Identification, biochemical characterization, and evolution of the Rhizopus oryzae 99-880 polygalacturonase gene family.
A search of the recently sequenced Rhizopus oryzae strain 99-880 genome database uncovered 18 putative polygalacturonase genes with two genes being identical and only one with similarity to a previously reported R. oryzae polygalacturonase gene. The 17 different genes share 50% to greater than 90% identity at the nucleotide level as well as the deduced protein sequence level. The cDNA of the different genes was isolated directly or recombinantly and used to express the encoded proteins in Pichia pastoris. Recombinant protein expression demonstrated that 15 of the 17 genes encode active enzymes with twelve genes encoding for endo-polygalacturonase enzymes and three genes encoding for exo-polygalacturonase enzymes. Phylogenetic analysis indicates that the genes form a distinct monophyletic group among fungal polygalacturonase enzymes. Finally, our results also suggest that the ancestral form of polygalacturonase in fungi is endolytic and exolytic function evolved later, at least two independent times.


Moisture content and CO2 exchange of lichens : I. Influence of temperature on moisture-dependent net photosynthesis and dark respiration in Ramalina maciformis.
Net photosynthesis (10 klx light intensity, 150 μE m-2 s-1 PAR) and dark respiration of the lichen Ramalina maciformis at different temperatures are measured in relation to thallus water content. Both first increase with increasing hydration. Dark respiration then remains constant with increased water content until thallus saturation. In contrast, a further increase in water content leads to a depression of net photosynthesis, as shown in previous studies, after a maximum of CO2 uptake has been attained. However, the extent of this depression depends strongly on temperature. In saturated thalli (160% water content in relation to lichen dry weight) the depression amounts to about 15% and 63% of the maximum unsaturated rate at 5°C and 25°C thallus temperature, respectively. The moisture compensation-point of net photosynthesis is also decisively determined by temperature (for 0°C at 20% water content; for 25°C at 15%), and the water content that allows maximum rates of CO2 uptake (for 0°C at 80%; for 25°C at less than 40% water content). An electrical analogue of CO2 exchange in a lichen thallus is presented, and it is suggested that the experimental results may be interpreted in terms of temperature-dependent CO2 diffusion resistances in imbibed lichen thalli.


Semiautomated Segmentation and Analysis of Airway Lumen in Pediatric Patients Using Ultra Short Echo Time MRI.
Ultra short echo time (UTE) magnetic resonance imaging (MRI) pulse sequences have shown promise for airway assessment, but the feasibility and repeatability in the pediatric lung are unknown. The purpose of this work was to develop a semiautomated UTE MRI airway segmentation pipeline from the trachea-to-tertiary airways in pediatric participants and assess repeatability and lumen diameter correlations to lung function. A total of 29 participants (n = 7 healthy, n = 11 cystic fibrosis, n = 6 asthma, and n = 5 ex-preterm), aged 7-18 years, were imaged using a 3D stack-of-spirals UTE examination at 3 T. Two independent observers performed airway segmentations using a pipeline developed in-house; observer 1 repeated segmentations 1 month later. Segmentations were extracted using region-growing with leak detection, then manually edited if required. The airway trees were skeletonized, pruned, and labeled. Airway lumen diameter measurements were extracted using ray casting. Intra- and interobserver variability was assessed using the Sørensen-Dice coefficient (DSC) and intra-class correlation coefficient (ICC). Correlations between lumen diameter and pulmonary function were assessed using Spearman's correlation coefficient. For airway segmentations and lumen diameter, intra- and interobserver DSCs were 0.88 and 0.80, while ICCs were 0.95 and 0.89, respectively. The variability increased from the trachea-to-tertiary airways for intra- (DSC: 0.91-0.64; ICC: 0.91-0.49) and interobserver (DSC: 0.84-0.51; ICC: 0.89-0.21) measurements. Lumen diameter was significantly correlated with forced expiratory volume in 1 second and forced vital capacity (P < .05). UTE MRI airway segmentation from the trachea-to-tertiary airways in pediatric participants across a range of diseases is feasible. The UTE MRI-derived lumen measurements were repeatable and correlated with lung function.


Frunevetmab, a felinized anti-nerve growth factor monoclonal antibody, for the treatment of pain from osteoarthritis in cats.
Frunevetmab, a felinized antinerve growth factor monoclonal antibody, effectively decreases osteoarthritis (OA) pain in cats. To evaluate the efficacy of frunevetmab given at monthly intervals in a randomized, placebo-controlled, parallel-group, double-blind superiority study. Two hundred seventy-five client-owned cats with naturally-occurring OA pain and associated mobility impairment and disability. Randomized, placebo-controlled, parallel-group, double-blind, superiority study. Following screening, cats received frunevetmab (nominal dose of 1.0 mg/kg, SC [effective dose range of 1.0-2.8 mg/kg]) or placebo on days 0, 28, and 56. Outcome measures were owner questionnaires and veterinary physical and orthopedic evaluations at days 28, 56, and 84. Success/failure rates (and numbers needed treat, NNT) and change in scores (and standardized effect size, ES) were analyzed. Frunevetmab (182) and placebo (93) treated cats were enrolled and received at least 1 treatment. Significant improvement with frunevetmab over placebo occurred at days 28 and 56 for the client specific outcome measures (CSOM) questionnaire (success rates and total scores [NNT of 9 and ES of 0.3 at day 56]); at days 28 and 56 for owner-assessed global treatment response; and at days 56 and 84 for veterinarian-assessed joint pain (ES of 0.18 at day 56). Adverse events did not differ between groups, except skin disorders which collectively occurred significantly more frequently in frunevetmab treated (32/182 cats) vs placebo (8/93 cats). Frunevetmab has the potential to address a critical gap in the treatment of pain because of osteoarthritis in cats.


Lateral supraorbital approach as an alternative to the classical pterional approach.
The standard pterional approach has been used to approach aneurysms of the anterior circulation and the basilar tip, suprasellar tumors, cavernous lesions. The senior author (JH) established a lateral supraorbital approach as an alternative to the pterional approach after continuous trial and error. We describe the techniques of this approach based on clinical experiences. The lateral supraorbital approach is more subfrontal and anterior than the pterional approach. This approach has been regularly used by the senior author (JH) in the last decade in more than 2000 operations for mostly aneurysms of anterior circulation, but also for tumors of the anterior fossa and parasellar area as well as the sphenoid wing area. This approach can be used to operate on most cases, in which the classical pterional approach would be used. There are almost no craniotomy-related complications with this approach. This approach is not suitable in certain lesions which need to be exposed from a more temporal perspective. This approach is simpler, faster, safer and less invasive than the classical pterional approach.


Exercise-induced asthma in children.
Exercise-induced asthma (EIA) is a relatively common problem in children, but may not be recognized because children either do not report their symptoms, or avoid activities that cause it. Clarifying the diagnosis of EIA, in particular separating EIA from other causes of exertional dyspnea, is essential. Treating EIA in children is challenging because of the nature of their physical activities, which are often not planned, and may be prolonged. Keeping children active is an important goal to ensure healthy physical and social development. Many children with EIA are well managed with an inhaled short-acting beta(2)-adrenoceptor agonist before exercise or if symptoms develop. The approach to more troublesome EIA depends on whether the child has persistent asthma and requires better prevention, or the EIA is an isolated clinical problem. The options for treatment also depend on the timing, frequency, and duration of activity that induces EIA. Options include the addition of a cromone, a leukotriene modifier, an inhaled corticosteroid, or switching to use a long-acting beta(2)-adrenoceptor agonist. The use of warm-up exercises has been shown to be helpful by using the refractory period but is not practical for most children with EIA. A final consideration for successful management of EIA in children is that the delivery of medication needs to be age-appropriate.


Bayesian accounts and black swans: Questioning the erotetic theory of delusional thinking.
Parrott and Koralus argue that a particular cognitive factor--"impaired endogenous question raising"--offers a parsimonious account of three delusion-related phenomena: (1) the development of the Capgras delusion; (2) evidence that patients with schizophrenia outperform healthy control participants on a conditional reasoning task; and (3) evidence that deluded individuals "jump to conclusions". In this response, I assess these claims, and raise my own questions about the "erotetic" theory of delusional thinking.


Effect of chronic ethanol treatment on specific [3H]ouabain binding to (Na+ + K+)-ATPase in different areas of cat brain.
Chronic ethanol administration to cats increased specific [3H]ouabain binding by 63% in cerebral cortex, 47% in cerebellum, 84% in amygdala, and 100% in hippocampus when the binding assays were performed in the presence of 160 nM [3H]ouabain. There was no significant change in specific [3H]ouabain binding in hypothalamus, thalamus, corpus striatum, and brain stem following chronic ethanol ingestion. Scatchard analysis revealed that enhancement of specific [3H]ouabain binding following chronic ethanol treatment in some areas of cat brain is primarily due to changes in densities of ouabain binding sites. Since ouabain is a specific inhibitor of (Na+ + K+)-ATPase the present observations suggest that the molecular mechanism for the enhancement of (Na+ + K+)-ATPase activity after chronic ethanol ingestion may be due to increased net rate of synthesis of (Na+ + K+)-ATPase molecules or exposure of non-functional enzyme system following conformational change of plasma membrane.


Retraction: Altitude cardiomyopathy is associated with impaired stress electrocardiogram and increased circulating inflammation makers.
[This retracts the article DOI: 10.3389/fphys.2021.640302.].


EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis.
Preoperative diagnosis of solid pancreatic lesions remains challenging despite advancement in imaging technologies. EUS has the benefit of being a minimally invasive, well-tolerated procedure, although results are operator-dependent. The addition of FNA (EUS-guided FNA) provides samples for cytopathologic analysis, a major advantage over other imaging techniques. To determine the diagnostic accuracy of EUS-FNA for pancreatic cancer. This is a meta-analysis of published studies assessing the diagnostic capability of EUS-FNA. Relevant studies were identified via MEDLINE and were included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. Data from selected studies were analyzed by using test accuracy meta-analysis software, providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. Cytology results were classified as inadequate, benign, atypical, suspicious, or malignant. Predefined subgroup analysis was performed. Thirty-three studies published between 1997 and 2009 were included, with a total number of 4984 patients. The pooled sensitivity for malignant cytology was 85% (95% confidence interval [CI], 84-86), and pooled specificity was 98% (95% CI, 0.97-0.99). If atypical and suspicious cytology results were included to determine true neoplasms, the sensitivity increased to 91% (95% CI, 90-92); however, the specificity was reduced to 94% (95% CI, 93-96). The diagnostic accuracy of EUS-FNA was enhanced in prospective, multicenter studies. Publication bias was not a significant determinant of pooled accuracy. This meta-analysis demonstrates that EUS-FNA is a highly accurate diagnostic test for solid neoplasms of the pancreas and should be considered when algorithms for investigating solid pancreatic lesions are being planned.


Seasonal variation in pituitary responsiveness to luteinizing hormone-releasing hormone of mallards and canvasbacks.
Endocrine profiles of wild mallards (Anas platyrhynchos) and canvasbacks (Aythya valisineria) were determined during the spring and the summer. Males and females of each species were treated with a single intravenous injection of 12 micrograms of synthetic luteinizing hormone-releasing hormone (LHRH). Preinjection and postinjection blood samples were collected and LH levels were determined by radioimmunoassay. LHRH evoked a brisk and significant elevation in serum LH in all ducks indicating the pituitary glands of both species contain readily releasable pools of LH. In March, the preinjection baseline levels of LH in the two groups did not differ. However, mallards responded to LHRH with a twofold increase in serum LH, while canvasbacks responded with a fourfold increase (F = 17.1, P less than 0.001). At the summer blood sampling period, mallards had significantly higher circulating levels of serum LH than canvasbacks (F = 35.9, P less than 0.001). Both species responded to LHRH with a twofold increase in circulating LH. These data indicate that seasonal variations in reproduction shown by the two species in captivity may be associated with differences in LHRH-sensitive pools of LH.


Pretreated EGFRdel19/BRAFV600E Lung Adenocarcinoma With Leptomeningeal Disease Achieving Long-Lasting Disease Control on Osimertinib, Dabrafenib, and Trametinib: A Case Report.
Oncogene-addicted NSCLC inevitably becomes resistant to targeted therapy by developing acquired resistance through on- or off-target mechanisms, potentially detectable by liquid biopsy. We present the first reported case of a patient with pretreated EGFRdel19/BRAFV600E lung adenocarcinoma and symptomatic leptomeningeal metastasis obtaining durable clinical benefit on osimertinib, dabrafenib, and trametinib treatment.


Hemodynamic status and treatment of aggressive dural arteriovenous fistulas.
In this study the hemodynamic status and treatment modality of aggressive dural arteriovenous fistulas (dAVFs) was evaluated. Of 145 intracranial dAVFs treated in our clinic, there were 38 aggressive lesions presenting with hemorrhage, infarction, seizures, and symptoms of increased intracranial pressure. They included 3 (5% of all cavernous sinus lesions) cavernous sinus, 24 (44%) transverse-sigmoid and superior sagittal sinus, and 11 (46%) direct cortical types of dAVFs. Of these 38 aggressive lesions, retrograde leptomeningeal venous drainage was disclosed in 35 lesions, and retrograde sinus drainage in 3. Eighteen cases were treated only with endovascular procedures, 7 with surgical interventions, and 13 with combined endovascular and surgical procedures. Angiographic results were complete obliteration in 66% of the cases, subtotal and partial obliteration in 34%. Clinical outcome was GR (good recovery) in 58% of cases, MD (moderate disability) in 18%, SD (severe disability) in 13%, VS (vegetative state) in 8%, and D (death) (due to acute cardiac infarction) in 3%. Symptomatic procedural complication occurred in 3 cases. In conclusion, aggressive dural AVF resulted from retrograde leptomeningeal venous drainage. Combined surgical and endovascular treatment played the leading part in the management of this aggressive type of lesion.


Transcriptional and epigenetic status of protamine 1 and 2 genes following round spermatids injection into mouse oocytes.
The use of round spermatids that are fully active at the transcriptional level to create zygotes (i.e. round spermatid injection; ROSI) raises the question regarding the downregulation of all specific genes that are transcribed from the paternal genome at fertilization. In this study, we show that protamine 1 and 2 mRNAs, which are specific to the round spermatid stage, are repressed at the two-pronuclei (6 h) and two-cell (30 h) stages postfertilization, respectively, in ROSI embryos, by distinct mechanisms. Both genes are fully methylated in round spermatids and sperm but unmethylated in oocytes. At 6 h postfertilization, the protamine 1 and 2 genes are actively demethylated, but the demethylation process happens more rapidly in ROSI than in sperm zygotes. Treatment of zygotes with trichostatin A, a histone deacetylase (HDAC) inhibitor, maintained the protamine 2 mRNAs expression up to 30 h postfertilization while the DNA methylation status of the gene is not affected. Thus, HDACs are involved in the clearance of protamine 2 mRNAs in ROSI two-cell embryos independently of the methylation status of the repressed gene. Contrastingly, HDACs are not directly involved in protamine 1 regulation since trichostatin A does not reverse the silencing of the gene in ROSI embryos at 6 h. The protamine 1 CpG island located in the coding region is actively demethylated in ROSI one-cell embryos where the gene is repressed and may contribute to the regulation of protamine 1 gene expression. The comparison with gene reprogramming occurring during nuclear transfer makes ROSI embryos an attractive model to study the mechanisms involved in gene silencing elicited by the oocyte.


Adverse electrocardiographic effects of rituximab infusion in pemphigus patients.
Pemphigus encompasses a group of chronic autoimmune blistering diseases of the skin and/or mucosa. Rituximab (RTX) has shown promising efficacy for the treatment of pemphigus in the past decade. Considering potential cardiac side effects, this study was conducted to assess the effects of RTX on electrocardiogram (ECG) parameters in pemphigus patients. This observational cross-sectional study was conducted in 80 consecutive patients with pemphigus who were eligible for RTX infusion. The patients' heart rhythm was monitored before, during and after RTX infusion and ECG parameters were compared before and after the infusion. Eighty patients were included in the study. The median age of the patients was 42 years. The mean and maximum heart rate (HR) increased significantly after RTX infusion compared with pre-infusion mean and maximum HR. The mean corrected QT (QTc) interval, premature atrial contraction (PAC), and premature ventricular contraction (PVC) counts increased significantly after RTX infusion (P value: 0.009, 0.004 and 0.007 respectively). According to the results of this study, RTX has potential arrhythmogenic side effects including increased mean and maximum HR, QTc interval, PAC and PVC count. However, these findings are minor and should not prevent eligible patients from receiving RTX infusion.


Fist report on fumagillin production by Aspergillus fumigatus sensu stricto gliotoxigenic strains recovered from raw cow milk and clinical samples in Argentina.
In Argentina there are no reports on Aspergillus fumigatus fumagillin-producing strains. In this study we describe the isolation and mycotoxin production capacity of ten A. fumigatus strains isolated from farm and clinical samples. Farm strains were isolated from milk samples taken from dairy cows in Córdoba province, some of which were associated with subclinical mastitis. A culture medium was defined to optimize fumagillin production and a detection method was developed by HPLC chromatography. It is known that in addition to the host immune status, strain virulence is a fundamental characteristic that will determine its pathogenicity and, in this sense, fumagillin is considered to be among the virulence factors. In the present work, all the strains tested for the production of fumagillin were able to synthesize it, highlighting that the strain A. fumigatus RC2243, from a milk sample from a cow with clinical mastitis, was the most productive. The existence of fumagillin-producing strains represents a potential risk of mycotoxins being transferred to raw milk, constituting a public health risk.


Open abdominal management after ruptured abdominal aortic aneurysm repair: from a single-center study in Japan.
We investigated the utility of the open abdominal management (OA) technique for ruptured abdominal aortic aneurysm (rAAA). Between January 2016 and August 2021, 33 patients underwent open surgery for rAAA at our institution. The patients were divided into OA (n = 12) and non-OA (n = 21) groups. We compared preoperative characteristics, operative data, and postoperative outcomes between the two groups. The intensive care unit management and abdominal wall closure statuses of the OA group were evaluated. The OA group included significantly more cases of a preoperative shock than the non-OA group. The operation time was also significantly longer in the OA group than in the non-OA group. The need for intraoperative fluids, amount of bleeding, and need for blood transfusion were significantly higher in the OA group than in the non-OA group. Negative pressure therapy (NPT) systems are useful in OA. In five of the six survivors in the OA group, abdominal closure was able to be achieved using components separation (CS) technique. NPT and the CS technique may increase the abdominal wall closure rate in rAAA surgery using OA and are expected to improve outcomes.


Management of urethral diverticulum complicating hypospadias repair.
Urethral diverticula can occur after hypospadias repair, and may lead to stone formation, incomplete voiding, infection, postvoid dribbling, haematuria and other problems. We previously reviewed our experience with hypospadias complications. We separately analyzed those patients who developed urethral diverticula to attempt to identify predisposing factors and appropriate management strategies. We reviewed the available medical records and charts of 123 patients undergoing re-operation for hypospadias complications at The Children's Mercy Hospital from 1 May 1984 until 1 January 2003. Hypospadias cripples, traumatic fistulae, complications after circumcision and true intersex patients were excluded. Diverticula accounted for 11% of all complications (13 patients). The patients with diverticula were more likely to have perineal/proximal hypospadias. The initial repair was island tube urethroplasty in five, island onlay urethroplasty in seven and bladder mucosal graft in one child. The repair of the diverticulum in one stage was successful in 10 of the 13 patients. There was one recurrent diverticulum and two fistulas. A stricture was present in only one of the 13 patients but was detected overall in 14 of the 123 patients (11%). Diverticula are uncommon after hypospadias repair, accounting for 11% of all complications in the present series. The stricture was not causative in 12 of 13 children. Repair of the diverticulum was successful after one attempt in 10 of 13 patients. The management of this complication is discussed.


On the relation between seizures and brain lesions after intracerebroventricular kainic acid.
To analyze the relation between kainic acid-induced limbic seizures and the associated brain lesions, various doses of kainic acid (117-940 pmol) were administered intracerebroventricularly to unanesthetized rats. Rats which experienced status epilepticus developed lesions in several limbic, neocortical and thalamic regions. However, rats which experienced only temporally discrete seizures (less than 30 min each) suffered neuronal degeneration exclusively in the CA3-CA4 area ipsilateral to the kainic acid infusion, even when other regions exhibited the same total electrographic seizure duration. These results can best be explained by postulating that, in addition to evoking seizures, kainic acid also enhances the toxic effects of seizures on CA3-CA4 neurons.


A neutralising monoclonal antibody against a paramyxovirus reacts with a brain antigen.
A monoclonal antibody against simian virus (SV5) HN glycoprotein which specifically neutralises the virus cross-reacts in immunofluorescence with an antigen in the cytoplasm of Purkinje cells of adult rat brain. After fixation in acetic acid-ethanol a cross-reaction is also seen with a myelin component. Cross-reaction of this antibody with human brain was also observed on section using immunofluorescence and in tissue extracts using ELISA and radioimmune assays. Monoclonal antibodies against other viruses, against another epitope on the same virus polypeptide and against another SV5 polypeptide of the same isotype were all negative in these tests.


Urinary PCA3 to predict prostate cancer in a cohort of 1015 patients.
To evaluate the performance of urinary PCA3 test to predict prostate biopsy outcome in a large French cohort. A urine sample was prospectively obtained in 1015 patients undergoing prostate biopsies to determine the PCA3 score. The predictive value of PCA3 was explored using receiver operating characteristic curve analysis (ROC), multivariable logistic regression analysis and decision curve analysis. The median PCA3 score was significantly higher in patients with positive biopsies. The PCA3 score AUC was 0.76 (0.73-0.79), significantly higher than that of PSA (0.55; 0.51-0.58). At the cut-off of 35, sensitivity was 68 %, specificity 71 %, positive and negative predictive values 67 % and 71 %, and accuracy 69 %. Using multivariate analysis, PCA3 score appeared as an independent predictor of biopsy outcome and its addition to a base model including usual clinico-biological parameters resulted in a significant increase in predictive accuracy. At the cut-off of 20, about 1/2 of the eventual useless biopsies would have been avoided while ignoring 7 % of cancers with Gleason score ≥ 7. PCA3 score did not correlate to Gleason score but correlated to tumor volume (proportion of invaded cores). Urinary PCA3 is a useful test with high diagnostic performance for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score.


Sensitive detection of mercury (II) ion using water-soluble captopril-stabilized fluorescent gold nanoparticles.
In our work, a simple, facile, and green method was developed for the synthesis of water-soluble and well-dispersed fluorescent gold nanoparticles (Au NPs) within 5 min, using captopril as a capping agent. The as-prepared Au NPs showed strong emission at 414 nm, with a quantum yield of 5.5%. The fluorescence of the Au NPs can be strongly quenched by mercury (II) ion (Hg(2+)) due to the stronger interactions between thiolates (RS(-)) and Hg(2+). It was applied to the detection of Hg(2+) in water samples in the linear ranges of 0.033-0.133 μM and 0.167-2.500 μM, with a detection limit of 0.017 μM. Therefore, the as-prepared Au NPs can meet the requirement for monitoring Hg(2+) in environmental samples.


Effect of repeated injections of iron dextran on the haematological, serological and pathological changes in experimental avian tuberculosis.
Eight intramuscular injections of 200 mg/kg of iron (DFe), given as iron dextran twice weekly in the week before and the three weeks after intravenous infection with about 10(7.5) colony-forming units of Mycobacterium avium, significantly prolonged (by about 11 days) the mean 'time-to-death' of immature male fowl (Gallus domesticus) compared with corresponding regimes using dextran (Dx) only or saline, When a proportion of the birds were examined 21 days after infection many of the abnormalities associated with the disease, including a marked hypochromic anaemia, were less severe in DFe-treated than in the Dx- or saline-treated chicks and there were about 10- to 85-fold fewer viable tubercle bacilli in the liver and spleen of the DFe-treated birds.


Sandwich type ELISA and a fluorescent cytometric microbead assay for quantitative determination of hepatitis B virus X antigen level in human sera.
The hepatitis B virus X protein (HBxAg) is responsible for severe complications of HBV infections including primary hepatocellular carcinoma. A sandwich type ELISA and a flow cytometric microbead assay for quantitative determination of serum levels of Hbx-Ag are introduced. We have previously developed monoclonal antibody families against well-conserved epitopes on HbxAg, characterized by different immunohistochemical and immunoserological techniques. Special selection of the antibody pairs provided highly sensitive and highly specific tools for quantitative immunoassay development. The resulting assays were tested on human sera (208 samples) collected from patients suffering from different clinical forms of HBV infection. The sensitivity range of the sandwich type ELISA was between 4 and 2000 ng/ml as measured on both the recombinant antigen and the sera of chronic hepatitis patients. A further flow cytometric microbead assay was established and tested in parallel with the ELISA. The quantitative results of these two immunoserological techniques were in strong correlation and they were found to be highly specific and sensitive on clinical samples. The HBxAg ELISA technique is applicable for routine clinical laboratory measurements, and our HBxAg microbead technique is recommended for complex multiparametric measurements combined with other markers.


Normocholesterolemic dysbetalipoproteinemia with xanthomatosis.
A patient is described who has marked palmar xanthomatosis associated with a normal concentration of plasma cholesterol. Analysis of xanthomas revealed them to contain large quantities of cholesterol with both intra- and extracellular lipids. Examination of plasma lipoproteins showed them to be consistent with a pattern of dysbetalipoproteinemia (Type III hyperlipoproteinemia). VLDL had beta-mobility on electrophoresis, a high cholesterol/triglyceride ratio, and increased apoprotein B. However, arginine-rich apoprotein was not increased in VLDL, in contrast to hypercholesterolemic patients with the Type III pattern. Nevertheless, the E3 subfraction of the arginine-rich apoprotein was virtually absent, which is characteristic of dysbetalipoproteinemia. Cholesterol and bile acid synthesis were in the normal range. Thus, of particular interest was the development of severe xanthomatosis without hypercholesterolemia in this patient. Therefore, tissue accumulation of cholesterol was apparently the result of a qualitative abnormality in lipoproteins and not due to an excess of plasma cholesterol.


Triazole fungicides exert neural differentiation alteration through H3K27me3 modifications: In vitro and in silico study.
Considering that humans are unavoidably exposed to triazole fungicides through the esophagus, respiratory tract, and skin contact, revealing the developmental toxicity of triazole fungicides is vital for health risk assessment. This study aimed to screen and discriminate neural developmental disorder chemicals in commonly used triazole fungicides, and explore the underlying harmful impacts on neurogenesis associated with histone modification abnormality in mouse embryonic stem cells (mESCs). The triploblastic and neural differentiation models were constructed based on mESCs to expose six typical triazole fungicides (myclobutanil, tebuconazole, hexaconazole, propiconazole, difenoconazole, and flusilazole). The result demonstrated that although no cytotoxicity was observed, different triazole fungicides exhibited varying degrees of alterations in neural differentiation, including increased ectodermal differentiation, promoted neurogenesis, increased intracellular calcium ion levels, and disturbance of neurotransmitters. Molecular docking, cluster analysis, and multiple linear regressions demonstrated that the binding affinities between triazole fungicides and the Kdm6b-ligand binding domain were the dominant determinants of the neurodevelopmental response. This partially resulted in the reduced enrichment of H3K27me3 at the promoter region of the serotonin receptor 2 C gene, finally leading to disturbed neural differentiation. The data suggested potential adverse outcomes of triazole fungicides on embryonic neurogenesis even under sublethal doses through interfering histone modification, providing substantial evidence on the safety control of fungicides.


Integration of flowering dates in phenology and pollen counts in aerobiology: analysis of their spatial and temporal coherence in Germany (1992-1999).
We studied the possibility of integrating flowering dates in phenology and pollen counts in aerobiology in Germany. Data were analyzed for three pollen types (Betula, Poaceae, Artemisia) at 51 stations with pollen traps, and corresponding phenological flowering dates for 400 adjacent stations (< 25 km) for the years 1992-1993 and 1997-1999. The spatial and temporal coherence of these data sets was investigated by comparing start and peak of the pollen season with local minima and means of plant flowering. Our study revealed that start of birch pollen season occurred on average 5.7 days earlier than local birch flowering. For mugwort and grass, the pollen season started on average after local flowering was observed; mugwort pollen was found 4.8 days later and grass pollen season started almost on the same day (0.6 days later) as local flowering. Whereas the peak of the birch pollen season coincided with the mean flowering dates (0.4 days later), the pollen peaks of the other two species took place much later. On average, the peak of mugwort pollen occurred 15.4 days later than mean local flowering, the peak of grass pollen catches followed 22.6 days after local flowering. The study revealed a great temporal divergence between pollen and flowering dates with an irregular spatial pattern across Germany. Not all pollen catches could be explained by local vegetation flowering. Possible reasons include long-distance transport, pollen contributions of other than phenologically observed species and methodological constraints. The results suggest that further research is needed before using flowering dates in phenology to extrapolate pollen counts.


How Best to Estimate Insertion Length of Multichannel Intraluminal Impedance pH Probes in Children.
To assess the reliability of the KidZ Health Castle formula (KHC-F) to determine the correct probe position of a multichannel intraluminal impedance pH. A retrospective cohort study was performed on 222 children between 1 month and 18 years of age undergoing multichannel intraluminal impedance pH. The primary outcome was the comparison of the pH sensor location determined by the KHC-F with the radiological target position. The margin of error was defined as 1 cm from the target position. Performance of the KHC-F and existing formulas was determined via the percentage with a correct position, mean error, 95% limits of agreement (Bland-Altman plots), and Spearman correlation. A post hoc analysis was performed with an updated KHC-F v2, subtracting -0.5 cm from the KHC-F. Positioning with KHC-F was correct in two-thirds of the participants, with a very strong correlation (ρ = 0.91) with the target position. Bland-Altman plots showed good agreement between KHC-F and target position (mean error of -0.44 cm, lower limit -3.2 cm, upper limit 2.3 cm). A post hoc analysis with the KHC-F v2 showed a correct positioning in 74% of patients. Comparison with other formulas showed a stronger performance of KHC-F and KHC-F v2 on correct positioning, mean error, and 95% limits of agreement. The KHC-F leads to reliable results. KHC-F v2 outperforms all other existing formulas in children, thereby reducing the need for repositioning and the amount of x-ray exposure. The age distribution of the sample may be a limitation, as well as the retrospective nature of the study.


Role of squamous cell carcinoma antigen 1 expression in the invasive potential of head and neck squamous cell carcinoma.
Serine proteases have important roles in tumor invasion and metastasis, and their inhibitors, serine protease inhibitors (serpins), are attractive targets for therapeutic strategies. On chromosome 18q21, there is a cluster of serpins: maspin, headpin, and squamous cell carcinoma antigen 1 (SCCA1)/SCCA2. Others and we have reported that the expression of these serpins is down regulated in head and neck squamous cell carcinoma (HNSCC) cells compared with normal squamous epithelial cells. In this study, we hypothesized that expression of SCCA1 is biologically disadvantageous to HNSCC cells. HNSCC cell lines were transfected with a mammalian expression vector with SCCA1 cDNA. In vitro proliferation, migration, or invasive potential (matrigel assay) of the transfectants were assayed. In addition, the in vivo growth and invasion was analyzed using the floor-of-mouth model of nude mice. SCCA1 expression did not alter the in vitro growth rate of established HNSCC cells. However, SCCA1 expression significantly inhibited the in vitro invasion in matrigel assays. Furthermore, the in vivo growth and invasion in nude mice was also inhibited by SCCA1 expression. Overexpression of SCCA1 in a HNSCC cell line inhibited its invasive potential. Loss of expression of the serpin SCCA1 may play a role in the malignant progression of HNSCC.


Impact of a dry inoculum deposition on the efficacy of copper-based antimicrobial surfaces.
The introduction of antimicrobial surfaces into healthcare environments is believed to impact positively on the rate of healthcare-associated infections by significantly decreasing pathogen presence on surfaces. To report on a novel efficacy test that uses a dry bacterial inoculum to measure the microbicidal efficacy of antimicrobial surfaces. An aerosolized dry inoculum of Staphylococcus aureus or Acinetobacter baumannii was deposited on copper alloy surfaces or a hospital-grade stainless-steel surface. Surviving bacteria were enumerated following incubation of the inoculated surfaces at an environmentally relevant temperature and relative humidity. Damage caused to bacteria by the aerosolization process and by the different surfaces was investigated. Dry inoculum testing showed a <2-log10 reduction in S. aureus or A. baumannii on the copper alloy surfaces tested after 24 h at 20°C and 40% relative humidity. Potential mechanisms of action included membrane damage, DNA damage and arrested cellular respiration. The aerosolization process caused some damage to bacterial cells. Once this effect was taken into account, the antimicrobial activity of copper surfaces was evident. Our test provided a realistic deposition of a bacterial inoculum to a surface and, as such, a realistic protocol to assess the efficacy of dry antimicrobial environmental surfaces in vitro.


Heroin detection in a droplet hosted in a 3D printed support at the miniaturized electrified liquid-liquid interface.
Simple sensing protocols for the detection of illicit drugs are needed. Electrochemical sensing is especially attractive in this respect, as its cost together with the analytical accuracy aspires to replace still frequently used colorimetric tests. In this work, we have shown that the interfacial transfer of protonated heroin can be followed at the electrified water-1,2-dichloroethane interface. We have comprehensively studied the interfacial behavior of heroin alone and in the presence of its major and abundant cutting agents, caffeine and paracetamol. To maximally increase developed sensing protocol applicability we have designed and 3D printed a platform requiring only a few microliters of the aqueous and the organic phase. The proposed sensing platform was equipped with a cavity hosting a short section of Ag/AgCl electrode, up to 20 µL of the aqueous phase and the end of the micropipette tip being used as a casing of a fused silica capillary having 25 µm as the internal pore diameter. The volume of the organic phase was equal to around 5 µL and was present inside the micropipette tip. We have shown that under optimized conditions heroin can be detected in the presence of caffeine and paracetamol existing in a sample with 10,000 times excess over the analyte of interest. The calculated limit of detection equal to 1.3 µM, linear dynamic range spanning to at least 50 µM, good reproducibility, and very low volume of needed sample is fully in line with forensic demands.


Chemo-mechanical and photodynamic approach in A deep dental cavity: A case report.
To test a chemical-mechanical method and antimicrobial photodynamic therapy (a-PDT) in combination to manage a deep dental carious lesion in a permanent molar pediatric patient. Due to specific characteristics of early-erupted teeth, as first permanent lower molars, techniques that provide less invasive tissue removal aiming keep healthy tooth parts, such as pulp tissue, are desired. Furthermore, especially to children, provide comfort, less noise and vibration are important issues that should be considered on the management of deep caries. The following case report presents an association of Papacarie Duo® (PD) and a-PDT used in a 9-year-old patient with a deep dental caries in the mandibular right first molar. After PD application, the carious tissue was carefully removed with the cavity stained for 1 min with rose bengal solution, irradiated with a high intensity LED constituting the a-PDT technique, and definitively restored with composite resin. At 6 months of follow-up, no signs of caries were verified, showing success to applied techniques. A microbiological evaluation attested the antimicrobial effects of the alternative procedures. Although it reached optimal clinical and bacterial reduction outcomes, the approach demonstrated an excessive length of time taken for the management of carious lesion. The use of new technologies should be encouraged, especially when treating deep caries aiming for a less invasive approach.


Effect of prednisolone on motor end-plate fine structure: a morphometric study in hamsters.
The fine structure of quadriceps motor end-plates in hamsters was analyzed quantitatively one, two, four, seven, and thirty-two weeks following intraperitoneal injections of prednisolone. Except for transient increases in postsynaptic length and membrane profile concentration after prednisolone administration at dosages of 4 mgper kilogram of body weight for one week and 2 mg per kilogram for four weeks, mean values for various measurable profiles in the presynaptic and postsynaptic regions showed no significant differences between control and treated animals.


Comparison of classic terminology with the FIGO PALM-COEIN system for classification of the underlying causes of abnormal uterine bleeding.
To compare classic terminology and the PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory disorders, endometrium, iatrogenic, and not classified) classification system among women who underwent surgery for abnormal uterine bleeding (AUB), and to subclassify the components of the PALM group for future studies. In a retrospective study, data were obtained for nonpregnant women aged 18-55years who underwent hysterectomy, myomectomy, or polypectomy for AUB at a center in Turkey in 2014. The patients were retrospectively classified according to the PALM-COEIN system, and the two terminologies were compared. A total of 471 women were included. The term "hypermenorrhea" covered 15 different pathology combinations, "menorrhagia" nine, "metrorrhagia" 14, and "menometrorrhagia" 18. Of 92 patients with polyp, 5 (5.4%) had two polyps and 1 (1.1%) had three. Of 146 patients with adenomyosis, 131 (89.7%) had diffuse adenomyosis and 12 (8.2%) had adenomyoma. Of 309 patients with myoma uteri, 108 (34.9%) had submucous myoma and 201 (65.1%) had other types of myoma. Classic terminology for AUB is insufficient and confusing with respect to etiologic pathologies among nonpregnant women of reproductive age. Widespread adoption of the PALM-COEIN system for AUB classification will facilitate more meaningful communication among both clinicians and investigators, and clarify the populations that should be evaluated in clinical trials, thereby enhancing communication with patients.


Long-term effects of ZnO nanoparticles on nitrogen and phosphorus removal, microbial activity and microbial community of a sequencing batch reactor.
The performance, microbial activity, and microbial community of a sequencing batch reactor (SBR) were investigated under the long-term exposure of ZnO nanoparticles (ZnO NPs). Low ZnO NPs concentration (less than 5mg/L) had no obvious effect on the SBR performance, whereas the removals of COD, NH4(+)-N, and phosphorus were affected at 10-60mg/L ZnO NPs. The variation trend of nitrogen and phosphorus removal rate was similar to that of microbial enzymatic activity with the increase of ZnO NPs concentrations. The richness and diversity of microbial community showed obvious variations at different ZnO NPs concentrations. ZnO NPs appeared on the surface and cell interior of activated sludge, and the Zn contents in the effluent and activated sludge increased with the increase of ZnO NPS concentration. The present results provide use information to understand the effect of ZnO NPS on the performance of wastewater biological treatment systems.


Genetic and epigenetic biomarkers in cancer diagnosis and identifying high risk populations.
Biomarkers present the normal and/or disease state in humans. Genetic and epigenetic biomarkers assessed in easily accessible biological materials are useful in diagnosis, early onset or risk of developing cancer or to predict the treatment efficacy or clinical outcome of different human malignancies. Moreover, some of these markers are expressed during early stages of the tumor development and hence provide an opportunity to develop intervention and treatment strategies. Attempts are being made to validate cancer biomarkers in non-invasively collected samples. Multiplexing of clinically validated markers is still a challenge. Once validated, these markers can be utilized in clinical settings and to identify high risk populations. In this review, the current status of the clinical genetic and epigenetic biomarkers and their implication in cancer diagnosis and risk assessment are discussed.


Use of androgen deprivation therapy in prostate cancer: indications and prevalence.
Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.


Epilepsy and pregnancy: an obstetric perspective.
The purpose of this study was to determine the obstetric and neonatal outcomes of women with prepregnancy diagnoses of epilepsy. This was a cohort study of women with epilepsy (n=414 women) who were delivered in a tertiary referral center (1978-2000). Outcomes were compared with women who did not have epilepsy (n=81,759 women) who were delivered during the same period, with the use of t tests or contingency table analyses. Comparison showed increased rates of nonproteinuric hypertension (P<.05), induction of labor (P<.001), and fetal cardiovascular malformations (P<.001) among women with epilepsy. Rates of other antenatal, intrapartum, and neonatal complications and congenital malformations were similar to those of control subjects. There were fewer instrumental vaginal deliveries. There were no live births with neural tube defects. The occurrence of major antepartum seizures did not increase the rate of adverse outcomes significantly. Major congenital malformations increased in proportion to the number of anticonvulsants that were prescribed. Women with epilepsy are not at increased risk for obstetric complications, provided that appropriate care is available during preconception, pregnancy, labor, delivery, and after delivery.


An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients.
We sought to perform a systematic review and meta-analysis of procalcitonin(PCT)-guided antibiotic therapy algorithms for critically ill adult patients. We performed a search in PubMed and in the Cochrane Central Register of Controlled Trials. Seven evaluable randomised clinical trials (RCTs) were identified and analysed. Primary outcomes included the duration of antibiotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurrences, and superinfections. Data on the duration of antibiotic therapy for the first episode of infection were provided in five out of seven included RCTs, while data on 28-day mortality were provided in all of the included RCTs. Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment [pooled weighted mean difference (WMD) = -3.15 days, random effects model, 95 % confidence interval (CI) -4.36 to -1.95, P < 0.001]. There was no difference in 28-day mortality between the compared arms [fixed effect model (FEM), odds ratio = 0.96, 95 % CI 0.79-1.15, P = 0.63). Antibiotic-free days were increased within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm (pooled WMD = 3.08 days, FEM, 95 % CI 2.06-4.10, P < 0.001). No difference was found regarding the remaining outcomes. Sensitivity analyses including studies of higher quality and studies using the TRACE method to measure PCT yielded similar results. Procalcitonin-guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival.


Seronegative myasthenic crisis: a multicenter analysis.
Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10-15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs.


The effects of indomethacin and PGE2 on vascular reactivity in spontaneously hypertensive rats: possible role of prostaglandins in the pathogenesis of hypertension.
Vascular reactivity was investigated in isolated perfused mesenteric vessels of young and adult SHR and age matched WKY. The primary objective was to investigate whether the difference in vascular reactivity between SHR and WKY would persist if endogenous prostaglandin synthesis was abolished and vascular reactivity restored with fixed exogenous quantities of PGE2. In young rats, when similar concentrations of PGE2 are infused in indomethacin blocked preparations, the difference in vascular reactivity between SHR and WKY is abolished. However, in adult rats the difference persists. It is concluded that enhanced prostaglandin synthesis in hypertension may participate in enhancing vascular reactivity.


Extracellular signal-regulated kinase (ERK) dictates osteogenic and/or chondrogenic lineage commitment of mesenchymal stem cells under dynamic compression.
Elucidating the intracellular signaling cascades which lead to differentiation programs can be a daunting but necessary task. Even more so when the nature of the differentiating stimuli can elicit different biochemical responses yet achieve the same functional outcome. In the field of cartilage and bone regeneration the importance of the extracellular signal-regulated kinase (ERK) pathway has been a controversial issue as of late. Whether differentiation results from a soluble chemical induction or a microenvironmental cue on the cells seems to have a determining effect on the role that this pathway plays in ultimate cell fate. Here we explore the role of the ERK1/2 pathway on the mechanical induction of chondrogenesis of bone marrow mesenchymal stem cells (MSC). The cells were encapsulated in fibrin gel scaffolds and subjected to a dynamic mechanical compression stimulus previously demonstrated to induce chondrogenic differentiation of the cells with and without the addition of PD98059, a selective inhibitor for the ERK1/2 pathway. Samples were then analyzed by RT-PCR and histochemical staining for markers of both chondrogenic and osteogenic differentiation. Our results show that dynamic compression induces the chondrogenic differentiation of the cells and that inhibition of the ERK1/2 pathway completely abolishes this chondrogenic response. On the other hand, inhibition of ERK1/2 under dynamic compression augments the osteogenic response of the cells and significantly increases their expression of alkaline phosphatase (ALP), collagen type I (COLI) and osteocalcin (OCN) (P<0.05). These results were confirmed by the histochemical staining where dynamically compressed samples show staining for sulfated glycosaminoglycans (sGAG) while the inhibited and compressed samples show no sGAG but present positive staining for microcalcifications. These results would suggest that the activation of ERK1/2 can determine the ultimate cell fate between the chondrogenic and osteogenic programs in cells stimulated under dynamic unconfined mechanical compression.


Prevention of arterial structural alterations with verapamil and trandolapril and consequences for mechanical properties in spontaneously hypertensive rats.
We compared the chronic effects in spontaneously hypertensive rats (SHR) of low doses of an angiotensin converting enzyme inhibitor, trandolapril, a Ca2+ channel antagonist, verapamil, and their combination (trandolapril-verapamil), on arterial mechanical properties, arterial wall hypertrophy and extracellular matrix proteins. Four-week-old SHR were randomly allocated to oral treatment with verapamil (50 mg kg(-1) day(-1)), trandolapril (0.3 mg kg(-1) day(-1)), the combination of verapamil (50 mg kg(-1) day(-1)) plus trandolapril (0.3 mg kg(-1) day(-1)), or placebo for 4 months. A group of Wistar Kyoto (WKY) control rats received placebo for the same period of time. At the end of the treatment, mean blood pressure was lower in verapamil-trandolapril than in trandolapril SHR, but remained higher than in WKY. Verapamil had no effects on blood pressure. Equivalent reduction in aortic wall hypertrophy was obtained in all treated SHR. Trandolapril and verapamil-trandolapril combination produced a significant reduction of aortic collagen density compared with placebo SHR. Carotid total fibronectin, EIIIA fibronectin isoform and alpha5beta1 integrin, were higher in the media of placebo SHR than in WKY. EIIIA fibronectin isoform and alpha5beta1 integrin were reduced in verapamil-SHR compared with placebo-SHR and normalized in trandolapril and verapamil-trandolapril-SHR compared with WKY. SHR-placebo and SHR treated with either verapamil or trandolapril as single-drug treatment showed a 4-fold increase in total fibronectin compared to the WKY. Only SHR treated with verapamil-trandolapril combination had total fibronectin not significantly different from that of WKY. Carotid arterial distensibility increased only in verapamil-trandolapril treated rats. Multivariate analysis showed arterial distensibility to be negatively correlated to mean blood pressure (P < 0.0001) and total fibronectin (P < 0.01). In conclusion, chronic treatment with the verapamil-trandolapril combination significantly improved in vivo arterial distensibility in SHR. The most important effects of the combination on arterial mechanics compared to those of verapamil or trandolapril alone may have been the consequence of its stronger action on arterial pressure, arterial wall hypertrophy and total fibronectin density. However we suggest that, in addition to the structural effects, complete normalization of blood pressure is necessary to obtain normal arterial distensibility.


Fibular bowing due to tibial shortening in isolated fracture of the tibia: failure of late segmental fibulectomy to relieve ankle pain.
Fracture of the tibia with an intact fibula is prone to delayed and nonunion or varus malunion and, as a complication of the latter, late arthrosis of the ankle joint. A less well-known type of malunion is tibial shortening with fibular bowing due to relative fibular lengthening. We present such a case with chronic ankle pain. Late segmental fibulectomy failed to improve the symptoms. We recommend primary segmental fibulectomy in all isolated fractures of the tibial shaft in adults and adolescents, in order to forestall the early and late complications.


[Development and Evaluation of Motivational Interviewing Pulmonary Rehabilitation Program Based on Self-Determination Theory for Patients with Chronic Obstructive Pulmonary Disease].
This study aimed to develop a motivational interviewing pulmonary rehabilitation program based on self-determination theory to maintain pulmonary rehabilitation-related health behaviors in patients with chronic obstructive pulmonary disease. The program was developed by reviewing the literature on pulmonary rehabilitation guidelines, drawing on the self-determinism theory to establish its contents, recruiting experts to test its validity, and conducting a preliminary survey. A quasi-experimental design was used to confirm the effect of the program. The participants were outpatients diagnosed with chronic obstructive pulmonary disease at three general hospitals in Busan. There were 33 subjects: 15 in the experimental group and 18 in the control group. The experimental group performed a motivational interviewing pulmonary rehabilitation program which comprised 11 sessions delivered over 10 weeks. The outcomes were measured using basic psychological needs, dyspnea, 6-minute walking distance, and functional status. Intervention effects were analyzed using repeated-measures ANOVA. The analysis revealed significant differences between the experimental and control groups in competence among the subdomains of basic psychological needs, dyspnea during exercise, and functional status. The developed program affects physical conditions and can be applied as an effective clinical nursing intervention to continuously improve the pulmonary rehabilitation behavior of patients with chronic obstructive pulmonary disease.


Aminoquinoline-anchored polynorbornene for sequential fluorescent sensing of Zn2+ and ATP.
A novel aminoquinoline functionalized norbornene (1) and its ring-opening metathesis polymerization (ROMP) copolymer P1 have been designed and synthesized. The polymer probe P1 can self-assemble nano aggregation in aqueous solution. The fluorescent experiments revealed that both 1 and P1 show a ratiometric fluorescence response toward Zn2+ over other mental ions in Tris-HCl buffer solution, with the polymer probe P1 shows a better photostability and higher binding affinity than that of the small molecular probe 1. Furthermore, the in situ formed P1-Zn2+ ensemble was successfully used as the secondary sensor for ATP. P1 is also successfully used for monitoring intracellular Zn2+ and ATP in living cells.


Looking for an accurate mirror: a model for the relationship between media use and anorexia.
Quantitative research suggests a relationship exists between anorexia and media messages which depict a "thin-ideal" female stereotype. Despite growing support for that relationship, little is known about the psychological processes and mechanisms involved in that relationship. This study used qualitative methods to explore those processes and mechanism to create a model for understanding the relationship between anorexia and media use. Interviews from 28 female participants were analyzed and coded for temporal, situational, and motivational relationships between the anorexic behaviors and media use. Results suggest an interactive, circular model similar to models used to explain other compulsive and addictive processes.


Central nervous system action of peptides to influence gastrointestinal motor function.
The central action of peptides to influence GI motility in experimental animals is summarized in Table 1. TRH stimulates gastric, intestinal, and colonic contractility in rats and in several experimental species. A number of peptides including calcitonin, CGRP, neurotensin, NPY, and mu opioid peptides act centrally to induce a fasted MMC pattern of intestinal motility in fed animals while GRF and substance P shorten its duration. The dorsal vagal complex is site of action for TRH-, bombesin-, and somatostatin-induced stimulation of gastric contractility, and for CCK-, oxytocin- and substance P-induced decrease in gastric contractions or intraluminal pressure. The mechanisms through which TRH, bombesin, calcitonin, neurotensin, CCK, and oxytocin alter GI motility are vagally mediated. An involvement of central peptidergic neurons in the regulation of gut motility has recently been demonstrated in Aplysia, indicating that such regulatory mechanisms are important in the phylogenesis. Alterations of the pattern of GI motor activity are associated with functional changes in transit. TRH is so far the only centrally acting peptide stimulating simultaneously gastric, intestinal, and colonic transit in various animals species. Opioid peptides acting on mu receptor subtypes in the brain exert the opposite effect and inhibit concomitantly gastric, intestinal, and colonic transit. Bombesin and CRF were found to act centrally to inhibit gastric and intestinal transit and to stimulate colonic transit in the rat. The antitransit effect of calcitonin and CGRP is limited to the stomach and small intestine. The delay in GI transit is associated with reduced GI contractility for most of the peptides except central bombesin that increases GI motility. Nothing is known about brain sites through which these peptides act to alter gastric emptying and colonic transit. Regarding brain sites influencing intestinal transit, TRH-induced stimulation of intestinal transit in the rat is localized in the lateral and medial hypothalamus and medial septum. The periaqueductal gray matter is a responsive site for mu receptor agonist- and neurotensin-induced inhibition of intestinal transit. The neural pathways from the brain to the gut whereby these peptides express their stimulatory or inhibitory effects on GI transit is vagal dependent with the exception of calcitonin. It is not known whether the vagally mediated inhibition of GI transit by these peptides results from a decrease activity of vagal preganglionic fibers synapsing with excitatory myenteric neurons or an activation of vagal preganglionic neurons synapsing with inhibitory myenteric neurons. The lack of specific antagonists for these peptides has hampered the assessment of their physiological role.(ABSTRACT TRUNCATED AT 400 WORDS)


Pathologic substrate of gastropathy in Anderson-Fabry disease.
In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.


[False-positive findings in the 99mTc-MIBI SPECT of left bundle branch block and angiographic excluded coronary artery disease].
In a patient with left bundle branch block exercise/rest SPECT using 99mTc-MIBI revealed exercise-induced ischemia. After exclusion of significant coronary artery stenosis by angiography early dilated cardiomyopathy was assumed. Scintigraphic findings using 99mTc-MIBI SPECT in patients with left bundle branch block are discussed.


Comparisons of the nonlinear dynamics of electroencephalograms under various task loading conditions: a preliminary report.
Comparison of the characteristics of electroencephalogram (EEG) records treated as realizations from a nonlinear process were compared under four different conditions: eyes shut resting, and three silent observation instructions to predict the patterns of randomly generated lights which illuminated every 10 seconds. The correlation dimension of the EEG was calculated by a method involving finding the correlation integral in m-dimensional space, and found to show some variations within time series. The degree and directions of changes in the dimensionality of the process varied between observers and did not clearly confirm some earlier reported findings, but it is demonstrable that the measures of nonlinear brain dynamics can be correlated with psychological variables. Reasons for this are discussed.


Antimicrobial activity in cord blood units: occurrence and levels of antibiotics.
Antibiotic prophylaxis treatment at delivery is highly recommended for reducing the risk of infection for mothers positive for group B streptococcus. It is therefore expected that some cord blood (CB) products will contain residual antibiotics. This study aimed to determine the incidence and level of β-lactam antibiotics in CB products. The antimicrobial activity of 60 CB plasma by-products was evaluated using disk diffusion assays on 10 bacteria species. Plasma samples showing antimicrobial activity were either treated with β-lactamase enzyme to inhibit β-lactam antibiotics or heated to 56°C for 30 minutes to inhibit complement proteins. β-Lactam antibiotic concentrations were determined by comparison with a standard curve obtained with known concentrations of antibiotics. Antimicrobial activity against mostly Gram-positive microorganisms was observed in 33% of CB units. The β-lactamase enzyme abolished the antimicrobial activity in the majority of these CB products. Up to 5 μg/mL penicillin and 14 μg/mL ampicillin were measured in these products. Approximately one-third of CB products contain significant amounts of plasma with residual antibiotics, which can affect the survival and growth of bacterial contaminants when performing the sterility test and potentially lead to false-negative results. Additional work is required to better understand whether residual antibiotics in CB affect penicillin-allergic patients.


Correction to: A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia.
The original article [1] contains an error in authorship whereby author, Robert Weinkove's name is mistakenly inverted. The configuration noted in this Correction article should be considered instead along with author's updated affiliation.


Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database.
The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone. From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy +/- chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age. Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base (p = 0.007). However, there is no significant difference between the survival curves (p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%. While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.


Catalysis of copper corrosion products on chlorine decay and HAA formation in simulated distribution systems.
This study investigated the effect of copper corrosion products, including Cu(II), Cu(2)O, CuO and Cu(2)(OH)(2)CO(3), on chlorine degradation, HAA formation, and HAA speciation under controlled experimental conditions. Chlorine decay and HAA formation were significantly enhanced in the presence of copper with the extent of copper catalysis being affected by the solution pH and the concentration of copper corrosion products. Accelerated chlorine decay and increased HAA formation were observed at pH 8.6 in the presence of 1.0 mg/L Cu(II) compared with that observed at pH 6.6 and pH 7.6. Further investigation of chlorine decay in the presence of both Suwannee River NOM and Cu(II) indicated that an increased reactivity of NOM with dissolved and/or solid surface-associated Cu(II), rather than chlorine auto-decomposition, was a primary reason for the observed rapid chlorine decay. Copper corrosion solids [Cu(2)O, CuO, Cu(2)(OH)(2)CO(3)] exhibited catalytic effects on both chlorine decay and HAA formation. Contrary to the results observed when in the absence of copper corrosion products, DCAA formation was consistently predominant over other HAA species in the presence of copper corrosion products, especially at neutral and high pH. This study improves the understanding for water utilities and households regarding chlorine residuals and HAA concentrations in distribution systems, in particular once the water reaches domestic plumbing where copper is widely used.


How Can We Better Prevent Obesity in Children?
The aim of this review is to discuss the state of the art regarding the field of health promotion in the context of childhood obesity prevention in order to learn how we can better prevent childhood obesity. Challenges have been identified that exist within the different steps of health promotion programme development and implementation. Important steps forward include studying behaviours and determinants of behaviours as clusters, upgrading the importance of distal environmental factors in modelling determinants and understanding determinants as a dynamic system: a complex of interacting elements. An important note is that the process of implementation and the analysis thereof should more often come before the analysis of behaviours and the determinants of behaviour. In applied research, the expertise from the 'real world' practitioners should be used in an early stage to find out whether the answers on research questions really help us in preventing childhood obesity.


VAOS, a novel vanadyl complexes of alginate saccharides, inducing apoptosis via activation of AKT-dependent ROS production in NSCLC.
Previous studies have confirmed that protein tyrosine phosphatase 1B (PTP1B) can promote tumour progression in non-small cell lung cancer (NSCLC). Vanadyl alginate oligosaccharides (VAOS) is a new coordination compounds that possesses a good PTP1B inhibitory activity. However, the potent anticancer efficacy of VAOS in human NSCLC requires further study. In this study, VAOS exhibited effective inhibitory effects in NSCLC both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. Neither silencing of PTP1B by siRNA nor transient overexpression of PTP1B had an effect on the AKT phosphorylation triggered by VAOS, indicating that PTP1B inhibition was not involved in VAOS-induced apoptosis. Through phosphorus colorimetric assay, we demonstrated that VAOS notably inhibited phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylation activity, another member of the protein tyrosine phosphatases (PTPases)-upstream factor of AKT. Interestingly, PTEN knockdown sensitized cells to VAOS, whereas ectopic expression of PTEN markedly rescued VAOS-mediated lethality. In vivo, VAOS treatment markedly reduced PTEN activity and tumour cell burden with low systemic toxicity. Thus, our data not only provided a new therapeutic drug candidate for NSCLC, but presented new understanding into the pharmacological research of VAOS.


Association between a stromal cell-derived factor 1 (SDF-1/CXCL12) gene polymorphism and microvascular disease in systemic sclerosis.
To investigate the possible implication of SDF1-3' polymorphism in systemic sclerosis (SSc) susceptibility or clinical phenotype, or both. 150 patients with SSc and 150 controls were enrolled. Skin involvement, autoantibodies, interstitial lung disease, pulmonary arterial hypertension (PAH), scleroderma renal crisis, past and/or current skin ulcers were assessed. Genotyping was performed by PCR-RFLP. Genotype distribution and allele frequency were similar in SSc and controls. SDF1-3'A allele and SDF1-3'GA/AA genotype frequencies were significantly higher in SSc-PAH than in SSc-non-PAH (33.3% vs 18.3%, p = 0.01) and in SSc with skin ulcers than in SSc without ulcers (27.3% vs 16.9%, p = 0.03). The SDF1-3'A allele influenced the predisposition to SSc-related PAH (OR = 2.52, 95% CI 1.11 to 5.69, p = 0.02) and skin ulcers (OR = 2.31, 95% CI 1.18 to 4.52, p = 0.01). After adjustment for age and gender, the SDF1-3'A allele remained a susceptibility factor for the SSc-related vascular manifestations (PAH: OR = 2.37, 95% CI 1.04 to 5.42, p = 0.04; ulcers: OR = 2.33, 95% CI 1.78 to 4.62, p = 0.01). The SDF1-3'A allele is significantly associated with microvascular involvement in SSc.


mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia.
Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.


A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway.
Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.


Cardiac magnetic resonance analysis of right ventricular function: comparison of quantification in the short-axis and 4-chamber planes.
To compare the methods of right ventricle segmentation in the short-axis and 4-chamber planes in cardiac magnetic resonance imaging and to correlate the findings with those of the tricuspid annular plane systolic excursion (TAPSE) method in echocardiography. We used a 1.5T MRI scanner to study 26 patients with diverse cardiovascular diseases. In all MRI studies, we obtained cine-mode images from the base to the apex in both the short-axis and 4-chamber planes using steady-state free precession sequences and 6mm thick slices. In all patients, we quantified the end-diastolic volume, end-systolic volume, and the ejection fraction of the right ventricle. On the same day as the cardiac magnetic resonance imaging study, 14 patients also underwent echocardiography with TAPSE calculation of right ventricular function. No statistically significant differences were found in the volumes and function of the right ventricle calculated using the 2 segmentation methods. The correlation between the volume estimations by the two segmentation methods was excellent (r=0,95); the correlation for the ejection fraction was slightly lower (r=0,8). The correlation between the cardiac magnetic resonance imaging estimate of right ventricular ejection fraction and TAPSE was very low (r=0,2, P<.01). Both ventricular segmentation methods quantify right ventricular function adequately. The correlation with the echocardiographic method is low.


Risk Factors and Overcoming Strategies of Surgical Site Infection After Hepatectomy for Colorectal Liver Metastases.
The aim of this study was to investigate the risk factors of surgical site infection (SSI) in patients who underwent liver resection for colorectal liver metastases (CRLM). A total of 151 patients who underwent liver resection for CRLM were included in this study. We investigated the relationship between the patient characteristics and perioperative factors and the incidence of SSI. Nineteen (13%) of these patients developed SSI. Multivariate analysis revealed that modified Glasgow Prognostic Score (mGPS) (1 or 2, odds ratio 3.86, p=0.03) and presence of an enterostomy (yes, odds ratio 3.93, p=0.04) were significant and independent risk factors for SSI. A higher mGPS and an enterostomy were risk factors for SSI in patients who underwent a liver resection for CRLM.


Submassive hepatic necrosis associated with the use of progabide: a GABA receptor agonist.
Progabide, a recently introduced gamma-aminobutyric acid mimetic, is currently undergoing clinical evaluation for a variety of convulsive disorders. We describe a patient in whom severe hepatic failure developed after four weeks of Progabide therapy. The patient's course was marked by encephalopathy, jaundice, hypoglycemia, markedly elevated serum aminotransferase levels, and prolongation of the prothrombin time. Liver biopsy showed extensive hepatocellular necrosis. The patient recovered slowly after discontinuation of the drug. The finding of eosinophilia and increased serum IgE suggests an immunologically mediated mechanism for the Progabide-induced hepatic injury. Alternatively, the lipophilic moiety of Progabide may interact with hepatocyte cell membrane lipids leading to toxic injury. We conclude that Progabide may occasionally cause severe hepatic injury.


New therapies for ovarian cancer: cytotoxics and molecularly targeted agents.
Ovarian cancer, although a chemo-sensitive disease, is associated with high morbidity and mortality due to its often-late presentation. Platinums and taxanes have improved the prognosis over recent years but median overall survival is still unacceptably low (24-60 months). Apart from the manipulation of doses, schedules, mode of delivery, and combinations of existing drugs, new cytotoxics and molecularly targeted agents with different mechanisms of action must be evaluated in this patient population. This article will review the most recent clinical trials data pertaining to these new cytotoxic drugs including patupilone, telcyta, and trabectedin, as well as those of small molecules and inhibitors of the EGFR and VEGF receptor families. It will also discuss other potential signal transduction targets worthy of further evaluation in future trials.


Mouse models of nonalcoholic steatohepatitis and their application to new drug development.
Nonalcoholic steatohepatitis (NASH) is one of the important liver diseases currently attracting attention in liver research and drug development. Appropriate mouse models should be used to identify the mechanisms underlying the pathogenesis and progression of NASH in humans and to evaluate the efficacy of anti-NASH agents under development to treat this disease. In this review, we first summarised recent histopathology and pathogenesis of NASH in humans, including the concept of resolution of inflammation. We also examined whether these characteristics of NASH in humans are adequately reflected in mouse models. Through this review, we identified the usefulness and limitations of mouse models widely used in research on NASH. Mouse models can be divided into three main types: diet models, chemical models using toxic compounds, and genetic models using genetically transgenic mice. Genotype models are likely suitable for evaluating anti-NASH compounds because fibrosis, which is considered an important index to determine the drug efficacy of NASH inhibitors, is rapidly induced in genetic models. Using these models, we introduced some selected cases of NASH inhibitor development. This review aims to enhance the understanding of the pathogenesis of NASH and provide a basis for successfully selecting and utilising appropriate animal models of NASH in the development of effective inhibitors.


Multifunctional nanoadjuvant-driven microenvironment modulation for enhanced photothermal immunotherapy in breast cancer.
Intracellular redox imbalance, achieved by exploiting the tumor microenvironment (TME), has emerged as a promising strategy for cancer therapy. In this study, we developed a multifunctional nanoadjuvant, termed GITFe/Z-HA, by modified a metal-organic backbone Fe/ZIF-8 with hyaluronic acid (HA) targeting. The nanocarriers were loaded with glucose oxidase (Gox), neoindocyanine green (IR820) and tilazamine (TPZ). This design aimed to achieve a cascade reaction within tumor cells, mediated by Gox, Fe3+, and IR820, which consumes intrinsic glucose and oxygen, leading to an elevated production of reactive oxygen species (ROS). This cascade reaction creates a hypoxic environment conducive for TPZ to exert its therapeutic action. Consequently, the combination of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy demonstrates a good synergistic effect. Moreover, the imbalanced ROS/glutathione (GSH) induced by this treatment approach, along with PTT, promote immunogenic cell death (ICD). This ICD triggers the release of damage-related molecular patterns and CD8+ lymphocyte infiltration sensitizes the immune checkpoint blockade (αPD-L1) response, thereby eliciting a systemic anti-tumor immune response. Collectively, this comprehensive treatment regimen, driven by environmentally stimulated multiple pathways, overcomes the limitations of single therapeutic modalities, thereby improving tumor outcomes. Additionally, these findings provide valuable insights for strategies aimed at modulating the tumor immune microenvironment.


A novel model selection strategy using total error concept.
Our previous work had proved that accuracy profile theory could be employed as a means of validating one PLS model in Chinese material medica system. In this paper, accuracy profile theory is proposed as a powerful decision tool to demonstrate the prediction performance of multi-model at each concentration level rather than all concentration levels. Partial least square (PLS), interval partial least square (iPLS), backward interval partial least square (BiPLS) and moving window partial least square (MWPLS) were selected to construct visible and near-infrared (vis/NIR) spectroscopy models. Chemometric indicators, i.e., determination coefficient (R(2)), root-mean-square error of prediction (RMSEP) and ratio of performance to inter-quartile (RPIQ), were used to select the optimum model. However, the results clarified that these commonly used indicators could not clearly demonstrate different PLS models' ability because these indicators depend on all concentration levels to assess the multi-model. Therefore, "total error concept" (accuracy profile theory) was introduced to assess the ability of multi-model at each concentration level. Analytical methodology parameters, i.e., linearity, relative bias, uncertainty, repeatability, intermediate precision, lower limit of quantification (LLOQ) and risk, were calculated by accuracy profile theory. Final results showed that model selection strategy which was based on model assessment at every concentration level was more sensitive than the one based on all concentration levels. The analytical procedures involved in this work ensure that model selection strategy using total error concept is coherent.


Primary liposarcoma of the fibular head: A rare location for a rare tumor: A case report.
Primary bone liposarcoma are extremely rare tumors and their location in the fibular head is exceptional. A 19 year-old patient with a pain on the lateral of the proximal leg. The X-ray found an osteolytic lesion; MRI of the knee revealed a proximal epiphyseal-metaphyseal lesion process of the right fibula contours with cortical lysis and local medullary damage. The pathological study, follow by the immunohistochemical exam and the FISH concluded in an amplification of MDM2 (Murine double minute 2) confirming the presence of a liposarcoma. The primary bone localization of liposarcomas remains rare. Their localization at the level of the fibular head is exceptional. The proximal fibula is mainly affected by benign tumors, in particular giant cell. Malignant tumors localized to the head of the fibula as well as aggressive benign tumors most often require en bloc resection. Although rare, primary liposarcomas can localize to the head of the fibula. It is necessary to establish a clinical, radiological and histological diagnosis for adequate management.


Peritoneal Tuberculosis Mimicking Peritoneal Carcinomatosis on 68 Ga-FAPI-04 and 18 F-FDG PET/CT.
We report a case of tuberculosis peritonitis in a 26-year-old woman who presented with abdominal pain, fatigue, and weight loss for the last 4 months. Abdominal US and CT demonstrated intra-abdominal massive ascites, misty mesentery, and diffuse peritoneal thickening. In addition, 3 nodular lesions were detected in the right lung. 18 F-FDG PET/CT showed hypermetabolism in lung nodules, mesenteric area, peritoneal thickening, and ascites. 68 Ga-FAPI-04 (fibroblast activation protein-specific inhibitor) PET/CT imaging was also performed; high uptakes were detected in the same regions of 18 F-FDG PET/CT. Tuberculosis diagnosis was made after histopathological examination of wedge resection of the right lung.


The relation between caries prevalence and strontium concentrations in drinking water, plaque, and surface enamel.
Samples of plaque and surface enamel were collected from 80 boys aged 14 years living in five communities in Ohio (USA). Mean (+/- SE) strontium concentrations in plaque were 1.43 +/- 0.18 micrograms/g (wet) and 12.34 +/- 1.63 micrograms/g (dry). For surface enamel, the mean concentration was 421 +/- 31 micrograms Sr/g. Concentrations of strontium in both plaque and enamel were significantly related to strontium levels in the drinking water. Caries prevalence as DMFS was inversely related to strontium levels in water, plaque, and enamel.


Isolation and characterization of cidofovir resistant vaccinia viruses.
The emergence of drug resistant viruses, together with the possibility of increased virulence, is an important concern in the development of new antiviral compounds. Cidofovir (CDV) is a phosphonate nucleotide that is approved for use against cytomegalovirus retinitis and for the emergency treatment of smallpox or complications following vaccination. One mode of action for CDV has been demonstrated to be the inhibition of the viral DNA polymerase. We have isolated several CDV resistant (CDVR) vaccinia viruses through a one step process, two of which have unique single mutations within the DNA polymerase. An additional resistant virus isolate provides evidence of a second site mutation within the genome involved in CDV resistance. The CDVR viruses were 3-7 fold more resistant to the drug than the parental viruses. The virulence of the CDVR viruses was tested in mice inoculated intranasally and all were found to be attenuated. Resistance to CDV in vaccinia virus can be conferred individually by at least two different mutations within the DNA polymerase gene. Additional genes may be involved. This one step approach for isolating resistant viruses without serial passage and in the presence of low doses of drug minimizes unintended secondary mutations and is applicable to other potential antiviral agents.


Factors determining when to start levodopa/carbidopa/entacapone treatment in Spanish patients with Parkinson's disease.
Several therapeutic options are available for the symptomatic treatment of Parkinson's disease (PD).There is no reliable information about which factors are involved in the choice of treatment. To identify factors contributing to the decision to start treatment with levodopa/carbidopa/entacapone (LCE) in patients with PD. We completed a descriptive cross-sectional retrospective multicentre study of patients with idiopathic PD receiving LCE. Clinical data were collected with special attention to factors that could potentially determine when to initiate treatment with LCE in normal clinical practice. We studied 1050 patients with a mean age of 71.3±8.7 years (58.2% men). Average time from onset of symptoms to diagnosis was 13.8±12.9 months, with a latency time of 74.5±53.6 months before starting LCE treatment. The most common initial symptoms were tremor (70.6%), reduced dexterity (43.2%) and slowness of movement (41.5%). At the start of LCE treatment, most patients were in Hoehn and Yahr stage 2 (57.5%), with an average rating of 73.4% on the Schwab & England scale. Eight hundred twenty two patients (78.3%) received treatment with other drugs before starting LCE (mean time between starting any PD treatment and starting LCE was 40.5±47.2 months). Clinical factors with a moderate, marked, or crucial effect on the decision to start LCE treatment were bradykinesia (84.7%), daytime rigidity (72.2%), general decline (72.2%), difficulty walking (66.4%), tremor (62.7%), nocturnal rigidity (56.1%), and postural instability (53%). Difficulty performing activities of daily living was the only psychosocial factor identified as having an influence on the decision (84.3%). The decision to start patients with idiopathic PD on LCE treatment is mainly determined by motor deficits and disabilities associated with disease progression.


Development and internal validation of a risk model for hyperuricemia in diabetic kidney disease patients.
This research aimed to identify independent risk factors for hyperuricemia (HUA) in diabetic kidney disease (DKD) patients and develop an HUA risk model based on a retrospective study in Ningbo, China. Six hundred and ten DKD patients attending the two hospitals between January 2019 and December 2020 were enrolled in this research and randomized to the training and validation cohorts based on the corresponding ratio (7:3). Independent risk factors associated with HUA were identified by multivariable logistic regression analysis. The characteristic variables of the HUA risk prediction model were screened out by the least absolute shrinkage and selection operator (LASSO) combined with 10-fold cross-validation, and the model was presented by nomogram. The C-index and receiver operating characteristic (ROC) curve, calibration curve and Hosmer-Lemeshow test, and decision curve analysis (DCA) were performed to evaluate the discriminatory power, degree of fitting, and clinical applicability of the risk model. Body mass index (BMI), HbA1c, estimated glomerular filtration rate (eGFR), and hyperlipidemia were identified as independent risk factors for HUA in the DKD population. The characteristic variables (gender, family history of T2DM, drinking history, BMI, and hyperlipidemia) were screened out by LASSO combined with 10-fold cross-validation and included as predictors in the HUA risk prediction model. In the training cohort, the HUA risk model showed good discriminatory power with a C-index of 0.761 (95% CI: 0.712-0.810) and excellent degree of fit (Hosmer-Lemeshow test, P > 0.05), and the results of the DCA showed that the prediction model could be beneficial for patients when the threshold probability was 9-79%. Meanwhile, the risk model was also well validated in the validation cohort, where the C-index was 0.843 (95% CI: 0.780-0.906), the degree of fit was good, and the DCA risk threshold probability was 7-100%. The development of risk models contributes to the early identification and prevention of HUA in the DKD population, which is vital for preventing and reducing adverse prognostic events in DKD.