Social determinants of emotional well-being in new refugees in the UK.
Refugees are most vulnerable to mental health problems of all migrant groups, and an understanding of the role of postdisplacement social factors in refugee emotional well-being can help to shape the future interventions for this group. We aimed to investigate the effect of social determinants, such as employment, language ability and accommodation, on mental health in refugees in the UK. This prospective longitudinal cohort study was set in the UK. The study population of new UK refugees was drawn from an existing data set of the Longitudinal Survey of New Refugees (n = 5678), in which all new UK refugees (2005-2007) were sent a postal questionnaire at four time points across 2 years. Ordered logistic regression models were used to evaluate associations between social determinants and the dependent variables, emotional well-being or change in emotional well-being, using a question from the Short Form-36 Health Survey Questionnaire. Refugees who were unemployed in the UK, could not speak English well or were unsatisfied with their accommodation had significantly higher odds of poorer emotional well-being in the cross-sectional analysis (P < 0.05 at all time points measured). Postdisplacement social factors, including language ability, employment status and accommodation satisfaction, were important determinants of refugee emotional well-being. Changes in these social determinants have the potential to improve refugee mental health, making them legitimate, modifiable targets for important public health interventions. Accounting for this, further research into how to improve refugee well-being is crucial given the increase in refugee numbers around the developed world.


Knowledge assessment of a donor adverse reaction severity grading tool by the National Blood Donor Vigilance Programme of India.
The severity grading tool (SGT) was recently designed by the Association for Advancement of Blood and Biotherapies (AABB) to have more objectivity in severity assignment for an adverse donor reaction after blood donation. A study was performed in India to assess the knowledge (post-training) and determine the degree of agreement of the SGT between participating centres and the subject expert group. This prospective cross-sectional survey-based study was conducted by the National Coordinating Centre (NCC) of the National Blood Donor Vigilance Programme (NBDVP) of India. Thirty-five real-world case scenarios, validated by seven national and two international experts, were sent to the participating centres, and their responses received (diagnosis and severity grade) were compared and analysed. A total of 50 blood centres participated in the study. The overall agreement between the participating centres and the expert group was 66.4%, with a fair Kendall's coefficient of concordance (W) of 0.271 (p-value < 0.05). The degree of agreement was observed to be more than 80% for 12 centres, 60%-80% for 27 centres and <60% for 11 centres. The overall degree/percentage of agreement for cases with single and multiple types of donor adverse reaction was 71.3% and 42.6%, respectively. The SGT will be an efficient mode to have uniform objective reporting of the adverse donor reactions and may be implemented in the NBDVP of India. This study also highlights the need for training of the blood centres on the basic definitions and categorization of the donor's adverse reaction.


An optimized approach for the assessment of sexual behavior in male rats.
The improvement and optimization of methods used to detect reproductive disorders in experimental animals are among the main challenges facing researchers in this field. The conventional method for testing male sexual behavior uses ovariectomized females rendered sexually receptive by injection of estradiol benzoate and progesterone prior to testing. The receptive females are then mated with exposed male rats during the dark phase of the cycle under dim red light followed by direct visual and momentary observation of the mating activity. The ovariectomized females may respond differently to hormonal injection (individual differences), leading to variations in the intensity of lordosis. Additionally, the data obtained by the direct visual and momentary evaluation of copulatory activity are very subjective and may produce inaccurate results. In the optimized method, the sexual cycles of female rats are determined, and only those in estrus are selected and mated with sexually experienced male rats. The mating activity is videotaped, enabling the correct observation and evaluation of the different components of mating behavior. This method fosters animal welfare by avoiding surgical intervention and enables the videotape to be kept as permanent documentation.


Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis.
The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown. We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis. In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60%<FVC<90%, mean difference=-222.7, 95% CI -386.3 to -59.2, p=0.004; control vs FVC<60%, mean difference=-301.7, 95% CI of difference -474.1 to -129.34, p=0.0001; FVC>90% vs 60%<FVC<90%, mean difference=-189.6, 95% CI of difference -353.1 to -26.03, p=0.017; FVC>90% vs FVC<60%, mean difference=-268.6, 95% CI of difference -441.0 to -96.17, p=0.0007). Plasma tryptase levels were increased in IPF and negatively correlated with FVC (control vs FVC<60%, mean difference=-17.12, 95% CI of difference -30.02 to -4.22, p=0.006: correlation curves R=-0.045, p=0.025). In a transforming growth factor (TGF)-β1-induced pulmonary fibrosis model, chymase-positive and tryptase-positive mast cells accumulated in fibrotic lung. Lung tissue was decellularised and reseeded with bone marrow or peritoneum-derived mast cells; cells on fibrotic ECM released more TGF-β1 compared with normal ECM (active TGF-β1: bone marrow-derived mast cell (BMMC)-DL vs BMMC-TGF-β1 p=0.0005, peritoneal mast cell (PMC)-DL vs PMC-TGF-β1 p=0.0003, total TGF-β1: BMMC-DL vs BMMC-TGF-β1 p=0.013, PMC-DL vs PMC-TGF-β1 p=0.001). Mechanical stretch of lungs caused mast cell degranulation; mast cell stabilisers inhibited degranulation (histamine: cont vs doxantrazole p=0.004, β-hexosaminidase: cont vs doxantrazole, mean difference=1.007, 95% CI of difference 0.2700 to 1.744, p=0.007) and TGF-β1 activation (pSmad2/Smad2: cont vs dox p=0.006). Cromoglycate attenuated pulmonary fibrosis in rats (collagen: phosphate-buffered saline (PBS) vs cromoglycate p=0.036, fibrotic area: PBS vs cromoglycate p=0.031). This study suggests that mast cells may contribute to the progression of pulmonary fibrosis.


Optical coherence tomography angiography in adult-onset foveomacular vitelliform dystrophy.
To describe structural features of eyes with adult-onset foveomacular vitelliform dystrophy (AFVD) on optical coherence tomography angiography (OCT-A) and to evaluate the ability to detect the presence of choroidal neovascularisation (CNV). Consecutive patients presenting at the University Eye Clinic of Creteil with diagnosis of AFVD were included. All patients underwent a complete ophthalmological examination, including fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography and OCT-A by Optovue RTVue XR Avanti. Twenty-two eyes of 18 consecutive patients (8 women and 10 men; 68±12.8 years) were included. On OCT-A the presence of subretinal material leads to displacement of blood vessels at both the superficial and deep capillary plexuses of the retina. In one case, these vascular abnormalities were associated with long filamentous vessels running thorough the foveal avascular area. In all cases, a rarefaction of the choriocapillaris was also observed. In two eyes OCT-A distinctly disclosed the presence of a CNV secondary to AFVD while conventional imaging did not show clearly the neovascularisation due to masking effect of the subretinal vitelliform material. In patients with AFVD, OCT-A showed vascular network rarefaction with less blood vessels at the superficial and deep capillary plexuses, and the choriocapillaris layer. These vascular abnormalities may play a role in the pathogenesis or simply represent a consequence of material accumulation and reabsorption in AFVD. In two cases, the conventional imaging did not show clearly the neovascularisation due to masking effect of the subretinal vitelliform material, while OCT-A showed distinctly the CNV.


Risk factors and clinical characteristics of tacrolimus-induced acute nephrotoxicity in children with nephrotic syndrome: a retrospective case-control study.
Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS. Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated. Tacrolimus-induced nephrotoxicity occurred in 25 of 129 patients, 13 patients were grade 1, and the renal function was recovered in 22 patients. Multivariate regression analysis showed that the maximum trough concentrations (C12h) of tacrolimus (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001), huaiqihuang granules (OR, 0.095; 95% CI, 0.014 to 0.66; P = 0.017), and diarrhea (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) were independently associated with tacrolimus-induced nephrotoxicity. The maximum C12h were significantly higher in patients with nephrotoxicity (median 9.0 ng/ml) and the cut-off value for acute nephrotoxicity was 6.5 ng/ml. The area under the receiver operating characteristic curve was 0.821 for the proposed model based on the observations used to create the model and 0.817 obtained from k-fold cross-validation. High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.


The relationship between platelet-lymphocyte ratio, neutrophil-lymphocyte ratio, and survival in metastatic gastric cancer on firstline modified docetaxel and cisplatinum plus 5 Fluorourasil Regimen: A single institute experience.
The association between platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and survival with response rates were evaluated in metastatic gastric cancer (MGC). MGC patients on firstline modified docetaxel/cisplatinum/5-fluorourasil [mDCF; docetaxel 60 mg/m2 (days 1-5), cisplatin 60 mg/m2 (day 1), 5FU 600 mg/m2 (days 1-5), q3w] were evaluated retrospectively. The cutoff values were 160 for PLR and 2.5 for NLR. Progression-free survival (PFS) and overall survival (OS) were estimated for group I (PLR >160), group II (PLR ≤ 160), group III (NLR ≥ 2.5), group IV (NLR < 2.5), group V (PLR > 160 and NLR ≥ 2.5), group VI (PLR ≤ 160 and NLR <2.5), and group VII [VIIa (PLR > 160 and NLR < 2.5) and VIIb (PLR ≤160 and NLR ≥ 2.5)]. One hundred and nine MGC patients were evaluated for basal hematological parameters and survival analysis, retrospectively. Most of the patients were male in their fifties with grade III adenocarcinoma (62.9%) and liver metastasis (46.7%). Patients with PLR > 160 and/or NLR ≥ 2.5 had significantly shorter PFS and OS (P = 0.04, 0.01, 0.019, and P = 0.003, 0.002, 0.000, respectively). High PLR (> 160) and/or NLR (≥ 2.5) seem to be poor prognostic factors in MGC.


Kinetic study of the interaction of glutathione with four antitumor disulfides: possible mechanism for cellular glutathione depletion.
The reactions between the cellular tripeptide, glutathione (GSH) and four disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) (compounds 1-4) were studied kinetically. The decyl and phenyl derivatives of 6-MP and 6-TG were reacted with GSH in phosphate buffer (pH 7.4 or 6.0) at 25.0 degrees C and were monitored spectrophotometrically by observing the release of 6-MP and 6-TG. Second order kinetics were observed, with rate constants of 142, 564, 4174 and 429 M-1 s-1 being measured for compounds 1-4, respectively. When the reactions were carried out in the presence of GSH-S-transferase the rates were enhanced 1.3-5.4 times those observed in the absence of enzyme. Products of the reactions were isolated by chromatography and tentatively identified by TLC or fast atom bombardment mass spectrometry. It was observed that GSH reacted with each disulfide in a 1:1 manner, forming a mixed disulfide between GSH and decanethiol or thiophenol while releasing 6-MP or 6-TG. It was concluded that the reported depletion of GSH from EMT6 cells after exposure to these disulfides could be due to their reaction with GSH, and the formation of the mixed disulfides.


Comparison of cynomolgus and rhesus monkey kidney cells for recovery of viruses from clinical specimens.
In a study of virus recovery from clinical specimens, cynomolgus monkey kidney cells demonstrated sensitivity equivalent or slightly superior to rhesus kidney cells for siolation of myxo- and paramyxoviruses, adenoviruses, and enteroviruses.


Disentangling the Role of Biphone Probability From Neighborhood Density in the Perception of Nonwords.
In six experiments we explored how biphone probability and lexical neighborhood density influence listeners' categorization of vowels embedded in nonword sequences. We found independent effects of each. Listeners shifted categorization of a phonetic continuum to create a higher probability sequence, even when neighborhood density was controlled. Similarly, listeners shifted categorization to create a nonword from a denser neighborhood, even when biphone probability was controlled. Next, using a visual world eye-tracking task, we determined that biphone probability information is used rapidly by listeners in perception. In contrast, task complexity and irrelevant variability in the stimuli interfere with neighborhood density effects. These results support a model in which both biphone probability and neighborhood density independently affect word recognition, but only biphone probability effects are observed early in processing.


Naturally cytotoxic tonsillar lymphocytes: a manifestation of heterogeneity among human NK cells.
Lymphocytes isolated from human tonsils are capable of lysing cells of the natural killer (NK)-susceptible line K562. Although weak compared with that of autochthonous peripheral lymphocytes, cytotoxicity is invariably manifest at high effector-to-target ratios. Like peripheral NK cells, tonsillar cytotoxic lymphocytes possess a low buoyant density, which makes possible their partial enrichment from non-cytotoxic cells by centrifugation on discontinuous Percoll gradients. However, examination of cytotoxic fractions indicates that, unlike blood lymphocyte-mediated cytotoxicity, effector function is not associated with the presence of large granular lymphocytes. Furthermore, a functional distinction from classical NK cells is apparent since, although tonsillar cytotoxicity is significantly enhanced after exposure to supernatants from polyclonally activated allogeneic tonsils, pretreatment with lymphoblastoid (Namalva) interferon (IFN-alpha) at doses shown to potentiate maximally the cytotoxicity of peripheral blood lymphocytes fails to influence reactivity. These data provide preliminary evidence for the existence of, at least limited, heterogeneity among human NK cells.


Amesuviridae: a new family of plant-infecting viruses in the phylum Cressdnaviricota, realm Monodnaviria.
The phylum Cressdnaviricota comprises viruses with single-stranded, circular DNA genomes that encode an HUH-type endonuclease (known as Rep). The phylum includes two classes, eight orders, and 11 families. Here, we report the creation of a twelfth family in the order Mulpavirales, class Arfiviricetes of the phylum Cressdnaviricota. The family Amesuviridae comprises viruses that infect plants and is divided into two genera: Temfrudevirus, including the species Temfrudevirus temperatum (with temperate fruit decay-associated virus as a member), and Yermavirus, including the species Yermavirus ilicis (with yerba mate-associated circular DNA virus as a member). Both viruses encode Rep proteins with HUH endonuclease and SH3 superfamily helicase domains. Phylogenetic analysis indicates that the replicative module of amesuviruses constitutes a well-supported monophyletic clade related to Rep proteins from viruses in the order Mulpavirales. Furthermore, both viruses encode a single capsid protein (CP) related to geminivirus CPs. Phylogenetic incongruence between the replicative and structural modules of amesuviruses suggests a chimeric origin resulting from remote recombination events between ancestral mulpavirales and geminivirids. The creation of the family Amesuviridae has been ratified by the International Committee on Taxonomy of Viruses (ICTV).


In vitro and in vivo chloroquine-potentiating action of Strychnos myrtoides alkaloids against chloroquine-resistant strains of Plasmodium malaria.
Crude alkaloids of Strychnos myrtoides Gilg & Busse, empirically used as an adjuvant to chloroquine (CQ) in Malagasy herbal remedies, were practically devoid of intrinsic in vitro and in vivo antimalarial activity. However, when combined with CQ at a dose level much lower than their IC50 value, they markedly enhanced in vitro the effectiveness of the synthetic drug against a CQ-resistant strain of Plasmodium falciparum. They also enhanced in vivo CQ activity against a resistant strain of Plasmodium yoelii. By counter-current distribution (CCD) separation of the crude alkaloid extract, the two major alkaloids strychnobrasiline (1) and malagashanine (2), together with four minor alkaloids, were isolated. Strychnobrasiline and malagashanine were devoid of both intrinsic antimalarial activity and cytotoxicity effect, but exhibited significant CQ-potentiating actions. These findings could account for the above-mentioned empirical use of S. myrtoides. The present state of research on antimalarial drug from Strychnos genus is also discussed.


Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy.
Molecular oxygen (O2) is a universal electron acceptor that is eventually synthesized into ATP in the mitochondrial respiratory chain of all metazoans. Therefore, hypoxia biology has become an organizational principle of cell evolution, metabolism and pathology. Hypoxia-inducible factor (HIF) mediates tumour cells to produce a series of glucose metabolism adaptations including the regulation of glucose catabolism, glycogen metabolism and the biological oxidation of glucose to hypoxia. Since HIF can regulate the energy metabolism of cancer cells and promote the survival of cancer cells, targeting HIF or HIF mediated metabolic enzymes may become one of the potential treatment methods for cancer. In this review, we summarize the established and recently discovered autonomous molecular mechanisms that can induce cell reprogramming of hypoxic glucose metabolism in tumors and explore opportunities for targeted therapy.


Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy.
Hybrid drug delivery system containing both organic and inorganic nanocarriers is expected to achieve its complementary advantages for the aim of improving the performance of antineoplastic drugs in tumor therapy. Here we report the use of liposomes and gold nanoparticles to construct a liposome with a hybrid Cluster Bomb structure and discuss its unique multi-order drug release property for liver tumor treatment. A very simple method is used for the hybrid liposome preparation and involves mixing two solutions containing liposomes loaded with either non-covalent or covalent Paclitaxel (PTX, namely free PTX or PTX-conjugated GNPs, respectively) by different ratio of volume (25:75, 50:50, 25:75, v/v). Various mixed liposomes were tested to determine the optimal conditions for maximum drug delivery. The optimized liposome was then tested using xenograft Heps tumor-bearing mice and showed the best efficacy for chemotherapeutic inhibition of tumor at PTX liposome: PTX-conjugated GNP liposome of 25:75 ratio (v/v). This system allows for simple and easy preparation while providing a more accurate site- and time-release mode for tumor treatment using antitumor drugs.


The influence of a right-to-left cardiac shunt on lidocaine pharmacokinetics.
The pharmacokinetics of lidocaine were studied in 1-2-month-old lambs with surgically created, intracardiac right-to-left shunts (RLS) and in age-matched control lambs. Shunts were prepared by anastomosing the pulmonary artery to the left atrial appendage to achieve arterial oxygen saturation of 65-75%. Catheters were implanted both in the right atrium for drug infusion and in the ascending aorta for blood sampling. Lidocaine, 1 mg/kg, injected as a rapid bolus, or 12 mg/kg, injected as a continuous infusion over 15 min, was delivered into the right atrium. Serial samples of arterial blood were obtained every 2.5 s for 1 min following the bolus injection and up to 4 h following the continuous infusion. Samples were analyzed for lidocaine by gas chromatography. Peak arterial whole blood concentration of lidocaine in the shunted animals was 37.0 +/- 2.1 micrograms/ml compared to 21.1 +/- 0.1 microgram/ml in the control animals; P less than .01. The peak arterial concentrations during the lidocaine infusion were 12.6 +/- 3.5 micrograms/ml in the RLS and 5.8 +/- 1.5 micrograms/ml in the controls. Total body clearance of lidocaine was decreased in the shunted animals to 30.7 +/- 13.2 ml.kg-1.min-1 from 68.1 +/- 12.1 ml.kg-1.min-1 in the control animals; P less than .001. The steady-state volume of distribution was also decreased in the shunted animals, 1.0 +/- 0.2 l/kg versus 2.0 +/- 0.7 l/kg in the controls; P less than .02. To induce convulsions 4.75 +/- 0.46 mg/kg of lidocaine was required in the shunted animals and 7.37 +/- 0.44 mg/kg in the control animals (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of the acrosome reaction of sea urchin spermatozoa by a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7).
A calmodulin antagonist, W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide), inhibited induction of the acrosome reaction of sea urchin spermatozoa by egg jelly at 20-50 microM, but W-5 did not. The latter, a chlorine-deficient derivative of W-7, has a lower affinity for calmodulin than does W-7. These results suggest that a Ca2+-calmodulin-dependent process plays an important role in the triggering process of the acrosome reaction of sea urchin spermatozoa.


In vitro study on the effect of Saccharomyces cerevisiae strains on growth and mycotoxin production by Aspergillus carbonarius and Fusarium graminearum.
The effect of Saccharomyces cerevisiae RC008 and RC016 strains, previously selected based on their aflatoxin B₁ mycotoxin binding ability and beneficial properties, against Aspergillus carbonarius and Fusarium graminearum under different interacting environmental conditions was evaluated. In vitro studies on the lag phase, growth rate and ochratoxin A/zearalenone and DON production were carried out under different regimens of a(w) (0.95 and 0.99); pH (4 and 6); temperature (25 and 37 °C) and oxygen availability (normal and reduced). Both yeast strains showed antagonistic activity and decreasing growth rate compared to the control. In general, the RC016 strain showed the greatest inhibitory activity. Except at the interacting condition 0.95 a(W), normal oxygen availability and 37 °C, at both pH values, A. carbonarius and F. graminearum were able to produce large amounts of mycotoxins in vitro. In general, a significant decrease in levels of mycotoxins in comparison with the control was observed. S. cerevisiae RC008 and RC016 could be considered as effective agents to reduce growth and OTA, ZEA and DON production at different interacting environmental conditions, related to those found in stored feedstuff. The beneficial and biocontrol properties of these strains are important in their use as novel additives for the control of mycotoxigenic fungi in stored feedstuffs.


Comparison of five major airflow limitation criteria to identify high-risk individuals with COPD: a contemporary population-based cohort.
Different airflow limitation criteria are often used to diagnose COPD. We investigated head-to-head whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) (FEV1/FVC <0.70) and four lower limit of normal (LLN) (FEV1/FVC <LLN) criteria to diagnose airflow limitation differ in identifying individuals at risk of COPD exacerbations and mortality. 108 246 individuals aged 20-100 years randomly selected from the general population were followed from 2003 through 2018 to determine risk of COPD exacerbations, respiratory mortality and all-cause mortality. LLN criteria used equations from Global Lung Initiative (GLI), National Health and Nutrition Examination Survey (NHANES), European Community for Steel and Coal (ECSC) and Copenhagen City Heart Study (CCHS)/Copenhagen General Population Study (CGPS). Prevalence of airflow limitation was 17% for GOLD, 8.6% for GLI, 10% for NHANES, 8.2% for ECSC and 14% for CCHS/CGPS. During 14.4 years follow-up, we observed 2745 COPD exacerbations, 762 respiratory deaths and 10 338 all-cause deaths. Comparing individuals with versus without airflow limitation, HRs for COPD exacerbations were 17 (95% CI 14 to 20) for GOLD, 21 (18 to 24) for GLI, 20 (17 to 23) for NHANES, 21 (18 to 24) for ECSC and 18 (16 to 21) for CCHS/CGPS. Corresponding HRs for respiratory mortality were 3.7 (3.1 to 4.3), 6.4 (5.6 to 7.5), 5.7 (4.9 to 6.6), 6.2 (5.3 to 7.2) and 4.5 (3.9 to 5.2), and for all-cause mortality 1.5 (1.4 to 1.5), 1.9 (1.8 to 2.0), 1.8 (1.7 to 1.9), 1.9 (1.8 to 2.0) and 1.7 (1.6 to 1.7), respectively. Differences in Harrell's C were minute for these outcomes; nonetheless, Harrell's C was slightly higher for LLN criteria compared with GOLD for mortality outcomes. The prevalence of airflow limitation ranged from 8% to 17% using GOLD and four different LLN criteria; however, identified individuals with the five different criteria had similar risk of COPD exacerbations and mortality.


Regulation of htrA expression in Yersinia enterocolitica.
In Escherichia coli, envelope stress is regulated by the alternative sigma factor sigma(E) and the two-component regulatory system CpxRA. Both systems overlap in the transcriptional regulation of the htrA gene encoding a protease that degrades misfolded proteins in the periplasm. In Yersinia enterocolitica, HtrA is important for intracellular survival and full virulence in animal models. Here we show that regulation of htrA expression in Y. enterocolitica is dependent on CpxR and putatively also on RpoE. However, the stimuli inducing both systems were different from E. coli. Most strikingly, we found that overproduction of an outer membrane protein, a typical stimulus for the induction of htrA expression via RpoE in E. coli, led to the induction of htrA expression via the Cpx system in Y. enterocolitica. Interestingly, a Y. enterocolitica CpxR mutant strain was not impaired for virulence in a mouse model of infection.


The alkynylphosphonate analogue of calcitriol EM1 has potent anti-metastatic effects in breast cancer.
The active form of vitamin D3, calcitriol, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and prodifferentiating agent. However, when effective antitumor doses of calcitriol are employed, hypercalcemic effects are observed, thus precluding its therapeutic application. To overcome this problem, structural analogues have been designed with the aim at retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report shows the biological evaluation of an alkynylphosphonate vitamin D less-calcemic analogue in a murine model of breast cancer. We demonstrate that this compound has potent anti-metastatic effects through its action over cellular migration and invasion likely mediated through the up-regulation of E-cadherin expression. Based on the current in vitro and in vivo results, EM1 is a promising candidate as a therapeutic agent in breast cancer.


(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial.
We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.


Delayed esophageal reconstruction for aortoesophageal fistula caused by an aortic arch aneurysm with microvascular anastomosis of the left gastric artery and vein.
We report a case of aorto esophageal fistula (AEF) with delayed esophageal reconstruction employing microvascular anastomosis. We demonstrate here that our method is useful for delayed esophageal reconstruction following AEF.


Testing and estimating the non-disjunction fraction in Meiosis I using reference priors.
In this paper we analyze the fraction of non-disjunction in Meiosis I assuming reference (non-informative) priors. We consider Jeffreys's approach to built a non-informative prior (Jeffreys's prior) for the fraction of non-disjunction in Meiosis I. We prove that Jeffreys's prior is a proper distribution. We perform Monte Carlo studies in order to compare Bayes estimates obtained assuming Jeffreys's and uniform priors. We consider full Bayesian significance test (FBST) and Bayes factor (BF) for testing precise hypothesis on the fraction of non-disjunction in Meiosis I. The ultimate goal of this paper is to compare these two test procedures through simulation studies using both prior specifications. An application to Down Syndrome data is also presented.


Dilated cardiomyopathy and left bundle branch block associated with ingestion of colloidal gold and silver is reversed by British antiLewisite and vitamin E: the potential toxicity of metals used as health supplements.
A case of left bundle branch block and a dilated, nonhypertrophic cardiomyopathy associated with ingestion of colloidal gold and silver as an 'energy tonic' is described. The cardiac disease was reversed within two months by a course of dimercaprol (Akorn Inc, USA) (British antiLewisite) and vitamin E. This is the first case of gold and silver cardiomyopathy in humans, and highlights the risks of these colloidal metal 'health supplements'.


Biodistribution and Pharmacokinetic Study of 3,3' Diseleno Dipropionic Acid (DSePA), A Synthetic Radioprotector, in Mice.
3,3' Diseleno dipropionic acid (DSePA), a synthetic compound has been shown to have radioprotective activity, especially as a lung radioprotector. In this study, the pharmacokinetics and biodistribution of DSePA in MX-1 tumour bearing SCID mice were evaluated. Twenty SCID mice were administered DSePA (50 mg/kg bodyweight) by oral gavage following which four animals each were sacrificed at 15, 30 min, 1, 2 and 4 h. Blood and tissue samples were collected for determination of DSePA concentration by graphite furnace atomic absorption spectrometry (GFAAS) method. The control group (n = 4) was administered sterile water and sacrificed at 4 h. Peak plasma concentration (C max) of 2.7 µg/ml was observed at 15 min which returned to near baseline (baseline = 0.6 µg/ml) at 1 h following drug administration. Biphasic pharmacokinetics characterized by rapid distribution phase and a slower elimination phase were observed. Highest maximal concentration (C max) of the drug was observed in lung (19.2 µg/g at 30 min) followed by intestine (14.64 µg/g at 15 min) and kidney (12.96 µg/g at 15 min). There was negligible uptake in tumor tissue and no uptake in brain. DSePA has a favorable pharmacokinetic profile which makes it a potentially good candidate for further development as a radioprotective agent.


Comorbidity in head and neck cancer: a critical appraisal and recommendations for practice.
Comorbidity, the presence of additional illnesses unrelated to the tumor, has a significant impact on the prognosis of patients with head and neck cancer. In these patients, tobacco and alcohol abuse contributes greatly to comorbidity. Several instruments have been used to quantify comorbidity including Adult Comorbidity Evaluation 27 (ACE 27), Charlson Index (CI) and Cumulative Illness Rating Scale. The ACE 27 and CI are the most frequently used indices. Information on comorbidity at the time of diagnosis can be abstracted from patient records. Self-reporting is less reliable than record review. Functional status is not a reliable substitute for comorbidity evaluation as a prognostic measure. Severity as well as the presence of a condition is required for a good predictive instrument. Comorbidity increases mortality in patients with head and neck cancer, and this effect is greater in the early years following treatment. In addition to reducing overall survival, many studies have shown that comorbidity influences disease-specific survival negatively, most likely because patients with high comorbidity tend to have delay in diagnosis, often presenting with advanced stage tumors, and the comorbidity may also prompt less aggressive treatment. The impact of comorbidity on survival is greater in younger than in older patients, although it affects both. For specific tumor sites, comorbidity has been shown to negatively influence prognosis in oral, oropharyngeal, laryngeal and salivary gland tumors. Several studies have reported higher incidence and increased severity of treatment complications in patients with high comorbidity burden. Studies have demonstrated a negative impact of comorbidity on quality of life, and increased cost of treatment with higher degree of comorbidity. Our review of the literature suggests that routine collection of comorbidity data will be important in the analysis of survival, quality of life and functional outcomes after treatment as comorbidity has an impact on all of the above. These data should be integrated with tumor-specific staging systems in order to develop better instruments for prognostication, as well as comparing results of different treatment regimens and institutions.


1,2,4-benzothiadiazine linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity.
Benzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These new classes of hybrid molecules exhibit cytotoxicity against many cancer cell lines. Their DNA thermal denaturation studies have been carried out and one of the compounds (4b) elevates the DNA helix melting temperature of the CT-DNA by 6.7 degrees C after incubation for 36 h.


Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development.
Rituximab (MabThera®/Rituxan®), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab's benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue. F. Hoffmann-La Roche Ltd.


High-Resolution Neurovascular Imaging at 7T: Arterial Spin Labeling Perfusion, 4-Dimensional MR Angiography, and Black Blood MR Imaging.
Ultrahigh field offers increased resolution and contrast for neurovascular imaging. Arterial spin labeling methods benefit from an increased intrinsic signal-to-noise ratio of MR imaging signal and a prolonged tracer half-life at ultrahigh field, allowing the visualization of layer-dependent microvascular perfusion. Arterial spin labeling-based time-resolved 4-dimensional MR angiography at 7T provides a detailed depiction of the vascular architecture and dynamic blood flow pattern with high spatial and temporal resolutions. High-resolution black blood MR imaging at 7T allows detailed characterization of small perforating arteries such as lenticulostriate arteries. All techniques benefit from advances in parallel radiofrequency transmission technologies at ultrahigh field.


Feasibility of quantitative MR-perfusion imaging to monitor treatment response after uterine artery embolization (UAE) in symptomatic uterus fibroids.
In 25% of women, symptomatic uterus myomas are diagnosed with clinical and functional impairment ranging from abdominal and pelvic pain to dys- and hypermenorrhea, dyspareunia, pollakiuria and infertility. Women undergoing a treatment increasingly prefer nowadays minimal invasive, uterus preserving therapies like uterine artery embolization (UAE) over surgical hysterectomy, nowadays. To emphasize the efficacy of UAE as a uterus preserving treatment with targeted therapy of myomas only, analysis of tissue perfusion pre and post embolization is required. The purpose of this study was to assess treatment response in UAE in females with symptomatic uterus myomas by quantitative magnetic resonance perfusion imaging. Seven females scheduled for uterus myoma embolization underwent three MRI examinations (pre, post, follow-up) including morphological and dynamic contrast enhanced perfusion imaging at 3 T. To measure tumor volume, regions-of-interest covering the tumor and the uterus were drawn by two readers in consensus. Blood flow, blood volume, and mean transit time were calculated by a pixel-by-pixel deconvolution approach. Kruskal-Wallis/Friedman test was employed to test whether the group medians differ significantly with correction for multiple comparisons using Bonferroni method. Change of volume could be observed in all patients after embolization but was significantly different only between pre/post and follow-up time point. Measured differences in all perfusion parameters were significant between pre-intervention and post-intervention/follow-up in the myomas, no significant differences could be detected for the uterus tissue. Our results demonstrate devascularization of symptomatic myomas which correlates with cessation of hypermenorrhea in all treated patients without affecting healthy uterus tissue. Supplementing UAE with perfusion imaging to monitor early treatment response is feasible and might provide valuable information for the follow-up of patients and contribute to providing confidence for the patients in treatment success.


Towards continuous mAb purification: Clearance of host cell proteins from CHO cell culture harvests via "flow-through affinity chromatography" using peptide-based adsorbents.
The growth of advanced analytics in manufacturing monoclonal antibodies (mAbs) has highlighted the challenges associated with the clearance of host cell proteins (HCPs). Of special concern is the removal of "persistent" HCPs, including immunogenic and mAb-degrading proteins, that co-elute from the Protein A resin and can escape the polishing steps. Responding to this challenge, we introduced an ensemble of peptide ligands that target the HCPs in Chinese hamster ovary (CHO) cell culture fluids and enable mAb purification via flow-through affinity chromatography. This study describes their integration into LigaGuard™, an affinity adsorbent featuring an equilibrium binding capacity of ~30 mg of HCPs per mL of resin as well as dynamic capacities up to 16 and 22 mg/ml at 1- and 2-min residence times, respectively. When evaluated against cell culture harvests with different mAb and HCP titers and properties, LigaGuard™ afforded high HCP clearance, with logarithmic removal values (LRVs) up to 1.5, and mAb yield above 90%. Proteomic analysis of the effluents confirmed the removal of high-risk HCPs, including cathepsins, histones, glutathione-S transferase, and lipoprotein lipases. Finally, combining LigaGuard™ for HCP removal with affinity adsorbents for product capture afforded a global mAb yield of 85%, and HCP and DNA LRVs > 4.


Further errors in polymorph identification: furosemide and finasteride.
Reassessment of the reported single-crystal X-ray diffraction characterization of polymorphs of furosemide and finasteride shows that, in each case, incomplete data collections have resulted in the mistaken identification of two forms that are, in fact, identical.


The burden of influenza in healthy children in South Australia.
To describe the influenza-related morbidity and mortality in healthy children aged under 5 years in South Australia, in order to further understand the potential role of influenza vaccination. We undertook a descriptive analysis of SA hospital separations data and Australian Bureau of Statistics death data for children aged under 5 years admitted to hospital for influenza. All diagnoses related to an influenza admission were examined to determine whether children were at risk of complications from influenza, according to the criteria of the National Health and Medical Research Council. Mean influenza admission rates per 100 000 population per year in children aged under 5 years between 1996 and 2006, and the proportion of children admitted to hospital who did not have a secondary diagnosis putting them at higher risk of influenza-related complications. From 1996 to 2006, 649 children aged under 5 years were admitted to hospital for influenza. Mean annual admission rates per 100 000 were highest in children aged under 1 year (151.0), and decreased with age. Aboriginal and Torres Strait Islander children aged under 5 years had a mean admission rate of 161.8 per 100 000. Most children under 5 years (81%) admitted to hospital did not have an underlying illness that would put them at risk of influenza-related morbidity. Healthy children aged under 2 years and Aboriginal and Torres Strait Islander children under 5 years old have high rates of hospital admission, which may have implications for the target group recommendations for influenza immunisation. Currently, vaccination is recommended only for children with specified chronic diseases.


Analytical methodologies for the determination of cisplatin.
cis-Diamminedichloroplatinum(II) (cisplatin) is a important chemotherapeutic drug for cancer treatment since 1978. Unfortunately, because of the severe side-effects like nephrotoxicity, ototoxicity, etc., they are administered in small doses at low concentration establishing the maximum limit dosage to 100 mg/m(2) (21 days). A variety of analytical methods have been proposed for the determination of cisplatin in biological fluids and tissues that permit the accurate determination at or below the part per billion level in the native sample. The purpose of the current review is to provide a systematic survey of the latest analytical techniques for the determination of cisplatin in biological samples.


Interleukin (IL)-31 activates signal transducer and activator of transcription (STAT)-1, STAT-5 and extracellular signal-regulated kinase 1/2 and down-regulates IL-12p40 production in activated human macrophages.
Interleukin-31 is a cytokine expressed by activated T cells. A major function of IL-31 in atopic dermatitis (AD) is the induction of pruritus in the skin. We recently showed that IL-31 induces pro-inflammatory cytokines following staphylococcal exotoxins' stimulation in human macrophages. However, signalling pathways of IL-31 in activated human macrophages still remain unclear. The aim of the study was to investigate the signalling pathways of IL-31 receptor as well as functional effects of IL-31 in activated macrophages. Human macrophages were prestimulated with staphylococcal exotoxins (SEB, α-toxin) to up-regulate the IL-31 receptor with and without IL-31. Phospho-signal transducer and activator of transcription (pSTAT) 1/3/5, phospho-extracellular signal-regulated kinase (ERK 1/2), β-actin as well as p21/WAF/Cip1 levels were determined by means of Western blot analysis. Interleukin-12p40, IL-12p70 and IL-23 secretions were assessed by using an enzyme-linked immunosorbent assay. Interleukin-31 strongly activated STAT-1 and 5 but not STAT-3 in human macrophages after up-regulation of IL-31 receptor with staphylococcal exotoxins. p21/WAF/Cip1 expression was induced by IL-31 in activated human macrophages. Furthermore, IL-31 down-regulated. IL-12p40 secretion via ERK 1/2 phosphorylation in human macrophages following up-regulation of IL-31 receptor with staphylococcal exotoxins. The T helper (Th) 2 cytokine IL-31 induces pro-inflammatory effects in activated human macrophages via STAT-1 and 5 phosphorylation. Interleukin-31-induced ERK 1/2 activation contributes to the underlying mechanism of Th1 cytokine IL-12 suppression in macrophages. This mechanism may be relevant in Th2 inflammatory responses and may help to develop therapeutic strategies in IL-31-associated diseases such as AD.


Heat stroke. Report of three fatal cases with emphasis on findings in skeletal muscle.
Three fatal cases of heat stroke were encountered in the central New York area over a two-month period. Although in each instance one or more predisposing factors were identified, exertion clearly played a role in its development in only one case. In addition to laboratory and postmortem findings indicative of dysfunction of many organ systems, there was morphological evidence of widespread damage to skeletal muscle.


Measurement of neuromuscular blockade in man. A simple modification of a clinical pressure transducer.
A simple modification of a clinical blood pressure transducer is described, which permits it to be used for the quantitative estimation of neuromuscular blockade in man. The instrument remains available for other pressure measurements since only the plastic dome is modified.


Metallic ions as negative modifiers of cholinesterase.
Copper and Zinc have been found to be potent inhibitors of pseudo-cholinesterase of human plasma and true-cholinesterase of erythrocytes and rat brain.


Blood dyscrasias and topically applied chloramphenicol in ophthalmology.
The case reports presented so far, concerning a possible causative relationship between the ophthalmological use of chloramphenicol (O-CAP) and blood dyscrasias, are few in number, not always fully documented and therefore not always convincing. The overall use of this drug in a restricted area in the Netherlands was assessed. On a yearly basis 1:29 people used O-CAP. In a four-year period in the same area, 12 patients with aplastic anemia and 190 patients with other cytopenic dyscrasias were found. After exclusion of all cases with other possible causes of the dyscrasia, e.g. cancer and related therapy, other drugs than O-CAP and infectious diseases, 59 cases remained in which a definite cause could not be established. We traced back the use of O-CAP in the relevant period. No dyscrasias were found that unequivocally were caused by O-CAP. The rate of O-CAP use in the dyscrasia-group was approximately equal to that in the population as a whole. Hence we concluded that it is highly improbable that O-CAP played a part in the etiology of blood dyscrasias in the region. Statistical evaluation of material derived from a much larger region may, however, lead to a more differentiated conclusion.


Serum concentrations of two endometrial proteins are not useful for monitoring postmenopausal estrogen/progesterone therapy.
Measurements of the serum concentrations of the endometrial proteins IGFBP-1 and PP14 were made in an attempt to monitor the adequacy of the P effect in women receiving 1 year of 100 to 200 micrograms of percutaneous E2 for 28 days each month and 10 mg oral MPA given during the last 12 days of E2 administration. There were no significant changes in IGFBP-1 levels; a small, but significant increase in PP14 levels after E2 plus MPA was noted, but there was substantial overlap between basal and postprogestogen therapy serum PP14 concentrations. Serum concentrations of PP14, but not IGFBP-1, were slightly higher in women whose endometrial biopsies demonstrated a P effect, but again, there was substantial overlap with the values found in women whose biopsies showed only an estrogen effect. Serum measurements of IGFBP-1 and PP14 are not useful for monitoring postmenopausal replacement therapy with percutaneous E2 and oral MPA.


Extracorporeal shock wave lithotripsy and its effect on renal function.
Extracorporeal shock wave lithotripsy has become a major treatment modality for symptomatic upper tract renal stone disease. Although proved to be effective in disintegrating stones the short-term and long-term effects on renal function are not yet known. We evaluated several basic physiological parameters, namely creatinine clearance, fractional sodium excretion, protein excretion and urine osmolality before and after extracorporeal shock wave lithotripsy in 26 consecutive patients in an attempt to quantitate changes in renal function. In addition, a 3 to 6-month followup study of patients showing excessive protein excretion with extracorporeal shock wave lithotripsy also is reported. Our data suggest that with extracorporeal shock wave lithotripsy transient nephrotic range proteinuria occurs immediately after treatment, returning to normal values within 3 to 6 months after treatment without a change in the glomerular filtration rate. The glomerular filtration rate increases after successful extracorporeal shock wave lithotripsy in patients with kidneys obstructed by the treated stone before the start of the procedure, and the kidney appears to maintain its ability to dilute urine and to conserve sodium after treatment.


End posture selection in manual positioning: evidence for feedforward modeling based on a movement choice method.
Although it is well known that the postures adopted at the ends of movements depend on where one starts and how one moves, it is not yet clear whether those differing end postures are selected before movements begin. Two experiments were designed to test the hypothesis that end postures for positioning movements are chosen before movements commence. The experiments were further designed to check whether movements are internally simulated before overt movements occur and end-postures are still being selected. To address these questions we used a movement choice method. Participants were presented with two possible end postures and were asked to choose between them by moving to the one that seemed easier to adopt. End-posture choices were affected by starting positions and also by the movements that would have to be made, as affected by having obstacles in the way. The results suggest that participants relied on feedforward modeling of prospective movements as they selected end postures prior to overt movement production. The fact that the movement choice method could confirm this suggests that the method holds considerable promise as a tool for investigating motor planning.


From Interferon to Checkpoint Inhibition Therapy-A Systematic Review of New Immune-Modulating Agents in Bacillus Calmette-Guérin (BCG) Refractory Non-Muscle-Invasive Bladder Cancer (NMIBC).
In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the gold standard. The advent of immune checkpoint inhibitors (CPIs) has permanently changed the therapy landscape of bladder cancer (BC). This article presents a systematic review of immune-modulating (IM) therapies (CPIs and others) in BCG-refractory NMIBC. In total, 406 articles were identified through data bank research in PubMed/Medline, with data cutoff in October 2021. Four full-text articles and four additional congress abstracts were included in the review. Durvalumab plus Oportuzumab monatox, Pembrolizumab, and Nadofaragene firadenovec (NF) show complete response (CR) rates of 41.6%, 40.6%, and 59.6% after 3 months, with a long-lasting effect, especially for NF (12-month CR rate of 30.5%). Instillations with oncolytic viruses such as NF and CG0070 show good efficacy without triggering significant immune-mediated systemic adverse events. Recombinant BCG VPM1002BC could prove to be valid as an alternative to BCG in the future. The recombinant pox-viral vector vaccine PANVAC™ is not convincing in combination with BCG. Interleukin mediating therapies, such as ALT-803, are currently being studied. CPIs and other IM agents now offer an increasing opportunity for bladder-preserving strategies. Studies on different substances are ongoing and will yield new findings.


Retracted: Evolutionary Analysis of Supply Chain Integration Strategy on Chinese Steel-Producing Firms considering Policy Risk Cost Factor.
[This retracts the article DOI: 10.1155/2022/1136601.].


[Indications, value and limitations of azygos-portal disconnection in the treatment of esophageal varices].
Satisfactory results obtained, lasting for years in some cases, following azygos-portal disconnection in selected patients with bleeding oesophageal varices, portal hypertension, splenopathy and gastroduodenal ulcer are referred to. It is suggested that wider use should be made of this technique, particularly in patients in poor condition, because the long-term picture does not include the hyperammoniaemic encephalopathy often associated with extensive portosystemic shunts.


[Intraoperative MRI and epilepsy surgery].
Intraoperative imaging, in particular intraoperative MRI, is a developing area in neurosurgery and its role is currently being evaluated. Its role in epilepsy surgery has not been defined yet and its use has been limited. In our experience with a compact and mobile low-field intraoperative MRI system, a few epilepsy surgeries have been performed using this technique. As the integration of imaging and functional data plays an important role in the planning of epilepsy surgery, intraoperative verification of the surgical result may be highly valuable. Therefore, teams that have access to intraoperative MRI should be encouraged to use this technique prospectively to evaluate its current relevance in epilepsy surgery.


Increased ICP without ventriculomegaly. Diagnostic and therapeutic problems in a 1-year-old boy.
The case of a 1-year-old boy with pseudotumor cerebri is reported. After the diagnosis had been made, an epidural pressure transducer was implanted. Correlation calculation of the pulse amplitudes and the systolic ICP and Fourier analysis of the ICP modulations were performed. The ICP data reached values up to 50 mmHg and the mathematical calculations provided information on the reduced intracranial compliance. After the implantation of a ventriculoperitoneal shunt, all parameters normalized.


Use of model organisms for the study of neuronal ceroid lipofuscinosis.
Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.


Force during stretch and shortening of frog sartorius muscle: effects of intracellular acidification due to increased carbon dioxide.
The force-velocity relation of frog sartorius muscle was observed during slow stretch and during shortening in solutions with and without CO2 at extracellular pH (pHo) 6.9 and pHo 7.5 (5 degrees C). Less force was produced with CO2 than without CO2 during stretch, during shortening, and under isometric conditions. Compared with pHo 7.5, the effects were greater at pHo 6.9, where the concentration of CO2, a permeant acid, was greater and would cause a greater acidification of intracellular pH (pHi). The reduction of force caused by CO2 was smaller during stretch than during shortening or isometric contraction. This result indicates that the crossbridge states specific to stretch retain their ability to produce force better under acidic conditions than those characteristic of shortening and isometric conditions. This difference between stretch and shortening suggests that there may be compensating changes in the pattern of motor unit activity during fatigue in vivo.


Automated measurement of noise violations in the therapeutic workplace.
The present analysis was conducted to validate an automated measurement system of noise violations by participants in the therapeutic workplace, which is a model workplace that offers paid employment and vocational training programs to illicit drug users. We collected data on dB levels via an electronic dB meter in a computer classroom with many different sound sources, and defined noise violations as sounds exceeding 55 dB. Human observers recorded whether staff or participants were responsible for violations, the types of events that resulted in violations, and whether these events were a result of participant behavior. Our analyses revealed that participants caused the majority of noise violations. These results suggest that the automated measurement system collects valid data on participant behavior that contributes to noise violations. Our results also suggest that these behaviors can in principle be modified to reduce the frequency of noise violations. Suggestions for replication in other settings and interventions designed to reduce behaviors leading to noise violations involving feedback and incentives are discussed.


Future projections for Mexican faunas under global climate change scenarios.
Global climates are changing rapidly, with unexpected consequences. Because elements of biodiversity respond intimately to climate as an important driving force of distributional limitation, distributional shifts and biodiversity losses are expected. Nevertheless, in spite of modelling efforts focused on single species or entire ecosystems, a few preliminary surveys of fauna-wide effects, and evidence of climate change-mediated shifts in several species, the likely effects of climate change on species' distributions remain little known, and fauna-wide or community-level effects are almost completely unexplored. Here, using a genetic algorithm and museum specimen occurrence data, we develop ecological niche models for 1,870 species occurring in Mexico and project them onto two climate surfaces modelled for 2055. Although extinctions and drastic range reductions are predicted to be relatively few, species turnover in some local communities is predicted to be high (>40% of species), suggesting that severe ecological perturbations may result.


Pistachio hull polysaccharide protects Nile tilapia against LPS-induced excessive inflammatory responses and oxidative stress, possibly via TLR2 and Nrf2 signaling pathways.
Polysaccharides are polymeric carbohydrates found in living organisms, which have several physiological functions. In the present study, Nile tilapia (Oreochromis niloticus) were fed diets containing three levels (0%, 0.2%, and 0.6%) of Pistacia vera hull polysaccharide (PHP) for 45 days and then injected with PBS or bacterial lipopolysaccharide (LPS). Before the LPS challenge, Nile tilapia fed 0.2% and 0.6% PHP showed significantly increased mean final weight and weight gain compared to those received 0% PHP. The specific growth rate and feed conversion ratio were significantly improved in the treatment fed 0.6% PHP compared to the remaining groups. After LPS challenge, the activities of liver antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase exhibited the highest values in the 0.6% PHP group. Malondialdehyde (MDA) levels were significantly augmented in the model (fed 0% PHP diet and injected with LPS) and 0.2% PHP groups compared to the control. However, MDA showed decreased levels in the 0.6% PHP group. LPS induced higher mRNA and/or protein levels of Toll-like receptor 2 (TLR2), nuclear factor kappa B (NF-κB), myeloid differentiation primary response protein 88 (Myd88), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ) in Nile tilapia liver. However, PHP administration significantly upregulated the expression of interleukin 10 (IL-10), nuclear erythroid 2-related factor 2 (Nrf2), SOD, and CAT, but markedly suppressed TLR2, NF-κB, Myd88, and pro-inflammatory cytokine expression and/or production in the liver. The findings of the current study indicated that PHP has positive effects on growth performance, immune gene-related expression, and antioxidative activities. We can conclude that PHP can attenuate LPS-induced oxidative stress and inflammatory responses in vivo, possibly via induction of Nrf2 and blockade of TLR2/Myd88/NF-κB pathways in Nile tilapia.


Short- and long-term effects of L-dopa administration on striatal acetylcholinesterase activity.
Exogenously applied dopamine may interfere with cholinergic activity in the brain. The aim of the present work was to study the effect of L-dopa administration on acetylcholinesterase (EC 220.127.116.11) activity in rat (Wistar) brain striatum. Short-term administration of a mixture of L-dopa (10 mg/kg) and carbidopa (1 mg/kg) resulted in an increase in dopamine content and a decrease in acetylcholinesterase activity of the tissue. The greatest changes were found 30 min postinjection, and activity returned to near-control values after 2 h. When the drug mixture was injected for a period of 30 d and the animals were killed 24 h after the last injection, a lower dopamine content and higher enzyme activity were seen, compared to control values. It would appear that chronic administration of L-dopa gradually reduced the dopamine-storage capacity of the striatum and that the activity of acetylcholinesterase might be controlled by the levels of dopamine in the brain striatum.


Autoradiographic localization of a novel peptide binding site in rat brain using the substance P analog, eledoisin.
Using slide mounted sections of rat brain sausage, we have characterized the binding of [125I]Bolton Hunter conjugated eledoisin and [125I]Bolton Hunter conjugated substance P. Structure activity studies suggest that the two radiolabeled peptides bind to different binding sites. Autoradiographic studies support this notion. Whereas [125I]BH-SP sparsely labels the interpeduncular nucleus and does not label the substantia nigra at all, [125I]BH-ED densely labels the former and sparsely labels the latter structure. Further, the cortical labeling patterns obtained with the two peptides are strikingly different. These data support the hypothesis that there exist two classes of tachykinin binding sites in rat nervous tissue.


Which factors affect the occurrence of severe cerebral lesions in preterm neonates who are born with intrauterine infection?
The purpose of this study was to evaluate which factors affect the occurrence of neonatal ultrasonographic evidence of severe cerebral lesions in the presence of intrauterine infection. From a cohort of 567 singleton neonates who were born between 24.0 and 31.6 weeks of gestation, we identified the 180 infants with histologic and/or clinical evidence of intrauterine infection. We excluded stillbirths and congenital anomalies. Obstetric and neonatal variables were related to evidence of severe neonatal ultrasonographic cerebral lesions with the use of logistic regression analysis. Severe cerebral lesions were identified in 10% of infants (18/180). After we controlled for variables that were clinically relevant, logistic regression analysis demonstrated that ultrasound evidence of severe neonatal cerebral lesions was associated independently with antenatal administration of corticosteroids (adjusted odds ratio, 0.3; 95% CI, 0.11-0.88; P = .03) and occurrence of placental abruption (adjusted odds ratio, 5.4; 95% CI, 1.4-20.7; P = .02). Antenatal administration of corticosteroids in the presence of intrauterine infection has a protective effect on the risk of ultrasonographic evidence of severe neonatal cerebral lesions.


Effect of anesthesia and surgery on renal function.
Interpretation of the effects of anesthesia and surgery on renal function should be based on careful appraisal of the methodology used. Currently, the most accurate measurement of in vivo RBF is provided by flow probes, although thermodilution techniques show promise. In addition, the many secondary factors that affect renal responses, such as intravascular volume status and positive pressure ventilation, should be taken into consideration in evaluating any study. Normal renal function appears to be regulated by a balance between opposing neurohormonal systems which control vasomotor tone, diuresis, and natriuresis. Surgical stress tips the balance in favor of renal vasoconstriction and salt and water retention, which may last for days after operation. Recent elucidation of the role of atrial natriuretic peptide enhances the concept that these changes can be prevented or modified by maintenance of normal or increased atrial volume. Anesthetic agents generally decrease GFR and urine output. Effects of RBF are variable and probably reflect overall circulatory responses rather than direct actions. All these changes are mild and usually reversed at the end of anesthesia. Positive pressure ventilation depresses renal function through its effects on the central circulation, which can be reversed by administration of fluid or inotropic agents. Controlled hypotensive anesthesia, aortic cross-clamping, and cardiopulmonary bypass represent anticipated renal insults which should be carefully managed.


Increased expression of hematological and neurological expressed 1 (HN1) is associated with a poor prognosis of hepatocellular carcinoma and its knockdown inhibits cell growth and migration partly by down-regulation of c-Met.
Hematologic and neurological expression 1 (HN1) has been reported to involved in certain cancers, but its role in hepatocellular carcinoma (HCC) is largely unknown. The contribution of HN1 to HCC progression was investigated in the present study. We found that HN1 was significantly up-regulated in HCC tissues, compared with normal tissues, by analyzing the Oncomine and Human Protein Atlas database; and found that high expression of HN1 was markedly associated with worse overall survival, relapse-free survival, progression- free survival and disease-specific survival in HCC patients via exploring the Kaplan-Meier plotter database. Functional assays revealed that HN1 knockdown by siRNA induced G1 cell cycle arrest, and inhibited the growth and migration of HCC cells; accordingly, HN1 over-expression promoted HCC cells proliferation and migration. Further studies indicated that HN1 knockdown reduced the expression of cyclin D1 and CDK4, while upregulated the cell cycle inhibitor p21WAF1/Cip1. Moreover, HN1 knockdown decreased c-Met (receptor tyrosine kinase of hepatocyte growth factor) expression, and suppressed ERK activation, which is a common downstream signaling pathway triggered by c-Met; consistently, HN1 over-expression reversed these effects. Meanwhile, down-regulation of c-Met partly eliminated the effect of HN1 over-expression in HCC cells. Thus, the present findings suggested that HN1 promotes the progression of HCC to some extent by up-regulating the expression of c-Met, and may act as a potential biomarker and therapeutic target for the treatment of HCC.


Toward understanding the influence of ethylbenzene in p-xylene selectivity of the porous titanium amino terephthalate MIL-125(Ti): adsorption equilibrium and separation of xylene isomers.
The potential of the porous crystalline titanium dicarboxylate MIL-125(Ti) in powder form was studied for the separation in liquid phase of xylene isomers and ethylbenzene (MIL stands for Materials from Institut Lavoisier). We report here a detailed experimental study consisting of binary and multi-component adsorption equilibrium of xylene isomers in MIL-125(Ti) powder at low (≤0.8 M) and bulk (≥0.8 M) concentrations. A series of multi-component breakthrough experiments was first performed using n-heptane as the eluent at 313 K, and the obtained selectivities were compared, followed by binary breakthrough experiments to determine the adsorption isotherms at 313 K, using n-heptane as the eluent. MIL-125(Ti) is a para-selective material suitable at low concentrations to separate p-xylene from the other xylene isomers. Pulse experiments indicate a separation factor of 1.3 for p-xylene over o-xylene and m-xylene, while breakthrough experiments using a diluted ternary mixture lead to selectivity values of 1.5 and 1.6 for p-xylene over m-xylene and o-xylene, respectively. Introduction of ethylbenzene in the mixture results however in a decrease of the selectivity.


An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity.
Lymphedema results from insufficient lymphatic drainage and typically affects the extremities. Recent studies revealed obesity as another cause of extremity lymphedema. Conservative treatment of patients with elephantiastic lymphedema of the lower extremity is limited and often inadequate. Resecting surgery plays an important role in these cases. Here, we investigated the effects of an integrated therapy concept on outcome and complication rates. We retrospectively analyzed the clinical outcome of 26 patients with elephantiastic lymphedema of the lower limb who underwent a complex decongestive physical therapy (CDP) perioperatively and reduction surgery in our clinic between 1998 and 2011. We subsequently compared these patients (group A) with a control group of 30 patients (group B) who received medial thigh lift due to post-bariatric or aesthetic issues between 2011 and 2013. The incidence of complications, reoperations, blood transfusion, and duration of hospital stay was analyzed. All patients in group A received CDP perioperatively in a specialized lymphological clinic. Both groups are comparable in terms of age and sex. Patients significantly differ in terms of BMI (p < 0.001). Thirty-six reductive procedures were performed in group A and 30 in group B. We did not see any significant difference in the incidence of complications (p = 1.000) and the rate of postoperative blood transfusions (p = 0.116). We were able to show that an integrative concept including surgery is a good additional option for the treatment of severe cases of lymphedema in appropriate candidates. Furthermore, an adequate perioperative conservative setting helps to minimize possible complications.


Technical possibilities and limitations of stereotaxy.
The availability of CT-Scanners and MRI coupled to stereotactic systems has made a stereotactic neurosurgical intervention an everyday tool. The indications, contra-indications and complications concerning intracranial tumours, the hypophysis, combined open stereotactic procedures, third ventriculostomy, diseases of the extrapyramidal motor system, pain, epilepsy, psychosurgery and the transplantation of embryonal cells are discussed.


Ecological Effects of Single-Walled Carbon Nanotubes on Soil Microbial Communities and Soil Fertility.
The manufacturers of single-walled carbon nanotubes (SWCNTs) are continuously expanding their manufacturing and commercial markets, indicating that the environmental release and accumulation of SWCNTs in soil is inevitable. However, little is known about the effects of SWCNTs on soil physicochemical properties and soil microbial communities. Our results showed that treatment with SWCNTs resulted in an enhancement of microorganism metabolism related to soil organic compound degradation and a change in the structure of soil microbial communities, but the diversity of soil microorganisms was not significantly affected. The decrease in soil urease activity and the increase in the relative abundance of Nitrospirae after SWCNTs exposure might be relevant to the induction of soil nitrification. The relative abundances of phosphate-solubilizing microorganisms increased after exposure to SWCNTs, which was beneficial for phosphorus bioavailability in the soil. Our current study highlights that exposure to SWCNTs at concentrations of 3 and 10 µg/g can change the composition of soil microorganism communities, promote soil organic degradation and improve soil fertility by enhancing N and P availability in a short time.


[A rare motive for genetic counseling: the risk of leukemia: apropos of a familial form].
Authors report one family with three cases of myeloblastic acute leukaemia in three generations. In this family, without chromosomal abnormalities (the only one possible laboratory examination), the risk is certainly increased, but it remains, fortunately, low.


ECONOMIC IMPACTS OF VISA RESTRICTIONS ON TOURISM: A CASE OF TWO EVENTS IN CHINA.
Increasing attention has been paid to evaluate the impacts of large scale events on tourism demand. For providing policy suggestions, it should consider the economic impact of both events themselves and other factors. This paper evaluates the economic effects of visa restrictions on tourism as a result of the 1989 Tian'an Men Square Incident and the 2008 Beijing Olympic Games by using an innovative combination of econometric and computable general equilibrium (CGE) models. The results show that both events generated economic losses. The unexpected negative economic impact of the Beijing Olympics seems attributable to visa restrictions. Suggestions for the alleviation of the negative impact of visa regulations are provided.


Cholecystokinin, gastrin and stress hormone responses in marathon runners.
The purpose of this investigation was to determine the influence of long-distance running on the secretion of the gastrointestinal peptide hormones cholecystokinin (CCK) and gastrin. Several known stress hormones, ACTH, cortisol and norepinephrine, were also measured. The hormones were estimated before and after a competitive marathon run of 46.5 km and under control conditions a few weeks later. Except gastrin, all hormones were significantly higher under prerun conditions than under control conditions and were highest after the run. The most marked prerun elevation was in CCK. Therefore, CCK seems to be an important regulation factor in response to anticipatory stress.


Biocompatibility testing of a posterior composite and dental cements using a new organ culture model.
Mandibular first molars from day 14 and 17 mouse embryos were cultured in vitro for 7 days in chemically defined Pratt's medium in a submerged culture system. Ameloblast and odontoblast polarization and morphogenesis occurred in the control tooth germs. Discs of Occlusin, Silicate, ChemFil, IRM and Dycal were exposed to the culture system as either fresh material, leached discs (by pre-incubation in media) or the leachate from the incubated discs. Their effects on dental differentiation were assessed histologically. Day 17 tooth germs were slightly more sensitive to the effects of the exogenous agents than day 14 tooth germs. In general, silicate and ChemFil were toxic, IRM was slightly less toxic and the major effect was from the leachate. Dycal was toxic but most of this effect resulted from pH changes in the leachate. Occlusin was the most biocompatible material tested. Only a very mild adverse effect was detected, and this appeared to be caused by an agent (not a pH change) released into the leachate.


Nicotine modulates human brain plasticity via calcium-dependent mechanisms.
Nicotine (NIC) modulates cognition and memory function by targeting the nicotinic ACh receptor and releasing different transmitter systems postsynaptically. With both NIC-generated mechanisms, calcium influx and calcium permeability can be regulated, which is a key requirement for the induction of long-term potentiation, comprising the physiological basis of learning and memory function. We attempt to unmask the underlying mechanism of nicotinic effects on anodal transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity based on the hypothesis of calcium-dependency. Abolished tDCS-induced neuroplasticity as a result of NIC administration is reversed by calcium channel blockade with flunarizine in a dose-dependent manner. The results of the present study suggest that there is a dose determination of NIC/NIC agonists in therapeutical settings when treating cognitive dysfunction, which partially explains the heterogeneous results on cognition observed in subjects in different experimental settings. Nicotine (NIC) modulates neuroplasticity and improves cognitive performance in animals and humans mainly by increased calcium permeability and modulation of diverse transmitter systems. NIC administration impairs calcium-dependent plasticity induced by non-invasive brain stimulation with transcranial direct current stimulation (tDCS) in non-smoking participants probably as a result of intracellular calcium overflow. To test this hypothesis, we analysed the effect of calcium channel blockade with flunarizine (FLU) on anodal tDCS-induced cortical excitability changes in healthy non-smokers under NIC. We applied anodal tDCS combined with NIC patch and FLU at three different doses (2.5, 5 and 10 mg) or with placebo medication. NIC abolished anodal tDCS-induced neuroplasticity. Under medium dosage (but not under low and high dosage) of FLU combined with NIC, plasticity was re-established. For FLU alone, the lowest dosage weakened long-term potentiation (LTP)-like plasticity, whereas the highest dosage again abolished tDCS-induced plasticity. The medium dosage turned LTP-like plasticity in long-term depression-like plasticity. The results of the present study suggest a key role of calcium influx and calcium levels in nicotinic effects on LTP-like plasticity in humans. This knowledge might be relevant for the development of new therapeutic strategies in cognitive dysfunction.


Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: implications for subsensitivity of alpha(2)-adrenergic receptors in depression.
To determine whether alpha(2)-adrenergic receptor (alpha2AR) subsensitivity is a state or a trait marker of depression, we consecutively challenged 32 drug-free depressed patients with a clonidine REM suppression test (CREST). We then treated the patients with fluvoxamine, a selective serotonin reuptake inhibitor, or mirtazapine, a selective alpha(2)-adrenergic receptor antagonist. The first 10 patients from each treatment group who recovered were given a second challenge test. The CREST values of the two treatment groups at each time point were compared, and also compared with the CREST values of a group of 10 normal subjects. Before treatment, the REM sleep response to clonidine in the two groups of patients was significantly blunted compared with the REM sleep response in the healthy subjects. After treatment, there was still an abnormal REM sleep response to clonidine in the fluvoxamine-treated patients, despite clinical recovery, but there was a normalized REM sleep response in the mirtazapine-treated patients. These results are compatible with the hypothesis that alpha2AR subsensitivity is a trait marker of depression and suggest that the effects of these two antidepressants on alpha2AR sensitivity may not be linked to the alleviation of depression.


Is there any relation between anthropometric indices and decrease in seminal parameters?
To investigate the influence of anthropometric indices on seminal parameters. Men who underwent treatment for conjugal infertility during the period of October, 2011, to March, 2012, were randomly selected. Patients with any prior diseases related to sperm alterations were excluded. Patients were submitted to an anthropometric evaluation to obtain body mass index, and the seminal analysis was made through a spermogram. Two anthropometric methods of classification were used: body mass index (normal and altered) and abdominal circumference (<94 cm and >94 cm). Data were analyzed by statistical tests. The group with the altered body mass index presented lower volumes of ejaculated volume and a larger percentage of patients with abdominal circumference <94 cm presented with progressive forms of spermatozoa below reference values. However, in the statistical tests, there was no significant difference. No significant difference was found in the sperm quality relative to the body mass index or abdominal circumference.


Spring distraction system for dynamic growth guidance of early onset scoliosis: two-year prospective follow-up of 24 patients.
Current surgical treatment options for early onset scoliosis (EOS), with distraction- or growth-guidance implants, show limited growth and high complication rates during follow-up. We developed a novel implant concept, which uses compressed helical springs positioned around the rods of a growth-guidance construct. This spring distraction system (SDS) provides continuous corrective force to stimulate spinal growth, can be easily contoured, and can be used with all standard spinal instrumentation systems. To assess curve correction and -maintenance, spinal growth, complication rate, and health-related quality of life following SDS treatment. Prospective cohort study. All skeletally immature EOS patients with an indication for growth-friendly surgery and without bone- or soft tissue weakness were eligible to receive SDS. For this study, all included patients with at least 2-year follow-up were analyzed. Coronal Cobb angle, sagittal parameters, T1-T12, T1-S1, and instrumented (ie, bridged segment) spinal height and freehand length, complications and re-operations, and the 24-Item Early Onset Scoliosis Questionnaires (EOSQ-24) score. All primary- and conversion patients (conversion from failed other systems) with SDS and ≥2 years follow-up were included. Radiographic parameters were compared preoperatively, postoperatively and at latest follow-up. Spinal length increase was expressed as mm/year. Twenty-four skeletally immature EOS patients (18 primary and 6 conversion cases) were included. There were five idiopathic, seven congenital, three syndromic, and nine neuromuscular EOS patients. Mean age at implantation was 9.1 years (primary: 8.4; conversion: 11.2). Major curve improved from 60.3° to 35.3°, and was maintained at 40.6° at latest follow-up. Mean spring length increase during follow-up was 10.4 mm/year. T1-S1 height increased 9.9mm/year and the instrumented segment height showed a mean increase of 0.7 mm/segment/year. EOSQ-24 scores dropped after surgery from 75.6 to 67.4 but recovered to 75.0 at latest follow-up. In total, 17 reoperations were performed. Ten reoperations were performed to treat 9 implant-related complications. In addition, 7 patients showed spinal growth that exceeded expected growth velocity; their springs were retensioned during a small reoperation. The 2-year follow-up results from this prospective cohort study indicate that the concept of spring distraction may be feasible as an alternative to current growing spine solutions. Curve correction and growth could be maintained satisfactory without the need for repetitive lengthening procedures. However, as in all growth-friendly implants, complications and reoperations could not be prevented, which emphasizes the need for further improvement.


Copy Number Variation Analysis by Droplet Digital PCR.
The health impact of many copy number variants in our genome remains still largely to be discovered. Detecting and genotyping this often complex variation presents a technical challenge. Here we describe a 96-well format droplet digital PCR (ddPCR) protocol for genotyping a common copy variant in the human haptoglobin gene. ddPCR allows for high-throughput and accurate quantitation of gene copy numbers.


Endoscopic Ultrasound-Guided Biliary Drainage of First Intent With a Lumen-Apposing Metal Stent vs Endoscopic Retrograde Cholangiopancreatography in Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Study (ELEMENT Trial).
Endoscopic ultrasound-guided choledochoduodenostomy with a lumen-apposing metal stent (EUS-CDS) is a promising modality for management of malignant distal biliary obstruction (MDBO) with potential for better stent patency. We compared its outcomes with endoscopic retrograde cholangiopancreatography with metal stenting (ERCP-M). In this multicenter randomized controlled trial, we recruited patients with MDBO secondary to borderline resectable, locally advanced, or unresectable peri-ampullary cancers across 10 Canadian institutions and 1 French institution. This was a superiority trial with a noninferiority assessment of technical success. Patients were randomized to EUS-CDS or ERCP-M. The primary end point was the rate of stent dysfunction at 1 year, considering competing risks of death, clinical failure, and surgical resection. Analyses were performed according to intention-to-treat principles. From February 2019 to February 2022, 144 patients were recruited; 73 were randomized to EUS-CDS and 71 were randomized to ERCP-M. The mean (SD) procedure time was 14.0 (11.4) minutes for EUS-CDS and 23.1 (15.6) minutes for ERCP-M (P < .01); 40% of the former was performed without fluoroscopy. Technical success was achieved in 90.4% (95% CI, 81.5% to 95.3%) of EUS-CDS and 83.1% (95% CI, 72.7% to 90.1%) of ERCP-M with a risk difference of 7.3% (95% CI, -4.0% to 18.8%) indicating noninferiority. Stent dysfunction occurred in 9.6% vs 9.9% of EUS-CDS and ERCP-M cases, respectively (P = .96). No differences in adverse events, pancreaticoduodenectomy and oncologic outcomes, or quality of life were noted. Although not superior in stent function, EUS-CDS is an efficient and safe alternative to ERCP-M in patients with MDBO. These findings provide evidence for greater adoption of EUS-CDS in clinical practice as a complementary and exchangeable first-line modality to ERCP in patients with MDBO. gov, Number: NCT03870386.


circNUDT21 promotes bladder cancer progression by modulating the miR-16-1-3p/MDM2/p53 axis.
Bladder cancer (BC) is a common genitourinary malignancy. This study investigated the regulatory effects of an exonic circRNA, circNUDT21, in the progression of BC. The circNUDT21 level was overexpressed in BC tissues and cell lines as compared to normal controls. Overexpression and silencing of circNUDT21 promoted and inhibited, respectively, the proliferative and invasive abilities of BC cells. Mechanistical analysis showed that circNUDT21 acted as a miR-16-1-3p sponge and that MDM2 was a potential downstream target of miR-16-1-3p. We further verified that overexpression of circNUDT21 was associated with elevated MDM2 and reduced p53 expression. CircNUDT21 promoted BC progression by acting as a sponge of miR-16-1-3p to activate the miR-16-1-3p/MDM2/p53 axis. These findings suggest that circNUDT21 functions as an oncogenic circRNA and may be a potential therapy target for BC.


Cu(II) promotes amyloid pore formation.
The aggregation of α-synuclein is associated with dopamine neuron death in Parkinson's disease. There is controversy in the field over the question of which species of the aggregates, fibrils or protofibrils, are toxic. Moreover, compelling evidence suggested the exposure to heavy metals to be a risk of PD. Nevertheless, the mechanism of metal ions in promoting PD remains unclear. In this research, we investigated the structural basis of Cu(II) induced aggregation of α-synuclein. Using transmission electron microscopy experiments, Cu(II) was found to promote in vitro aggregation of α-synuclein by facilitating annular protofibril formation rather than fibril formation. Furthermore, neuroprotective baicalein disaggregated annular protofibrils accompanied by considerable decrease of β-sheet content. These results strongly support the hypothesis that annular protofibrils are the toxic species, rather than fibrils, thereby inspiring us to search novel therapeutic strategies for the suppression of the toxic annular protofibril formation.


Parental Self-Compassion and Child Adjustment: The Mediating Role of Parental Depressive Symptoms.
Previous research suggests that self-compassion is associated with mental health and well-being. However, little has been done to understand the role of self-compassion in the family context. Hence, the present study investigated the associations between parents' self-compassion, parent's depressive symptoms, and child adjustment. A total 189 Chinese parents (101 mothers) whose children were 2-8 years old were recruited to complete a questionnaire, including measures of parents' self-compassion, depressive symptoms, and children's prosocial behavior, internalizing problems, and externalizing problems. Findings indicated mediation effects, in that parents' depressive symptoms mediated the association between their self-compassion and child adjustment outcomes, namely children's internalizing and externalizing problems, after controlling for the effects of monthly family income, child gender, and parent gender. Competing hypothesis suggested that parents' self-compassion did not moderate between parents' depressive symptoms and child adjustment outcomes. Hence, the association between parental depressive symptoms and child adjustment was not dependent on the level of parents' self-compassion. As an implication, researchers and practitioners should be made aware of the benefits of parents' self-compassion on parents' mental health and child adjustment.


Roles for fibroblast growth factor-23 and α-Klotho in acute kidney injury.
Acute kidney injury is a global disease with high morbidity and mortality. Recent studies have revealed that the fibroblast growth factor-23-α-Klotho axis is closely related to chronic kidney disease, and has multiple biological functions beyond bone-mineral metabolism. However, although dysregulation of fibroblast growth factor-23-α-Klotho has been observed in acute kidney injury, the role of fibroblast growth factor-23-α-Klotho in the pathophysiology of acute kidney injury remains largely unknown. In this review, we describe recent findings regarding fibroblast growth factor-23-α-Klotho, which is mainly involved in inflammation, oxidative stress, and hemodynamic disorders. Further, based on these recent results, we put forth novel insights regarding the relationship between the fibroblast growth factor-23-α-Klotho axis and acute kidney injury, which may provide new therapeutic targets for treating acute kidney injury.


Efficacy and persistence of tooth bleaching using a diode laser with three different treatment regimens.
Studies have measured the effectiveness of tooth bleaching, however there are very few studies that have measured the persistence in color change after a 6-month follow-up. This study assessed the efficacy of the laser bleaching process using different regimens, and the persistence of color change over a 6-month period. Sixty patients divided into three equal groups were subjected to bleaching using a diode laser with 34% hydrogen peroxide. Group 1: patients subjected to one session of laser bleaching. Group 2: patients subjected to two sessions of laser bleaching with a 1-week interval. Group 3: the same as Group 2 but followed by home bleaching once a month for 3 months. The color was assessed four times: before bleaching, directly after bleaching, 3 months after bleaching, and 6 months after bleaching. All teeth had a significant color change at 6 months, but all teeth had regressed from the maximum value. There was significantly less regression in color for Group 3, followed by Groups 2 and 1, respectively. The combined technique of in-office laser bleaching for two sessions with a 1-week interval, followed by home bleaching once a month for 3 months gave more persistence in color change. In-office power bleaching using a laser assisted hydrogen peroxide system repeated after a week, combined with home bleaching once a month for 3 months, is an effective bleaching regimen with less color regression after 6 months compared to a regimen of in-office bleaching alone.


[Research Progress of Targeted Therapy for HER2 Gene in Advanced Non-small Cell Lung Cancer].
Lung cancer is the most common malignancy tumor. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer. Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor in ERBB/HER family, which activates downstream signal transduction with other family members such as epidermal growth factor receptor (EGFR). HER2 gene mutation is closely related to the progression of many epithelial cell cancers. Tumors with high expression of HER2 show strong metastasis and invasion ability, poor sensitivity to chemotherapy, and are prone to relapse. At present, lung cancer driven gene targeted therapy has made rapid progress. Although the frequency of HER2 gene mutation in NSCLC is lower than that of EGFR, its driving mechanism in lung cancer is clear and partial targeted therapy is effective, which may become a new standard treatment in the future. This review focuses on the research progress of HER2 gene mutation in the treatment of NSCLC. .


Spinal epidural hematoma after thrombolysis for deep vein thrombosis with subsequent pulmonary thromboembolism: a case report.
A 38-year-old male was initially admitted for left leg swelling. He was diagnosed as having deep vein thrombosis (DVT) in the left leg and a pulmonary thromboembolism by contrast-enhanced chest computed tomography (CT) with delayed lower extremity CT. The DVT was treated by thrombolysis and a venous stent. Four hours later, he complained of severe back pain and a sensation of separation of his body and lower extremities; he experienced paraplegia early in the morning of the following day. Magnetic resonance imaging showed a spinal epidural hematoma between T11 and L2, which decompressed following surgery. We, therefore, report a case of a spinal epidural hematoma after thrombolysis in a case of DVT with a pulmonary thromboembolism.


Delayed short-term administration of granulocyte colony-stimulating factor is a good mobilization strategy for harvesting autologous peripheral blood stem cells in pediatric patients with solid tumors.
PBSCs have become the preferred source of autologous stem cells for supporting high-dose chemotherapy in childhood solid tumors. The aims of this retrospective study were to examine the optimal timing for administration of G-CSF after chemotherapy and to identify the patients from whom an optimal dose of PBSCs can be harvested. We evaluated the timing of G-CSF administration for harvesting PBSCs in patients with childhood solid tumors. G-CSF was administered immediately after chemotherapy in eight patients (11 harvests, long-term group) and following recovery from hematological nadirs in 17 patients (21 harvests, short-term group). The median duration of G-CSF administration was 22 vs. 5 days, respectively (p < 0.005), and the dose of harvested CD34(+) cells (×10(6) /kg) was 1.4 vs. 2.9, respectively (p = 0.023). Our results suggest that short-term G-CSF administration is a good strategy for harvesting PBSCs in these patients.