasmic immunolabelling of osteopontin was found in all cases but the intensity (P = 0.66) and percentage of neoplastic cells labelled (P = 0.49) did not influence survival.


Identification of novel phospholipase A2 group IX members in metazoans.
Sequence homologues of the bacterium Streptomyces violaceoruber and sea anemone Nematostella vectensis PLA2 pfam09056 members were identified in several bacteria, fungi and metazoans illustrating the evolution of this PLA2 sub-family. Comparison of their molecular structures revealed that bacteria and fungi members are part of the GXIV of PLA2s while metazoan representatives are similar with GIX PLA2 of the marine snail Conus magus. Members of GXIV and GIX PLA2s show modest overall sequence similarity (21-35%) but considerable motif conservation within the putative Ca(2+)-binding, catalytic sites and cysteine residue positions which are essential for enzyme function. GXIV PLA2s of bacteria and fungi typically contain four cysteine residues composing two intramolecular disulphide bonds. GIX PLA2 homologues were identified in cnidarians and molluscs and in a single tunicate but appear to be absent from other metazoan genomes. The mature GIX PLA2 deduced peptides contain up to ten cysteine residues capable of forming five putative disulphide bonds. Three disulphide bonds were identified in GIX PLA2s, two of which correspond to those localized in GXIV PLA2s. Phylogenetic analysis demonstrates that metazoan GIX PLA2s cluster separate from the bacterial and fungal GXIV PLA2s and both pfam09056 members form a group separate from the prokaryote and eukaryote GXIIA PLA2 pfam06951. Duplicate PLA2 pfam09056 genes were identified in the genomes of sea anemone N. vectensis and oyster Crassostrea gigas suggest that members of this family evolved via species-specific duplication events. These observations indicate that the newly identified metazoan pfam09056 members may be classified as GIX PLA2s and support the idea of the common evolutionary origin of GXIV and GIX PLA2 pfam09056 members, which emerged early in bacteria and were maintained in the genomes of fungi and selected extant metazoan taxa.


Misuse of testosterone replacement therapy in men in infertile couples and its influence on infertility treatment.
We investigated the clinical characteristics of men with testosterone replacement therapy (TRT)-induced hypogonadism and its effect on assisted reproductive technology (ART) in infertile couples. This study examined the records of 20 consecutive male patients diagnosed with azoospermia or severe oligozoospermia (<5×106/mL) who visited a single infertility center from January 2008 to July 2018. All patients were treated at a primary clinic for erectile dysfunction or androgen deficiency symptoms combined with low serum testosterone. All men received a phosphodiesterase 5 inhibitor and TRT with testosterone undecanoate (Nebido®) or testosterone enanthate (Jenasteron®). Patients older than 50 years or with a chronic medical disease such as diabetes were excluded. The mean age of patients was 37 years and the mean duration of infertility was 16.3±11.6 months. At the initial presentation, eight patients had azoospermia, nine had cryptozoospermia, and three had severe oligozoospermia. Serum follicle-stimulating hormone levels were below 1.0 mIU/mL in most patients. Three ongoing ART programs with female factor infertility were cancelled due to male spermatogenic dysfunction; two of these men had normal semen parameters in the previous cycle. After withholding TRT, serum hormone levels and sperm concentrations returned to normal range after a median duration of 8 months. TRT with high-dose testosterone can cause spermatogenic dysfunction due to suppression of the hypothalamic-pituitary-testicular axis, with adverse effects on infertility treatment programs. TRT is therefore contraindicated for infertile couples attempting to conceive, and the patient's desire for fertility must be considered before initiation of TRT in a hypogonadal man.


Restless legs syndrome in Wilson's disease: frequency, characteristics, and mimics.
To determine characteristics, clinical significance, frequency, and mimics of restless legs syndrome (RLS) in a cohort of Wilson's disease (WD, n = 42/f = 18), compared to healthy, matched controls. Structured clinical interviews (patients and caregiving family members), repeated neurological examinations (afternoon and presleep), comprehensive laboratory tests, WD-, RLS-, and sleep-specific rating scales, and video-polysomnography. Thirteen patients with WD (13/42 = 31.0%) clearly fulfilled the five diagnostic criteria of RLS; in eight patients (19.1%), the burden of RLS was clinically significant. The RLS was of moderate severity, equally distributed among sexes, manifested mainly in the evening and before falling asleep, and had developed mostly after clinical manifestation of WD (time elapsed 10.2 ± 14.5 years), still at a young mean age (27.5 ± 11.5 years). The known RLS-associated features were absent (normal iron and kidney parameters) or rare (positive family history, polyneuropathy). Compared to WD patients without RLS, patients with RLS were significantly elder and had suffered longer from WD. WD-specific RLS mimics as well as RLS confounding motor comorbidities (dystonia, tremor, chorea) were frequent and a diagnostic challenge; in difficult cases, the differentiation was reached by clinical observation of the motor behavior in the evening or at nighttime. RLS was frequent in this cohort of WD and might be causally related to WD. RLS should be included in the diagnostic work-up of WD. In complex motor disorders, differential diagnosis of RLS might require evening/nighttime examination and video-polysomnography. In WD patients with a clinically significant RLS, treatment with dopaminergic substances may be considered.


Polyphyllin VII suppresses cell proliferation, the cell cycle and cell migration in colorectal cancer.
Colorectal cancer (CRC) is one of the most common types of human cancer. However, there is still an urgent need to identify novel treatment strategies for CRC. The present study aimed to validate the potential antitumor effects of polyphyllin VII in CRC. The present study revealed that polyphyllin VII could significantly inhibit CRC proliferation and induce cell cycle arrest and apoptosis. Moreover, the anti-metastatic effect of polyphyllin VII in CRC cells was implicated. Microarray analysis identified that polyphyllin VII could affect multiple protein coding genes and non-coding RNAs. Bioinformatics analysis revealed that polyphyllin VII regulated multiple pathways in CRC, including 'ER to Golgi vesicle-mediated transport', 'response to cAMP', 'Ras protein signal transduction', 'metabolic pathways', 'MAPK signaling pathway' and 'cell cycle'. Protein-Protein Interaction network analysis identified a series of key polyphyllin VII-regulating genes in CRC, including ribonucleoside-diphosphate reductase subunit M2, structural maintenance of chromosomes protein 4 and DNA replication licensing factor MCM4. Finally, the present results demonstrated that these key polyphyllin VII-regulating genes were dysregulated in CRC. Taken together, these results indicated that polyphyllin VII could be a novel antitumor drug for the treatment of CRC.


Routine use of intraoperative nerve monitoring is associated with a reduced risk of vocal cord dysfunction after thyroid cancer surgery.
The aim of this study was to investigate the associations between individual surgeon's intraoperative nerve monitoring (IONM) practice and factors associated with vocal cord (VC) dysfunction in patients with thyroid cancer undergoing thyroidectomy. Using Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) 2014-21 data, multivariable logistic regression analyses investigated variables associated with short- and long-term VC-dysfunction, associations of routine use of IONM with postoperative outcomes, and patient characteristics associated with IONM use. Among 5,446 patients (76.7% female, mean age 49 years), 68.5% had surgery by surgeons using IONM in ≥ 90% of cases (63% of surgeons, n = 73). Post-operative VC-dysfunction was diagnosed by laryngoscopy in 3.0% of patients in the short-term and 2.7% in the long-term. When surgeons routinely used IONM, the incidence of VC-dysfunction was 2.4% in the short-term and 2.2% in the long-term, compared to 4.4% and 3.7%, respectively, when surgeons did not routinely use IONM (p < 0.01). After adjustment, routine use of IONM was independently associated with reduced risk of short- (OR 0.48, p < 0.01) and long-term (OR 0.52, p < 0.01) VC-dysfunction, a lower risk of postoperative hypoparathyroidism in the short- (OR 0.67, p < 0.01) and long-term (OR 0.54, p < 0.01), and higher likelihood of same-day discharge (OR 2.03, p < 0.01). Extrathyroidal tumor extension and N1-stage were factors associated with postoperative VC-dysfunction in the short- (OR 3.12, p < 0.01; OR 1.92, p = 0.01, respectively) and long-term (OR 3.11, p < 0.01; OR 2.32, p < 0.01, respectively). Routine use of IONM was independently associated with a lower risk of endocrine surgery-specific complications and greater likelihood of same-day discharge.


Sarcoidosis-like disease with pulmonary infestation, meningoencephalitis and transverse myelitis after sigmoid cancer treatment.
We present the case of a 40-year-old male with recent history of moderately differentiated invasive adenocarcinoma of the sigmoid in whom both respiratory and neurological disease developed simultaneously, mimicking diffuse metastatic disease. The broad differential diagnosis and pitfalls (both diagnostic and therapeutic) are described. Pulmonary sarcoidosis as well as neurosarcoidosis occur very rarely after solid cancers.


Chronic interleukin-1β in the dorsal hippocampus impairs behavioural pattern separation.
Understanding the long-term consequences of chronic inflammation in the hippocampus may help to develop therapeutic targets for the treatment of cognitive disorders related to stress, ageing and neurodegeneration. The hippocampus is particularly vulnerable to increases in the pro-inflammatory cytokine interleukin-1β (IL-1β), a mediator of neuroinflammation, with elevated levels implicated in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, and in stress-related disorders such as depression. Acute increases in hippocampal IL-1β have been shown to impair cognition and reduce adult hippocampal neurogenesis, the birth of new neurons. However, the impact of prolonged increases in IL-1β, as evident in clinical conditions, on cognition has not been fully explored. Therefore, the present study utilized a lentiviral approach to induce long-term overexpression of IL-1β in the dorsal hippocampus of adult male Sprague Dawley rats and examine its impact on cognition. Following three weeks of viral integration, pattern separation, a process involving hippocampal neurogenesis, was impaired in IL-1β-treated rats in both object-location and touchscreen operant paradigms. This was coupled with a decrease in the number and neurite complexity of immature neurons in the hippocampus. Conversely, tasks involving the hippocampus, but not sensitive to disruption of hippocampal neurogenesis, including spontaneous alternation, novel object and location recognition were unaffected. Touchscreen operant visual discrimination, a cognitive task involving the prefrontal cortex, was largely unaffected by IL-1β overexpression. In conclusion, these findings suggest that chronically elevated IL-1β in the hippocampus selectively impairs pattern separation. Inflammatory-mediated disruption of adult hippocampal neurogenesis may contribute to the cognitive decline associated with neurodegenerative and stress-related disorders.


Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania.
Miltefosine (MT) (hexadecylphosphocholine) was implemented to cope with resistance against antimonials, the classical treatment in Leishmaniasis. Given the scarcity of anti- Leishmania (L) drugs and the increasing appearance of resistance, there is an obvious need for understanding the mechanism of action and development of such resistance. Metabolomics is an increasingly popular tool in the life sciences due to it being a relatively fast and accurate technique that can be applied either with a particular focus or in a global manner to reveal new knowledge about biological systems. Three analytical platforms, gas chromatography (GC), liquid chromatography (LC) and capillary electrophoresis (CE) have been coupled to mass spectrometry (MS) to obtain a broad picture of metabolic changes in the parasite. Impairment of the polyamine metabolism from arginine (Arg) to trypanothione in susceptible parasites treated with MT was in some way expected, considering the reactive oxygen species (ROS) production described for MT. Importantly, in resistant parasites an increase in the levels of amino acids was the most outstanding feature, probably related to the adaptation of the resistant strain for its survival inside the parasitophorous vacuole.


The importance of being CAFs (in cancer resistance to targeted therapies).
In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. However, the efficacy of these therapies is significantly limited by primary and acquired resistance, that relies not only on cell-autonomous mechanisms but also on tumor microenvironment cues. Cancer-associated fibroblasts (CAFs) are extremely plastic cells of the tumor microenvironment. They not only produce extracellular matrix components that build up the structure of tumor stroma, but they also release growth factors, chemokines, exosomes, and metabolites that affect all tumor properties, including response to drug treatment. The contribution of CAFs to tumor progression has been deeply investigated and reviewed in several works. However, their role in resistance to anticancer therapies, and in particular to molecular therapies, has been largely overlooked. This review specifically dissects the role of CAFs in driving resistance to targeted therapies and discusses novel CAF targeted therapeutic strategies to improve patient survival.


The amniotic band syndrome: antenatal sonographic diagnosis and potential pitfalls.
Amniotic band syndrome causes a variety of fetal malformations involving the limbs, craniofacial region, and trunk. Six prenatally diagnosed cases of amniotic band syndrome are discussed. The diagnosis was based on sonographic visualization of either amniotic sheets or bands associated with fetal deformation or deformities in nonembryologic distributions known to characterize the amniotic band syndrome. Seven additional cases are considered in which an aberrant sheet of tissue with a free edge was visualized within the amniotic cavity but no restriction of fetal motion or subsequent deformity was demonstrated.


Establishment of an acute rejection model by transplanting both renal grafts into two different rats using a modified method of ureterovesical anastomosis.
To establish an acute rejection model after kidney transplantation in the rat using a modified method of ureterovesical anastomosis. Thirty-nine Wistar rat donors, were transplanted into 70 male SD rats. Wistar rats (group 1; n = 18) underwent harvest of both kidneys, cold perfusion, and transplantation into 36 SD rats. Wistar rats (group 2; n = 18) underwent left kidney harvest, cold perfusion and transplantation into 18 SD rats. Groups 1 and 2 did not receive immunosuppression after transplantation. Six kidneys were harvested from 3 Wistar rats (group 3), were transplanted into 6 SD rats that were treated with CsA (5 mg/kg per day) postoperatively, and humanely killed at 21 days. There were 10 SD in sham operated rats (group 4). The renal allograft vein was end-to-end anastomosed to the recipient renal vein using an epidural catheter. The renal allograft was anastomosed end-to-side to the recipient abdominal aorta with an abdominal aortic flap. The renal allograft ureterovesical flap was directly inserted into the recipient bladder, and attached by 4-5 interrupted sutures. The recipient's right kidney vessels were ligated at 3 days postoperatively. The success rates were 91.7% and 88.9% in groups 1 and 2, respectively. Except for the time for removal of the renal allografts, the operative durations and warm ischemia times differed insignificantly between both groups (P > .05). Blood creatinine levels increased significantly after kidney transplantation in groups 1 and 2 compared with the sham operated and CsA-treated cohorts (P < .01), but insignificantly between groups 1 and 2 (P > .05). A dual renal allograft model was established in the rat using a modified ureterovesical anastomosis. The technique can be reproduced reliably, reducing costs and shorten using overall operative duration.


Cadaverine and Spermine Elicit Ca2+ Uptake in Human CP Cells via a Trace Amine-Associated Receptor 1 Dependent Pathway.
The choroid plexus (CP) constitutes a barrier between the blood and the cerebrospinal fluid (CSF) which regulates the exchange of substances between these two fluids through mechanisms that are not completely understood. Polyamines as spermine, spermidine and putrescine are produced by all cells and are present in the CSF. Interestingly, their levels are altered in some neuronal disorders as Alzheimer's and Parkinson's diseases, thus increasing the interest in their signalling in the central nervous system (CNS). Cadaverine, on the other hand, is synthetized by the intestinal microbiome, suggesting that the presence of this bacterial metabolite in the CSF requires that it is up taken to the CNS across brain barriers. We knew that polyamines are detected by the olfactory signalling cascade operating at the CP, but the receptor involved had not been identified. The zebrafish TAAR13c was the only receptor known to bind a polyamine-cadaverine. Thus, we searched for a human receptor with homology to TAAR13c and found that some human TAARs including TAAR1 showed great homology. Then, we confirmed the expression of TAAR1 mRNA and protein in a human cell line of the CP, and in human CP samples. Calcium imaging assays after TAAR1 knockdown in these cells with a specific siRNA against TAAR1 showed a consistent reduction in the responses of these cells to cadaverine and spermidine, but not to spermine, suggesting that TAAR1 is activated by cadaverine and spermidine, but not spermine.


Development of a secretion system for the production of heterologous proteins in Corynebacterium glutamicum using the Porin B signal peptide.
Corynebacterium glutamicum is one of the useful hosts for the secretory production of heterologous proteins because of intrinsic attributes such as the presence of few endogenous proteins and proteases in culture medium. Here, we report the development of a new secretory system for the production of heterologous proteins by using the porin B (PorB) signal peptide in C. glutamicum. We examined two different endoxylanases and an antibody fragment (scFv) as model proteins for secretory production. In the flask cultivations, all the examined proteins were successfully produced as active forms into the culture medium with high efficiency. For the high-level production of endoxylanase, fed-batch cultivation was also performed in a lab-scale (5L) bioreactor, and the endoxylanases were efficiently secreted in the culture medium at levels as high as 615mg/L. From the culture supernatant, the secreted endoxylanases could be purified with high purity via one-step affinity column chromatography.


Artifacts from agar-protein interaction simulating a bacterial growth in the haemocultures.
Some morphological, histochemical and biochemical properties of the particles taking origin from the polysaccharide-proteins interaction in the presence of platelets and lymphocytes are described.


Precise modification of the surface charge of antigen enhances vaccine immunogenicity.
Aluminum (alum) adjuvant is the most extensively used protein subunit vaccine adjuvant, and its effectiveness and safety have been widely recognized. The surface charge of the antigen determines its electrostatic adsorption to alum adjuvant, which directly affects the immune efficacy of the protein vaccine. In our study, we precisely modified its surface charge by inserting charged amino acids into the flexible region of the SARS-CoV-2 receptor-binding domain (RBD), achieving electrostatic adsorption and a site-specific anchor between the immunogen and alum adjuvant. This innovative strategy extended the bioavailability of the RBD and directionally displayed the neutralizing epitopes, thereby significantly enhancing humoral and cellular immunity. Furthermore, the required dose of antigen and alum adjuvant was greatly reduced, which improved the safety and accessibility of the protein subunit vaccine. On this basis, the wide applicability of this novel strategy to a series of representative pathogen antigens such as SARS-RBD, MERS-RBD, Mpox-M1, MenB-fHbp, and Tularemia-Tul4 was further confirmed. Charge modification of antigens provides a straightforward approach for antigenicity optimization of alum-adjuvanted vaccines, which has great potential to be adopted as a global defense against infectious diseases.


Application of poly (ethyleneimine) solution as a binding agent in DGT technique for measurement of heavy metals in water.
A 0.050 mol L(-1) solution of poly (ethyleneimine) (PEI), had been used as a novel binding agent of diffusive gradients in thin-films (DGT) technique (PEI-DGT) for measuring the concentrations of labile Cu(2+), Cd(2+) and Pb(2+) in waters. The binding capacities of the PEI-DGT for Cu(2+), Cd(2+) and Pb(2+) were 11.8, 10.2 and 10.6 μmol L(-1), respectively. The performance of PEI-DGT was independence of pH in the range of 4-8 and ionic strength in the range from 1×10(-4) to 0.1 mol L(-1) (as NaNO3). PEI-DGT could measure 104.7±5.2% of the total concentration of Cd(2+) (0.500 mg L(-1)), 95.2±4.3% of the total Cu(2+) (0.500 mg L(-1)) and 99.2±3.4% of the total Pb(2+) (0.500 mg L(-1)) in synthetic solution. Effects of the ligands on the measurement of labile metals were also investigated in synthetic solutions containing the various concentrations of EDTA and humic acid. In EDTA solution, the concentrations of labile metals measured by PEI-DGT showed good agreement with the theoretical concentrations of free metal ions. In humic acid solution, the concentrations of labile metals measured by PEI-DGT decreased with the increase of the concentrations of humic acid. Several DGT devices with various binding agents, including PEI, sodium polyacrylate and poly(4-styrenesulfonate) solution, were used for the measurement of labile fractions of Cu(2+), Cd(2+) and Pb(2+) in the spiked waters and in mine wastewaters. The results showed that the concentrations of labile metal measured by DGT devices with different binding agents could be significantly different, indicating that the labile fractions of metals were dependent on the binding strength of the binding agents with metals. By choosing binding agents, the useful information on the speciation and bioavailability of the analytes can be provided.


Computational Modeling of Attentional Impairments in Disruptive Mood Dysregulation and Attention-Deficit/Hyperactivity Disorder.
Computational models provide information about cognitive components underlying behavior. When applied to psychopathology-relevant processes, they offer additional insight to observed differences in behavioral performance. Drift diffusion models have been successfully applied to investigate processing efficiency during binary choice tasks. Using these models, we examine the association between psychopathology (irritability and inattention/hyperactivity) and processing efficiency under different attentional demands. A total of 187 youths with attention-deficit/hyperactivity disorder (ADHD), disruptive mood dysregulation disorder (DMDD), both disorders, or no major psychopathology (age, mean ± SD, 13.09 ± 2.55 y, 34% female) completed an Eriksen Flanker task. Of these, 87 youths provided complete data on dimensional measures of the core symptom of DMDD (irritability) and those of ADHD (inattention and hyperactivity). In a categorical diagnosis-based analysis (n = 187), we found significant interactive effects among ADHD, DMDD, and task condition on processing efficiency, whereby changes in processing efficiency between conflict and nonconflict conditions were larger in youths without psychopathology compared with patients. Analysis of symptom severity (n = 87) across diagnoses similarly revealed an interaction between symptom dimensions and task condition on processing efficiency. Irritability moderated the magnitude of association between inattention symptoms and difference in processing efficiency between conflict and nonconflict conditions. Adapting processing efficiency to cognitive demands may represent a shared cognitive endophenotype for both ADHD and DMDD. Highly irritable and/or inattentive youth may have difficulty adjusting processing efficiency to changing task demands, possibly reflecting impairments in cognitive flexibility.


Proximal femoral surface strain gauge analysis of a new epiphyseal prosthesis.
This paper describes a new type of proximal femoral, replacement arthroplasty and its preliminary, pre-clinical, evaluation. The prosthesis was designed as a replacement for the femoral capital epiphysis. It comprises a thin, metal, articular shell and an underlying 'epiphyseal' replacement which is modulus-matched to adjacent proximal femoral bone. Surface strain gauge analysis of the proximal femur under conditions simulating static single leg stance demonstrated that the new prosthesis maintains an essentially normal femoral strain distribution. It is hoped that selective load transmissions across the prosthesis-bone interface should result in less post-implantation proximal bone resorption.


Quality of life and cognitive and functional performance of octogenarians and nonagenarians undergoing hemodialysis.
To evaluate the quality of life, cognitive and functional capacity of older adult patients undergoing hemodialysis who are 80 years of age or older and compare them to older adults without chronic kidney disease (CKD) treated at a geriatrics outpatient clinic. First, 103 older adult patients undergoing hemodialysis and 103 older adults without CKD matched by gender and age were evaluated. Cognitive aspects as evaluated by the mini mental state examination, the Boston Naming Test and verbal fluency were analyzed; comorbidities according to the Charlson's comorbidity index; social support through the Medical Outcomes Study scale; functional ability through the chair sit-to-stand and gait speed tests, as well as the basic activities of daily living (BADL) and instrumental activities of daily living (IADL) and quality of life according to the Kidney Disease Quality of Life Short Form (KDQOL SF-36) questionnaires. The hemodialysis group had a higher rate of comorbidities (7.8 ± 2.4 vs. 5.8 ± 2.3, p < 0.001). In the multiple logistic regression analysis, the group undergoing hemodialysis presented a ninefold greater chance of dependence for IADL than controls, a 4.3 and 3.2 times greater chances for inadequacy on the gait speed and chair sit-to-stand tests, respectively, as well as a 4.4-fold higher risk of cognitive decline on the verbal fluency test. Long-lived patients undergoing hemodialysis presented worse quality of life and functional and cognitive performance compared to long-term patients attended at the outpatient clinic, indicating that preventive and protective measures should be considered and implemented.


Enzymatic Synthesis of Nucleoside Triphosphates and Deoxynucleoside Triphosphates by Surface-Displayed Kinases.
Nucleoside triphosphates and deoxynucleoside triphosphates are important biochemical molecules. In this study, recombinant Escherichia coli that could display nucleotide kinases (INP-N-NMKases) and acetate kinase (INP-N-ACKase) on the cell surface were constructed by fusing an enzyme (NMKase/ACKase) to the N-terminus of ice nucleation protein (INP-N). By using intact recombinant bacteria cells as a catalyst coupled with an ACKase-catalyzed adenosine-5'-triphosphate (ATP) regeneration system, nucleoside triphosphates (NTPs) and deoxynucleoside triphosphates (dNTPs) could be synthesized efficiently. In a reaction system with 5 mmol/l substrate, the conversion rates of cytidine-5'-triphosphate (CTP) and deoxycytidine-5'-triphosphate (dCTP) were 96% and 93%, respectively, the conversion rate of ATP and deoxyadenosine-5'-triphosphate (dATP) was 96%, the conversion rate of deoxythymidine-5'-triphosphate (dTTP) was 91%, and the conversion rate of uridine-5'-triphosphate (UTP) was 80%. There was no obvious degradation. At 37 °C, the stability of the surface-displayed fusion protein, especially in the presence of the substrate, was significantly improved. Each whole cell could be reused more than 8 times.


A cost-utility analysis of Amisulpride and Paliperidone in the treatment of Schizophrenia.
Schizophrenia is a severe, long-term neurodevelopmental disorder that results in increased morbidity and mortality. Amisulpride and Paliperidone are two antipsychotics used to treat schizophrenia in the UK. This evaluation compares the cost-utility of each drug; no similar research has been conducted in the UK. A cost utility analysis was performed looking at the benefits in terms of Quality Adjusted Life Years within one year of the treatment, and the costs in pound sterling, discounted to the 2016/2017 value. This evaluation was from the perspective of the National Health Service, the biggest provider of health within the United Kingdom. The cost utility analysis found an incremental cost effectiveness ratio of £10,941 per added Quality Adjusted Life Year for using Paliperidone, instead of the more widely used Amisulpride. This is below the NICE threshold of £20-30,000 per QALY. Hence, it is within reason to suggest shifting diagnostic practices to Paliperidone.


Twist to matricing: Restoration of adjacent proximal defects in a novel manner.
The quality treatment in an efficient way is the road map to successful clinical practice. Various methods are employed to achieve goals. Refurbishment of the adequate marginal ridge, proximal contact, and contour are the prime challenges in restoring two adjacent proximal defects. This paper presents an overview of achieving satisfactory proximal restorations in a time saving innovative manner.


Increased fetoplacental angiogenesis during first trimester in anaemic women.
Epidemiological studies describe an association between relative size of the placenta at delivery and cardiovascular morbidity and mortality during adult life. Some determinants of placental size, such as maternal anaemia, have been acknowledged, but no plausible mechanism has been advanced to explain the initiation of postnatal disease. Placental villous vascularisation in anaemic women (Hb<90 g/L) was assessed in the first and third trimesters of pregnancy by immunohistochemical identification of villous capillaries and compared with that of gestational age-matched groups of women with normal (Hb>110 g/L; control group) concentrations of haemoglobin, and an intermediate group (Hb 90-110 g/L). Anaemia, especially in the first trimester, was associated with increased numbers of capillaries per villous cross section (mean 11.70 [SE 0.35] vs 4.14 [0.27]) located mainly in the outer third of the stroma beneath the trophoblast (94% [1.15] vs 67% [1.82]) and with increased numbers of villous macrophages and of proliferating MIB-1-positive cells compared with the control group. Maternal anaemia in early pregnancy seems to influence the pattern of placental vascularisation. Such changes might alter placental vascular impedance during early fetal life, thereby exerting important effects on cardiovascular development.


PICC-PORT totally implantable vascular access device in breast cancer patients undergoing chemotherapy.
The increasing use of arm totally implantable vascular access devices for breast cancer patients who require chemotherapy has led to a greater risk of complications and failures and, in particular, to upper extremity deep vein thrombosis. This study aims to investigate the outcomes of the arm peripherally inserted central catheter-PORT technique in breast cancer patients. The peripherally inserted central catheter-PORT technique is an evolution of the standard arm-totally implantable vascular access device implant based on guided ultrasound venous access in the proximal third of the upper limb with subsequent placement of the reservoir at the middle third of the arm. A prospective study was conducted on 418 adult female breast cancer patients undergoing chemotherapy. The primary study outcome was peripherally inserted central catheter-PORT failure. Median follow-up was 215 days. Complications occurred in 29 patients (6.9%) and failure resulting in removal of the device in 11 patients (2.6%). The main complication we observed was upper extremity deep vein thrombosis, 10 (2.4%); all patients were rescued by anticoagulant treatment without peripherally inserted central catheter-PORT removal. The main reason for removal was reservoir pocket infection: 4 (0.9%) with an infection rate of 0.012 per 1000 catheter days. Cumulative 1-year risk of failure was 3.6% (95% confidence interval, 1.3%-7.1%). With regard to the patients' characteristics, body mass index <22.5 was the only significant risk for failure (p = 0.027). The peripherally inserted central catheter-PORT is a safe vascular device for chemotherapy delivery that achieves similar clinical results as traditional long-term vascular access devices (peripherally inserted central catheter and arm totally implantable vascular access device, in particular) in breast cancer patients.


Exploration of browning reactions during alkaline thermal hydrolysis of sludge: Maillard reaction, caramelization and humic acid desorption.
The browning reaction produces melanoidins, 5-hydroxymethylfurfural (HMF) and humic acids which influence subsequent anaerobic digestion and protein recovery. This paper systematically evaluates the variation of organics that make sludge browning with heating temperature and reaction time, the effect of browning organics on protein recovery and anaerobic digestion, and finally proposes a pathway for the occurrence of the Maillard reaction (MR) in the sludge environment. The results show that the browning of sludge hydrolysate is related to the comprehensive influence of the MR, caramelization and humic acid desorption. The increase of temperature (80 °C-150 °C) and pH (9-13) will promote the extent of browning of sludge hydrolysate, and the sludge browning reaction basically stabilizes at the reaction time of 1 h. Humic acid and melanoidin could co-precipitate with the protein, thereby reducing the purity of the recovered protein. The inhibition of anaerobic digestion starts when the melanoidin concentration is 8.01 mmol/L. The three-dimensional fluorescence, GC-MS and FT-IR analysis show that melanoidins have the same functional groups and fluorescence properties as humic acid does, and the humic acid in the supernatant of the sludge treated with ATH was not only converted at its adsorbed state, but also possibly generated by the reaction of the dissolved proteins with polysaccharides. Finally, LC-MS/MS was used to identify the intermediate products of the MR and the possible structural formula of melanoidin. This study further clarifies the browning reaction in hydrothermal sludge treatment and provides help for the accuracy of subsequent studies.


Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats.
Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.


On the inverse problem in flow cytometry recovering DNA distribution from FMF data.
The problem of recovering DNA distribution from cytofluorometric experimental data was investigated. Theoretical analysis led to a convenient formulation of the problem and to uniqueness results for its solution. A minimization algorithm has been implemented to get the optimal estimate of G1, S, G2, and M phase percentages. This algorithm was tested in some experimental cases.


Gene cloning of Porphyromonas gingivalis specific antigens recognized by serum of adult periodontitis patient.
1. Porphyromonas gingivalis is believed an important pathogen of adult periodontitis. A gene library of P. gingivalis 381 was constructed in lambda phage vector L47.1. The library was probed with serum obtained from patients of severe adult periodontitis. Two clones, lambda MDBG101 and lambda MDBG103 which were expressed, 200 and 160 kDa respectively, were selected and further studied. 2. The expressed antigens in these two clones were also reacted with rabbit antiserum against whole cells, capsular fraction and cell surface fraction of P. gingivalis. 3. Genes coding protein antigens in lambda MDBG101 and lambda MDBG103 were subcloned into high-copy-number plasmid vector pACYC184 and subclones obtained were designated as MD101 and MD103. Recombinant plasmids, pMD101 and pMD103, differed in their restriction endonuclease digestion. 4. Immunodiffusion analysis showed that cloned proteins from MD101 and MD103 reacted with antiserum against P. gingivalis but did not react with antiserum against Prevotella intermedia, Prevotella loescheii and Prevotella asaccharolyticus. 5. These data suggest that P. gingivalis species-specific antigens has been successfully cloned and expressed in Escherichia coli. Since these cloned specific antigens were recognized by adult periodontitis patient sera, the recombinant antigen will be useful material for the development of serodiagnosis of P. gingivalis infection in adults periodontitis.


Translation, cross-cultural adaptation, and measurement properties of the psychosomatic questionnaire for children and adolescents with musculoskeletal pain into Brazilian-Portuguese.
Psychosomatic symptoms seem to influence both the onset and development of pain. There is lack of Brazilian-Portuguese questionnaires that measure psychosomatic symptoms in children and adolescents. To translate and cross-culturally adapt the Psychosomatic Questionnaire for Children and Adolescents into Brazilian-Portuguese and English and test the measurement properties of the Brazilian-Portuguese version. The translation and cross-cultural adaptation (from Dutch to Brazilian-Portuguese and English) followed six steps. Interviews were conducted in 33 Brazilian children and adolescents. We also recruited 107 children and adolescents with musculoskeletal pain from schools to test the measurement properties of the Brazilian-Portuguese version. The questionnaire was completed twice with a 7-day interval. Ceiling and floor effects, missing data, internal consistency, reliability, measurement error and construct validity were assessed. We recruited 140 children and adolescents from public and private schools. During the cross-cultural adaptation process, no major difficulty answering and understanding the questionnaire were reported by children and adolescents. The questionnaire did not show ceiling or floor effects and had minimal missing data (0.37%). Internal consistency by the Cronbach's Alpha was 0.69. Test-retest reliability by the Intraclass Correlation Coefficient was 0.75 (95% CI: 0.64, 0.84). The smallest detectable change was 6.5 points out of 18 points. We observed a moderate correlation of 0.54 (p<0.01) with the Spence Children's Anxiety Scale, consistent with our a-priori hypothesis. The Brazilian-Portuguese version of the Psychosomatic Questionnaire for Children and Adolescents has acceptable measurement properties and is a good option for assessing psychosomatic symptoms in clinical practice and research.


Cryopreservation of human ovarian tissue: effect of spontaneous and initiated ice formation.
This investigation compared conventional freezing of human ovarian tissue using either spontaneous or initiated ('seeded') ice formation. Biopsies of ovarian tissue were obtained from women with indications for chemotherapy or radiotherapy. Small pieces of experimental tissue were randomly distributed into three groups that were then subjected to different treatments prior to culture in vitro for 16 days: the control group, no treatment, cultured immediately after biopsy (group 1); cryopreservation/thawing with spontaneous ice formation (group 2); and cryopreservation/thawing with initiated ice formation (group 3). Follicle viability and hormonal activity were then evaluated. There was no significant difference between groups regarding the concentration of oestradiol 17-beta in the culture supernatant, whereas progesterone concentration was significantly (P < 0.05) higher in group 1 compared with group 2 or 3. There was a significant (P < 0.05) difference in primordial and primary follicle density between all of the groups (group 1 having the highest and group 2 having the lowest) and group 2 had significantly (P < 0.05) fewer normal grade follicles than the other two groups. For optimal cryopreservation of human ovarian tissue, the protocol of conventional freezing should therefore include a step of initiated ice formation.


Cross-Coupling Reactions Enabled by Well-Defined Ag(III) Compounds: Main Focus on Aromatic Fluorination and Trifluoromethylation.
AgIII compounds are considered strong oxidizers of difficult handling. Accordingly, the involvement of Ag catalysts in cross-coupling via 2e- redox sequences is frequently discarded. Nevertheless, organosilver(III) compounds have been authenticated using tetradentate macrocycles or perfluorinated groups as supporting ligands, and since 2014, first examples of cross-coupling enabled by AgI /AgIII redox cycles saw light. This review collects the most relevant contributions to this field, with main focus on aromatic fluorination/perfluoroalkylation and the identification of AgIII key intermediates. Pertinent comparison between the activity of AgIII RF compounds in aryl-F and aryl-CF3 couplings vs. the one shown by its CuIII RF and AuIII RF congeners is herein disclosed, thus providing a more profound picture on the scope of these transformations and the pathways commonly associated to C-RF bond formations enabled by coinage metals.


Is the volume-regulated anion channel VRAC a "water-permeable" channel?
The volume-regulated anion channel, VRAC, plays an important role in cell volume regulation. This channel is permeable for a wide variety of anions, amino acids, and organic osmolytes, including taurine. However, nothing is known about possible water permeability of this channel. Water permeability of endothelial cells is estimated from the initial rate of cell swelling because of a hypotonic challenge. As a result of simultaneous volume and current measurements, it will be shown that water permeability is decreased by inhibition of VRAC. It is concluded that water permeates VRAC and might be able to accelerate water transport by providing an additional permeation pathway for water. Therefore VRAC can be considered as a water-permeable, "wet" channel.


Evaluation of Viral Recovery Methodologies from Solid Waste Landfill Leachate.
Leachate from solid waste landfill is a dark liquid of variable composition and possible source of contamination of groundwater and surface waters. This study aims to assess skimmed milk flocculation and ultracentrifugation as viral concentration methods associated to different nucleic acid extraction protocols in order to establish a methodology for virus recovery from sanitary landfill leachate. Spiking experiments using human adenovirus (HAdV) and bacteriophage PP7 revealed the association of QIAamp Fast DNA Stool mini kit® nucleic acid extraction and ultracentrifugation as an effective method for recovering HAdV (346.18%) and PP7 (523.97%) when compared to organic flocculation method (162.64% for HAdV and 0.61% for PP7) that presented PCR inhibition in all undiluted samples. Ultracentrifugation applied in three landfill samples confirm efficiency of the methodology detecting HAdV in all samples with a mean of 3.44E + 06 ± 1.56E + 06 genomic copies/mL. Nucleotide sequencing characterized HAdV as belonging to group B and F. JC polyomavirus (JCPyV) was also investigated in those samples; however, detection was not observed. Methodologies for detection of viruses in leachate can be useful to generate data for future health risk analysis of workers who have contact with solid urban waste, as well as populations exposed to different environmental matrices contaminated by these effluents.


Maturation of human gingival keratinocytes cultured with fibroblasts from keratinizing and non-keratinizing epithelia.
When keratinocytes from epidermis, gingiva and buccal mucosa are cultured in vitro they form a stratified squamous epithelium that lacks evidence of orthokeratinization or parakeratinization. We attempted to induce orthokeratinization or parakeratinization in cultured gingival keratinocytes by co-cultivation with fibroblasts from human skin, gingiva and buccal mucosa. Keratinization was defined by the morphological appearance of the cultured cells and by the presence of large molecular weight keratin proteins (63,000 and 67,000 mol. wt). Using these criteria, the chosen fibroblasts failed to induce any alteration in the pattern of keratinization. We conclude that under our present culture conditions, fibroblasts alone cannot induce keratinization in cultured keratinocytes.


Layer 2/3 Pyramidal Neurons Control the Gain of Cortical Output.
Initial anatomical and physiological studies suggested that sensory information relayed from the periphery by the thalamus is serially processed in primary sensory cortical areas. It is thought to propagate from layer 4 (L4) up to L2/3 and down to L5, which constitutes the main output of the cortex. However, more recent experiments point toward the existence of a direct processing of thalamic input by L5 neurons. Therefore, the role of L2/3 neurons in the sensory processing operated by L5 neurons is now highly debated. Using cell type-specific and reversible optogenetic manipulations in the somatosensory cortex of both anesthetized and awake mice, we demonstrate that L2/3 pyramidal neurons play a major role in amplifying sensory-evoked responses in L5 neurons. The amplification effect scales with the velocity of the sensory stimulus, indicating that L2/3 pyramidal neurons implement gain control in deep-layer neurons.


Androgen receptor expression in low grade serous ovarian cancer; clinical considerations in the diagnosis, treatment and surveillance of disease in a transgender male.
•Low grade serous (LGS) ovarian cancer is an uncommon cancer.•Androgen receptor expression testing is not routinely performed in patients with LGS ovarian cancer.•Systemic androgen levels may be elevated in patients with PCOS or those taking exogenous testosterone.•Consideration should be made to include androgen receptor testing for these patients.


Corrections to the spelling of species names in genera Psorophora and Verrallina, with a note on the correct gender of Udaya.
The spelling of specific names for a species of Psorophora and 4 species of Verrallina are corrected to correspond with the gender of the corresponding genus. An explanation is given for treating Udaya as masculine, rather than feminine as indicated in A Catalog of the Mosquitoes of the World.


Functionally-distinct pyramidal cell subpopulations during gamma oscillations in mouse hippocampal area CA3.
Gamma oscillations (γ-oscillations) in hippocampal area CA3 are essential for memory function. Particularly, CA3 is involved in the memory related process pattern completion, which is linked with the γ-oscillations in human hippocampus. Recent studies suggest that heterogeneity in the functional properties of pyramidal cells (PCs) in CA3 plays an important role in hippocampal function. By performing concomitant recordings of PC activity and network γ-oscillations in CA3 we found three functionally-different PC subpopulations. PCs with high spike-frequency adaptation (hAPC) have the strongest action potential gamma phase-coupling, PCs with low adaptation (lAPC) show lower phase-coupling and PCs displaying a burst-firing pattern (BPC) remained quiescent. In addition, we discovered that hAPC display the highest excitatory/inhibitory drive, followed by lAPC, and lastly BPC. In conclusion, our data advance the hypothesis that PCs in CA3 are organized into subpopulations with distinct functional roles for cognition-relevant network dynamics and provide new insights in the physiology of hippocampus.


The evaluation of long-pulsed Nd:YAG laser efficacy and side effects in the treatment of cutaneous vessels on the face and legs.
Long-pulsed Nd:YAG lasers have been used for the treatment of cutaneous vascular lesions on face and leg veins. To report our experience with long-pulsed Nd:YAG lasers for the treatment cutaneous vessels on the face and legs. A total of 145 patients with cutaneous vessels on the face and the legs were included in this study. All patients received two treatment sessions, first at the beginning and second after four weeks. Patients were evaluated three times: first at the beginning of the therapy, and second and third after the four weekly follow-ups. The laser settings of each treatment session were recorded. The physician's assessment of treatment efficiency was taken by comparing gross photograph and clinical evaluation. The grade of improvement, as the percent of reduction in the severity of veins after laser treatment, was determined as follows: <25% improvement (mild); 25%-50% improvement (moderate); 51%-75% improvement (good); and >75% improvement (excellent). The side effects were also recorded. Of the 145 patients who completed the study, 63.6% of patients had vessels on the face, and 36.4% had them on the legs. After the first session, 82.8% of patients have good improvement (51%-75%). After the second session, 78.6% of patients have excellent improvement (>75%). The clinical improvement after the second treatment session was significantly higher than the first treatment session (P ˂ .05). There were no statistical differences between the treatment areas (P ˃ .05). The most common side effect was erythema in 12.4% (P ˃ .05). The Nd:YAG laser is an effective and safe treatment option for the treatment of cutaneous vessels on the face and the legs.


Racial Discrimination in Late Adolescence and Mental Health Outcomes Among Participants in the Panel Study of Income Dynamics.
To assess whether racial discrimination experienced at ages 18-21 years is associated with psychological distress and well-being, and investigate potential moderators of this relationship. We used panel data collected from 2005 to 2017 from 661 participants in the Transition into Adulthood Supplement of the Panel Study of Income Dynamics. The Everyday Discrimination Scale measured racial discrimination. The Kessler six and Mental Health Continuum Short Form assessed psychological distress and well-being, respectively. Generalized linear mixed modeling was used to model outcomes and test potential moderating variables. Approximately 25% of participants experienced high levels of racial discrimination. In analyses of panel data, these participants had significantly worse psychological distress (odds ratio = 6.04, 95% confidence interval: 3.41, 8.67) and lower levels of emotional well-being (odds ratio = 4.61, 95% confidence interval: 1.87, 7.36) compared to those who did not. Race and ethnicity moderated the relationship. Exposure to racial discrimination in late adolescence was associated with worse mental health outcomes. This study has important implications for interventions addressing the need for mental health support that is critical for adolescents who experience racial discrimination.


A high concentration of dopamine preferentially permitted release of newly synthesized prolactin.
We used continuous labelling ([3H]leucine) of cultured adenohypophysial cells to investigate the relationship between the storage and release of newly synthesized and stored prolactin in response to dopamine (1 mumol/l) and thyrotropin-releasing hormone (TRH) (0.1 mumol/l) challenge. Newly synthesized prolactin was identified by the tritium radiation activity incorporated in prolactin. A maximal dose of dopamine (1 mumol/l) could not completely block prolactin release from a primary culture of lactotrophs. During 3 h of continuous labelling under maximal dopaminergic inhibition, newly synthesized prolactin was released which was of a significantly higher specific activity than control groups. In contrast, TRH stimulation produced results consistent with previous observations of the release of predominantly old, stored hormone. However, the absolute amount of the newly synthesized prolactin was increased by the TRH administration, and the increased release of the newly synthesized prolactin could be accounted for by increased levels of synthesis. Our results are consistent with the concept of the existence of a regulated route and a dopamine-insensitive constitutive route of prolactin release which predominantly encompasses newly synthesized hormone. However, the possibility that cellular heterogeneity or that non-dopaminergic prolactin-release inhibiting factor(s) (PIF) is responsible for this observed release cannot be ruled out.


Emerging role of long-acting anticholinergics in children with asthma.
Although the use of inhaled anticholinergics in obstructive airway disease has been established for several years, the clinical experience using these medications in treating patients with asthma is limited. Only few studies so far have included pediatric patients with asthma, but these studies demonstrate relevant therapeutic effects. This review will explore the pharmacological effects of inhaled anticholinergics, provide an overview about current adult and pediatric asthma studies using tiotropium, and describe future research needs. In a phase II study with tiotropium as add-on to maintenance treatment to inhaled corticosteroids (ICSs) in moderate persistent adolescent with asthma, significant improvement of peak and trough forced expiratory volume in 1 s (FEV1) with a good safety profile could be demonstrated. A pediatric phase II study in symptomatic patients with asthma aged 6-11with comparable study design also demonstrated significant improvement of peak FEV1 with no serious adverse events. However, both studies could not document a significant clinical improvement analyzed by standardized scores. Tiotropium might become an add-on treatment option in symptomatic pediatric and adolescent patients with asthma despite adequate therapy with ICS and long-acting β2-agonist (LABA) or as an alternative to LABA in patients with safety concerns related to LABA. For a better assessment of the clinical effect, long-term studies are needed.


Left atrium decompression devices across the spectrum of ejection fraction in heart failure: an updated systematic review and meta-regression analysis.
In patients affected by heart failure (HF) with reduced ejection fraction (HFrEF), pharmacological treatments have been proven to alleviate symptoms and improve prognosis, while no treatment other than sodium-glucose co-transporter-2 inhibitors have demonstrated significant effects in HF with preserved ejection fraction (HFpEF). Left atrium decompression devices (LADd) have been recently investigated as a new interventional approach in patients with HFpEF. To assess the efficacy of LADd on soft endpoints in HF patients across the spectrum of ejection fraction. PubMed and Web of Science were searched without restrictions from inception to 28 May 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified main outcomes were the change from baseline in 6-min walking distance (6MWD), NYHA class and health-related quality of life (HRQoL). Secondary outcomes were reduction in HF hospitalizations, echocardiographic, and hemodynamic parameters. Eleven studies, with a total of 547 patients, were included. LADd significantly improved 6MWD by 43.95 m (95% CI 29.64-58.26 m), decreased NYHA class by 0.93 (95% CI 1.20-0.67), and improved HRQoL questionnaire by 20.45 points (95% CI 13.77-27.14) with better results for all outcomes in patients with lower EFs. The present meta-analysis suggests that LADd are favorable in improving 6MWD, NYHA class, and HRQoL in HF across a wide spectrum of ejection fraction, with better outcomes in patients with lower EFs. CRD42022336077, URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=336077 .


Simultaneous proton magnetic resonance fingerprinting and sodium MRI.
The goal of this work is to demonstrate a method for the simultaneous acquisition of proton multiparametric maps (T1 , T2 , and proton density) and sodium density images in 1 single scan. We hope that the development of such capabilities will help to ease the implementation of sodium MRI in clinical trials and provide more opportunities for researchers to investigate metabolism through sodium MRI. We developed a sequence based on magnetic resonance fingerprinting (MRF), which contains interleaved proton (1 H) and sodium (23 Na) excitations followed by a simultaneous center-out radial readout for both nuclei. The receive chain of a 7T scanner was modified to enable simultaneous acquisition of 1 H and 23 Na signal. The obtained signal-to-noise ratio (SNR) was evaluated, and the accuracy of both proton T1 , T2 , and B1+ and sodium density maps were verified in phantoms. Finally, the method was demonstrated in 2 healthy subjects. The SNR obtained using the simultaneous measurement was almost identical to single-nucleus measurements (<1% change). Similarly, the proton T1 and T2 maps remained stable (normalized root mean square error in T1 ≈ 2.2%, in T2 ≈ 1.4%, and B1+ ≈ 5.4%), which indicates that the proposed sequence and hardware have no significant effects on the signal from either nucleus. In vivo measurements corroborated these results and demonstrated the feasibility of our method for in vivo application. With the proposed approach, we were able to simultaneously acquire sodium density images in addition to proton T1 , T2 , and B1+ maps as well as proton density images.


Injectable hyaluronan/MnO2 nanocomposite hydrogel constructed by metal-hydrazide coordinated crosslink mineralization for relieving tumor hypoxia and combined phototherapy.
Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H2O2 into O2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O2-enhanced efficient topical dual-phototherapy of breast cancer.


The carbohydrate on human chorionic gonadotropin produced by cancer cells.
Using the methods described, it is not possible to determine the number of N- and O-linked oligosaccharides on ectopic hCG beta. On standard hCG beta there are two NeuAc residues on each N- and O-linked oligosaccharide, so that the number of NeuAc residues is proportional to the number of oligosaccharides. Ectopic hCG beta and desialylated ectopic hCG beta are of similar molecular size to the standard preparations (gel filtration and RIA with anti-CTP antisera, data not presented). This suggests that ectopic hCG beta is sialylated to a similar extent as standard hCG beta, so the number of oligosaccharides on ectopic hCG beta could be similar to the number on standard hCG beta. There is a Fuc attached to the N-linked oligosaccharides of standard hCG beta (Fig. 3). Using the methods described, it was not possible to determine if this residue is also found on the N-linked oligosaccharides of ectopic hCG beta. Recently, a second form of ectopic hCG beta was identified (22). This form lacks the characteristic hCG beta carboxyterminal peptide, and as such is unrecognized by the RIA used in this study. Like the ectopic hCG beta described herein, and that produced by other cancers, this molecule only partially binds to Con A, and binds to Ricinus communis-120 following neuraminidase digestion. Intact hCG and free hCG subunits, which only partially bind to Con A, are found in cancer tissues, cancer sera, and the medium of cultured trophoblastic and nontrophoblastic cancer cells (Table 1). Our studies with DoT cancer of the cervix cells clearly indicate that the partial binding could be the consequence of the linkage of extra beta G1cNAc residues.


Proton beam therapy.
Conventional radiation therapy directs photons (X-rays) and electrons at tumours with the intent of eradicating the neoplastic tissue while preserving adjacent normal tissue. Radiation-induced damage to healthy tissue and second malignancies are always a concern, however, when administering radiation. Proton beam radiotherapy, one form of charged particle therapy, allows for excellent dose distributions, with the added benefit of no exit dose. These characteristics make this form of radiotherapy an excellent choice for the treatment of tumours located next to critical structures such as the spinal cord, eyes, and brain, as well as for paediatric malignancies.


The effects of caffeic acid phenethyl ester on tissue damage in lung after hindlimb ischemia-reperfusion.
The aim of this study was to investigate the effects of caffeic acid phenethyl ester (CAPE) on the lungs as a remote organ after performing hindlimb ischemia-reperfusion (I/R) and by assessing biochemical and histopathological analysis. The animals were divided into three groups: control, I/R, and I/R with CAPE. I/R period for 8 h was performed on the right hindlimb of all the anesthesied rats in I/R and CAPE with I/R group. In the CAPE with I/R group, the animals received CAPE 10 microM by intraperitoneal injection 1h before the reperfusion. The animals in the control and I/R groups received a similar volume of saline solution by means of intraperitoneal injection. At the end of the reperfusion period, a midsternotomy was performed. Blood, bronchoalveolar lavage (BAL) and lung tissue were obtained, and were used for biochemical and histopathological examination. The tissue and serum malondyaldehyde levels were significantly lower in the control (P=0.0001 and 0.001, respectively) and in the CAPE with I/R groups (P=0.0001 and 0.003, respectively) compared to the I/R group. Tissue Na(+)-K(+) ATPase activity in the CAPE with I/R group was significantly higher than in the I/R group (P=0.0001). Reduced activity was found in the I/R group compared to the control group (P=0.0001). Myeloperoxidase activity (P=0.001) and protein concentration (P=0.034) in BAL were significantly reduced in CAPE-treated animals when compared with the I/R group. A decreased activity and protein concentration were found in the control group compared to the I/R group (P=0.0001 and 0.024, respectively). The lungs of the I/R group displayed intense peribronchial and perivascular leukocytic infiltration in histopathological examination compared to the CAPE with I/R group (P<0.05). CAPE seems to be effective in protecting remote organ injury caused by increased oxidative stress and neutrophil accumulation that results from an I/R injury.