Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876; NCT01507831; NCT01623115; NCT01709500; NCT01617655; NCT01709513) were sequenced for mutations in LDLR, apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB-defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR-defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR-negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB-defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment.


Non-invasive pulmonary aerosol delivery in mice by the endotracheal route.
In this report we present in detail a non-invasive pulmonary application method that can be a useful tool in studying drug and vaccine delivery to the lower airways. In this method the formulation is sprayed directly into the lungs of mice via the endotracheal route using a MicroSprayer aerolizer. Mean droplet size produced was 8 microm, appropriate for deposition in the large airways. Endotracheal application of suspension of fluorescent nanospheres, 200 nm in size, by this method resulted in nanoparticle deposition in the smaller airways (bronchi and bronchioles). Mice showed full recovery one day after administration of 50 microl of formulation. Furthermore, no mortality was observed as a result of the technique. We conclude that this endotracheal application is a useful tool for studying pulmonary drug delivery in mice. The technique is especially useful for the pulmonary application of vaccines, since it enables multiple administrations without a need for analgesics.


How efficiently does a metabolically enhanced system with denitrifying anaerobic methane oxidizing microorganisms remove antibiotics?
In this work, the novel N-damo (Nitrite dependent anaerobic methane oxidation) process was investigated at high biomass activities for its potential to remove simultaneously nitrite and methane, as well as selected antibiotics commonly found in sewage in trace amounts. For this purpose, two MBRs were operated at three high nitrite loading rates (NLRs), namely 76 ± 9.9, 161.5 ± 11.4 and 215.2 ± 24.2 mg N-NO⁻2 L-1 d-1, at long-term operation. The MBRs performance achieved a significantly high nitrite removal activity for an N-damo process (specific denitrifying activity of up to 540 mg N-NO⁻2 g-1 VSS d-1), even comparable to heterotrophic denitrification values. In this study, we have implemented a novel operational strategy that sets our work apart from previous studies with similar bioreactors. Specifically, we have introduced Cerium as a trace element in the feeding medium, which serves as a key differentiating factor. It allowed maintaining a stable reactor operation at high NLRs. Microbial community composition evidenced that both MBRs were dominated with N-damo bacteria (67-87% relative abundance in period III and I, respectively). However, a decrease in functional N-damo bacteria (Candidatus Methylomirabilis) abundance was observed during the increase in biomass activity and concentration, concomitantly with an increase of the other minor families (Hypomicrobiaceae and Xanthobacteraceae). Most of the selected antibiotics showed high biotransformation such as sulfamethoxazole, trimethoprim, cefalexin and azithromycin, whereas others such as roxithromycin and clarithromycin were only partially degraded (20-35%). On the contrary, ciprofloxacin showed almost no removal. Despite the metabolic enhancement, no apparent increase on the antibiotic removal was observed throughout the operation, suggesting that microbiological composition was of greater influence than its primary metabolic activity on the removal of antibiotics.


Body image dissatisfaction and depression in postbariatric patients is associated with less weight loss and a desire for body contouring surgery.
Overhanging skin in postbariatric patients leads to a negative body image. In patients with obesity, negative body image is related to more depressive symptoms and a higher weight. This relationship might also be important in postbariatric patients, because improvement of body image via body contouring surgery (BCS) could lead to better weight loss results. To evaluate the relationship between body image, depressive symptoms, and weight loss in a postbariatric population, focusing on desire for BCS. Outpatient clinic. One thousand twenty-four primary bariatric surgery patients were contacted, and 590 patients agreed to participate and filled in online questionnaires regarding body image (Body Shape Questionnaire and Multidimensional Body-Self Relations Questionnaire-Appearance Scales) and depression (Beck Depression Inventory-II). Differences between patients who had BCS, patients who desired BCS, and patients who did not desire BCS were studied. The mediating role of body image in the association between percentage total weight loss and depressive symptoms was assessed via a 2-mediator model. There was a desire for BCS in 368 patients (62.4%); these patients had significantly lower scores on appearance evaluation and body image satisfaction scales and showed more depressive symptoms. Patients without a desire (n = 157, 26.6%) had lowest rates of depressive symptoms and a more positive body image. Sixty-five patients (11.0%) had undergone BCS. In the patients who desired BCS, percentage total weight loss was negatively affected by depressive symptoms via appearance evaluation and body-area satisfaction. There are striking differences regarding body image satisfaction and depressive symptoms when comparing postbariatric patients and without desire for BCS. Body image satisfaction is associated with less depressive symptoms in all postbariatric patients. In patients who desired BCS, body image is one of the mediators of the relationship between percentage total weight loss and depressive symptoms. Therefore, body image should be taken seriously and be part of outcome assessment in postbariatric patients.


Brain co-delivery of first-line chemotherapy drug and epigenetic bromodomain inhibitor for multidimensional enhanced synergistic glioblastoma therapy.
Glioblastoma (GBM) is a central nervous system tumor with poor prognosis due to the rapid development of resistance to mono chemotherapy and poor brain targeted delivery. Chemoimmunotherapy (CIT) combines chemotherapy drugs with activators of innate immunity that hold great promise for GBM synergistic therapy. Herein, we chose temozolomide, TMZ, and the epigenetic bromodomain inhibitor, OTX015, and further co-encapsulated them within our well-established erythrocyte membrane camouflaged nanoparticle to yield ApoE peptide decorated biomimetic nanomedicine (ABNM@TMZ/OTX). Our nanoplatform successfully addressed the limitations in brain-targeted drug co-delivery, and simultaneously achieved multidimensional enhanced GBM synergistic CIT. In mice bearing orthotopic GL261 GBM, treatment with ABNM@TMZ/OTX resulted in marked tumor inhibition and greatly extended survival time with little side effects. The pronounced GBM treatment efficacy can be ascribed to three key factors: (i) improved nanoparticle-mediated GBM targeting delivery of therapeutic agents by greatly enhanced blood circulation time and blood-brain barrier penetration; (ii) inhibited cellular DNA repair and enhanced TMZ sensitivity to tumor cells; (iii) enhanced anti-tumor immune responses by inducing immunogenic cell death and inhibiting PD-1/PD-L1 conjugation leading to enhanced expression of CD4+ and CD8+ T cells. The study validated a biomimetic nanomedicine to yield a potential new treatment for GBM.


Radiation-induced trismus in head and neck cancer patients.
To determine the incidence of trismus in patients who had previously received curative doses of radiation therapy (RT) for head and neck cancer. In addition, we assessed if trismus was associated with quality of life deficits and radiation toxicity. Between February, 2005 and December, 2006, 40 patients with histologically confirmed head and neck cancer who had received curative doses of RT to the area(s) of the masticatory muscles and/or the ligaments of the temporomandibular joint (TMJ) were enrolled in this study. Differences in trismus incidence were compared between cancer treatment modalities [i.e., RT vs RT/chemotherapy (CT) and conventional RT vs intensity modulated RT]. Quality of life (QOL) was measured by using four questions from the EORTC QLQ-C30 that address pain and difficulty opening the jaw. Scores regarding impaired eating as a result of decreased range of motion of the mouth were derived from the Modified Common Toxicity Criteria (CTCAE Version 3.0). Trismus was identified in 45% of subjects who had received curative doses of RT. No differences were noted in the incidence of trismus between RT and RT/CT or between conventional RT and intensity modulated RT (IMRT). Those with trismus demonstrated more QOL deficits than the non-trismus group. Curative doses of RT for head and neck cancer result in trismus in a high percentage of patients, independent of other treatment modalities. Trismus has a negative impact on quality of life in this population.


Expression of KRT7 and WT1 differentiates precursor lesions of Wilms' tumours from those of papillary renal cell tumours and mucinous tubular and spindle cell carcinomas.
Wilms' tumours (WT) and adult papillary renal cell tumours (pRCT) are associated with precursor lesions of embryonic origin. The aim of this study was to analyse the expression of WT1, KRT7, KRT8, KRT18 and KRT19 genes by immunohistochemistry in 74 precursor lesions associated with WTs, pRCTs and mucinous tubular and spindle cell carcinomas (MTSCC). All precursor lesions associated with Wilms' tumours were positive for WT1, whereas all precursor lesions in pRCT and MTSCC-bearing kidneys were negative. None of the WT-associated lesions were positive for KRT7, but 69-80% of lesions associated with pRCTs and MTSCCs were positive for KRT7. KRT8, KRT18 and KRT19 were found to be expressed in 80-100% of all types of precursor lesions. Our findings indicate that the precursor lesions analysed in this study are committed in an early stage of cellular differentiation to the development of either Wilms' tumours or papillary RCTs and MTSCCs.


New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis.
Tissue fibrosis often presents as the final outcome of chronic disease and is a significant cause of morbidity and mortality worldwide. Fibrosis is driven by continuous expansion of fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) is a form of cell plasticity in which epithelia acquire mesenchymal phenotypes and is increasingly recognized as an integral aspect of tissue fibrogenesis. In this review, we describe recent insight into the molecular and cellular factors that regulate EMT and its underlying signaling pathways. We also consider how mechanical cues from the microenvironment affect the regulation of EMT. Finally, we discuss the role of EMT in fibrotic diseases and propose approaches for detecting and treating fibrogenesis by targeting EMT.


Giardia lamblia: uptake of pyrimidine nucleosides.
The aerotolerant, anaerobic parasite Giardia lamblia, which depends solely upon salvage pathways for its pyrimidine requirements, was found to transport uridine, cytidine, and thymidine by a carrier mediated mechanism. Support for this conclusion comes from the facts that uptake of radiolabeled uridine, cytidine, and thymidine exhibited saturation kinetics, and uptake of these same radiolabeled nucleosides was inhibited by unlabeled homologs, certain pyrimidine analogs, iodoacetate, and N-ethylmaleimide. Uridine and cytidine (perhaps uracil and cytosine also) are postulated to be transported at a common site which is distinct from the site for thymidine transport. Thymidine does appear to bind nonproductively to the uridine/cytidine transport site, but the reverse of this does not appear to occur.


Semantic and phonological contributions to short-term repetition and long-term cued sentence recall.
The function of verbal short-term memory is supported not only by the phonological loop, but also by semantic resources that may operate on both short and long time scales. Elucidation of the neural underpinnings of these mechanisms requires effective behavioral manipulations that can selectively engage them. We developed a novel cued sentence recall paradigm to assess the effects of two factors on sentence recall accuracy at short-term and long-term stages. Participants initially repeated auditory sentences immediately following a 14-s retention period. After this task was complete, long-term memory for each sentence was probed by a two-word recall cue. The sentences were either concrete (high imageability) or abstract (low imageability), and the initial 14-s retention period was filled with either an undemanding finger-tapping task or a more engaging articulatory suppression task (Exp. 1, counting backward by threes; Exp. 2, repeating a four-syllable nonword). Recall was always better for the concrete sentences. Articulatory suppression reduced accuracy in short-term recall, especially for abstract sentences, but the sentences initially recalled following articulatory suppression were retained better at the subsequent cued-recall test, suggesting that the engagement of semantic mechanisms for short-term retention promoted encoding of the sentence meaning into long-term memory. These results provide a basis for using sentence imageability and subsequent memory performance as probes of semantic engagement in short-term memory for sentences.


Added Value of 3- Versus 2-Dimensional Echocardiography Left Ventricular Ejection Fraction to Predict Arrhythmic Risk in Patients With Left Ventricular Dysfunction.
This study sought to evaluate the potential clinical impact of using 3-dimensional echocardiography (3DE) to measure left ventricular ejection fraction (LVEF) in patients considered for implantable cardioverter-defibrillator (ICD) implantation and to assess the predictive value of 3DE LVEF for arrhythmic events. ICD therapy is currently recommended to prevent sudden cardiac death in patients with symptomatic heart failure and LVEF ≤35%, and in asymptomatic patients with ischemic heart disease and LVEF ≤30%. Two-dimensional echocardiography (2DE) is currently used to calculate LVEF. However, 3DE has been reported to be more reproducible and accurate than 2DE to measure LVEF. The study prospectively enrolled 172 patients with LV dysfunction (71% ischemic). Both 2DE and 3DE LVEF were obtained during the same study. The outcome was the occurrence of major arrhythmic events (sudden cardiac death, aborted cardiac arrest, appropriate ICD therapy). After a median follow up of 56 (range 18 to 65) months, major arrhythmic events occurred in 30% of the patients. Compared with 2DE, 3DE changed the assignment above or below the LVEF thresholds for ICD implantation in 20% of patients, most of them having 2DE LVEFs within ± 10% from threshold. By cause-specific hazard model, 3DE LVEF was the only independent predictor of the occurrence of major arrhythmic events. LVEF by 3DE was an independent predictor of major arrhythmic events and improved arrhythmic risk prediction in patients with LV dysfunction. When compared with 2DE LVEF, 3DE measurement of LVEF may change the decision to implant an ICD in a sizable number of patients.


Smoke inhalation increases intensive care requirements and morbidity in paediatric burns.
Burn survival has improved with advancements in fluid resuscitation, surgical wound management, wound dressings, access to antibiotics and nutritional support for burn patients. Despite these advancements, the presence of smoke inhalation injury in addition to a cutaneous burn still significantly increases morbidity and mortality. The pathophysiology of smoke inhalation has been well studied in animal models. Translation of this knowledge into effectiveness of clinical management and correlation with patient outcomes including the paediatric population, is still limited. We retrospectively reviewed our experience of 13 years of paediatric burns admitted to a regional burn's intensive care unit. We compared critical care requirements and patient outcomes between those with cutaneous burns only and those with concurrent smoke inhalation injury. Smoke inhalation increases critical care requirements and mortality in the paediatric burn population. Therefore, early critical care input in the management of these patients is advised.


[The prevalence of IgG anticardiolipin antibody at the anticoagulant clinic of the Ignacio ChavezNational Institute of Cardiology. I. Unselected population].
The recently described antiphospholipid antibodies syndrome (APA) is recognized because recurrent abortion, thrombocytopenia and repeated arterial and/or, venous thrombosis plus the demonstration of serum antibodies reactive with anionic phospholipids. We studied 51 patients who attend the anticoagulation clinic at our Institute. In a representative sample, we search for serum IgG specific for cardiolipin using an standard assay. We did not pick up unrecognized APA cases. The low frequency of this condition could be an explanation for our negative results in non-selected cases. Besides, this study denies a relationship between the chronic use of coumarin anticoagulants and development of peculiar antibodies.


Downregulation of Talin-1 is associated with the increased expression of miR-182-5p and miR-9-5p in coronary artery disease.
Evidence indicates that the dysregulation of extracellular matrix (ECM) components can lead to cardiovascular diseases. The Talin-1 (TLN1) gene is a major component of the ECM, and it mediates integrin adhesion to the ECM. In this study, we aimed to determine microRNAs (miRs) that regulate the expression of TLN1 and determine expression alterations in TLN1 and its targeting miRs in coronary artery disease (CAD). Data sets of CAD and normal samples of blood exosomes were downloaded, and TLN1 was chosen as one of the genes with differential expressions in an in silico analysis. Next, miR-182-5p and miR-9-5p, which have a binding site on 3´-UTR of TLN1, were selected using bioinformatics tools. Then, the miR target site was cloned in the psiCHECK-2 vector, and direct interaction between the miR target site and the TLN1 3'-UTR putative target site was investigated by luciferase assay. The expression of miR-182-5p, miR-9-5p, and TLN1 in the serum samples of CAD and non-CAD individuals was assessed via a real-time quantitative polymerase chain reaction. Our data revealed that miR-182-5p directly regulated the expression of TLN1. Moreover, miR-182-5p and miR-9-5p were significantly upregulated in the CAD group. Hence, both bioinformatics and experimental analyses determined the downregulated expression of TLN1 in the CAD samples. Our findings demonstrated that miR-182-5p and miR-9-5p could play significant roles in TLN1 regulation and participate in CAD development by targeting TLN1. These findings introduce novel biomarkers with a potential role in CAD pathogenesis.


Differential protein expression in ovaries of uninfected and Babesia-infected southern cattle ticks, Rhipicephalus (Boophilus) microplus.
We used gel electrophoresis and mass spectrometry to investigate differences in protein expression in ovarian tissues from Babesia bovis-infected and uninfected southern cattle tick, Rhipicephalus (Boophilus) microplus. Soluble and membrane proteins were extracted from ovaries of adult female ticks, and analyzed by isoelectric focusing (IEF) and one-dimensional or two-dimensional (2-D) gel electrophoresis. Protein patterns were analyzed for differences in expression between infected and uninfected ticks. 2-D separation of proteins revealed a number of proteins that appeared to be up- or down-regulated in response to infection with Babesia, in particular membrane/membrane-associated proteins and proteins in a low molecular mass range between 6 and 36kDa. A selection of differentially expressed proteins was subjected to analysis by capillary-HPLC-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Among the ovarian proteins that were up-regulated in infected ticks were calreticulin, two myosin subunits, an endoplasmic reticulum protein, a peptidyl-prolyl cis-trans isomerase (PPIase), a cytochrome c oxidase subunit, a glutamine synthetase, and a family of Kunitz-type serine protease inhibitors. Among the down-regulated ovarian proteins were another PPIase, a hemoglobin subunit, and a lysozyme. This study is part of an ongoing effort to establish a proteome database that can be utilized to investigate specific proteins involved in successful pathogen transmission.


Do age and ethnicity predict breast cancer treatment received? A cross-sectional urban population based study. Breast cancer treatment: age and ethnicity.
To evaluate the treatment patterns of women aged 55 years or older with newly diagnosed breast cancer and to examine the association between age and ethnicity/race on treatment selection. A cross-sectional survey between January 1 and June 30, 2001 of 401 women was performed of Hispanic, black and non-Hispanic white women in Los Angeles County, aged 55 years or older with newly diagnosed breast cancer. Regression analysis examined the association between: (a) age and treatment selection and (b) ethnicity/race and treatment selection, adjusting for the effect of possible confounders. In this study of urban breast cancer patients (64.1% response rate), blacks were less likely to receive hormone (OR=0.36) or chemotherapy therapy (OR=0.50) while older patients were less likely to receive lymph node dissection after lumpectomy (OR=0.48) and chemotherapy (OR=0.22). Although there are racial and age disparities in breast cancer treatment, other factors such as education, income status, insurance plan, functional status, and comorbidity also play an important role.


In vitro colorimetric evaluation of the efficacy of various bleaching methods and products.
Various bleaching modalities are now offered to patients, either monitored by the dental office or self-directed, for which relative efficacy is unknown. The aim of this in vitro study was to evaluate the ability of different bleaching products and protocols to lighten enamel and dentin. Bovine tooth samples of standardized thickness (2.5 +/- 0.025 mm with similar dentin and enamel thicknesses) were prepared and stained with whole blood and hemolysate before being submitted to 11 different bleaching regimens: home bleaching using 10%, 15%, 16%, or 20% carbamide peroxide, power bleaching using 15% hydrogen peroxide, 30% hydrogen peroxide, or 25% carbamide peroxide with or without light activation, and over-the-counter bleaching strips containing 5.3% hydrogen peroxide. Colorimetric measurements were performed on each sample side, according to the CIE L*a*b* system, before and after staining as well as after each series of 5 bleaching sessions (number of applications varied from 5 to 20 times, according to the bleaching protocol). All products and protocols produced a similar bleaching effect on enamel, while the home bleaching regimen proved largely superior to lighten dentin. In-office bleaching techniques proved less efficient than home bleaching for removing stains deposited in dentin.


A rapid and simple measurement method for biofilm formation inhibitory activity using 96-pin microtiter plate lids.
The purpose of this study was to develop a rapid and simple measurement method for biofilm formation inhibitory activity, and to screen food additives and foodstuffs that inhibit biofilm formation. The measurement method for biofilm formation inhibitory activity was developed by combining biofilm formation on pins of microtiter plate lids and staining using crystal violet. The optimum conditions for biofilm formation on the pins were established for seven Gram-positive and six Gram-negative bacteria by investigations of media, incubation time, and pin materials. Minimum concentrations of food additives required to inhibit biofilm formation were determined using the proposed method. The values obtained by the proposed and conventional methods agreed well. In addition, by sequential measurements of minimum inhibitory concentrations and minimum bactericidal concentrations using the proposed method, mechanisms of inhibition of biofilm formation were assessed. Furthermore, inhibitory activities of the water extracts of 498 different plant foodstuffs on biofilm formation by Streptococcus mutans were measured; five of the extracts showed potent inhibitory activities. The method proposed here circumvents the tedious and time-consuming conventional method in which biofilms are cultivated on the bottom of wells of microtiter plates.


Long-term epidemiological survey of hepatitis B virus infection in a hyperendemic area (Afragola, southern Italy): results of a pilot vaccination project.
In 1983, a pilot project of universal hepatitis B vaccination was introduced in a hyperendemic area in southern Italy (Afragola) and is ongoing to date. In this area before the start of vaccination, we found significant evidence of HBV endemicity: the acute viral hepatitis B incidence in the general population averaged 63/100,000; the HBsAg and anti-HBc prevalence rates were 13.4% and 66.9%, respectively; there was involvement of hepatitis B virus (HBV) in 48.1% of chronic liver pathologies (46.3%) in chronic viral hepatitis, 49.5% in cirrhosis and 71.7% in hepatocellular carcinoma cases). We studied the acute viral hepatitis incidence during the vaccination period from 1983 to 1997 and compared the HBsAg and anti-HBc prevalences in 1978 to those in 1997, after 15 years of vaccination. The HBV-related chronic pathology prevalence was also studied. We found a remarkable drop in the acute viral hepatitis incidence, from an average annually of 63/100,000 in the five years before vaccination to 3/100,000 in the last five years of vaccination. In addition, the HBsAg carrier prevalence in the general population decreased from 13.4% in 1978 to 3.7% in 1997. The percentage dropped in children and adolescents from 6.8% to 0.7%, in young people from 10.2% to 1.1% and in adults from 15.8% to 4.0%. The anti-HBc carrier prevalence, found to be 66.9% in 1978, was 34.2% in 1997. Finally, we found a much less significant involvement of HBV in chronic liver pathologies; in fact, it was present in only 18.2% of cases in 1997 and in 48.2% in 1982. In the light of the data, we can assert that universal hepatitis B vaccination has had a substantial effect on HBV endemicity in the Afragola area. We believe that the reduction found in the incidence of acute viral hepatitis B and HBV-related chronic liver pathologies is connected to the decrease in HBV carriers in the area, which therefore reduces the risk of contagion for the unvaccinated.


Esophageal perforation in children: a review of one institution's experience.
The current approach to esophageal perforation treatment in children has shifted towards conservative management. However, the consensus of what constitutes conservative management is unclear, with various therapies and protocols described, including the need for various decompression and drainage procedures. Our institution utilizes conservative management with minimal intervention guided by the patient's clinical course. The purpose of this study is to report our management and add to the growing evidence for conservative management of esophageal perforation in children. We performed a retrospective chart review of all patients with an ICD-9 diagnosis of esophageal perforation from January 1995 to July 2009. Patients with postoperative anastomotic leaks with drains in place were excluded, although patients with anastomotic leaks that were not controlled by drains were included. Data collected included patient demographics, etiology, diagnosis, treatment, complications, and outcome. Eight patients were identified who met inclusion criteria. Mean age was 28 mo (1 d-10 y), and the average time from causative event to diagnosis was 1.4 d (0-2 d). The etiology for esophageal perforation included esophagoscopy with dilation (n = 4), button battery ingestion (n = 1), coin ingestion (n = 1), nasogastric tube placement (n = 1), and leak after stricture resection (n = 1). All the patients were treated conservatively without primary surgery or thoracic drainage, and the mean time to perforation healing was 10.2 d (1-24 d). The average length of antibiotic therapy was 10 d (0-26 d). Enteral nutrition was utilized in five patients, and total parenteral nutrition (TPN) was utilized in five patients. No patient developed a new-onset esophageal stricture. Conservative management, guided by the patient's clinical course, with antibiotics and nutritional support is a safe and effective treatment for esophageal perforations in children.


Differential pharmacologies of mecamylamine enantiomers: positive allosteric modulation and noncompetitive inhibition.
(+/-)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers of this drug show different profiles for inhibition of the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human alpha4beta2 NNR subtype expressed in subclonal human epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [S-(+)-mecamylamine] was more effective than TC-5213 [R-(-)-mecamylamine] in inhibiting the LS alpha4beta2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS alpha4beta2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS alpha4beta2 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, whereas it is more effective in suppressing LS receptor function. This feature could be relevant to therapeutic applications where such a selective mechanism of action is required.


Postmortem calpain changes in longissimus muscle from Lanyu native and Kaohsiung crossbred black pigs.
The purpose of this study was to compare postmortem calpain changes in porcine muscle between Lanyu native (n = 10) and Kaohsiung crossbred (50% Meishan and 50% Duroc, n = 10) black pigs. Longissimus dorsi (LM) muscles (4th to 10th ribs) from both sides of carcasses were hot-sectioned in 30 min postmortem, vacuum-packaged, and stored at 5°C. LM samples from the left side of carcasses were sampled at 0 (30 min postmortem), 3, 6, 12, 24, 48, and 72 h of storage. The 24 and 72 h samples of shear force measurement were taken from the LM at the 8th and 10th ribs of the right side of carcasses, respectively. Our results showed that the decreases in calpain-1 activity, desmin content, and shear force were slower (P < 0.05) in Lanyu native black pig than in Kaohsiung crossbred black pig samples. Therefore, postmortem proteolysis and tenderization were more limited in LM from Lanyu native pigs than from Kaohsiung crossbred pigs.


Water soluble nanocurcumin extracted from turmeric challenging the microflora from human oral cavity.
Water soluble nanocurcumin prepared from commercial turmeric powders was compared against ethanol extracted curcumin particles. The oral microflora from five different human volunteers was collected and the efficacy of solvent extracted curcumin versus water extracted nanocurcumin was demonstrated. Nanocurcumin activity against oral microflora confirms its antimicrobial potency. Confocal laser scanning microscopic results revealed the enhanced entry of nanocurcumin particles into microbial cells. The nanosized nature of nanocurcumin appears to have led to increased cellular interaction and thereby efficient destruction of microbial cells in the mouth. In addition, solubility of nanocurcumin is also believed to be a crucial factor behind its successful antimicrobial activity. This study proves that the bioactivity of a compound is greatly influenced by its solubility in water. This work recommends the use of water soluble nanocurcumin (extracted from turmeric) as potent substitute for curcumin in dental formulations.


Genotoxicity evaluation of a valsartan-related complex N-nitroso-impurity.
Recently, the formation of genotoxic and carcinogenic N-nitrosamines impurities during drug manufacturing of tetrazole-containing angiotensin-II blockers has been described. However, drug-related (complex) nitrosamines may also be generated under certain conditions, i.e., through nitrosation of vulnerable amines in drug substances in the presence of nitrite. An investigation of valsartan drug substance showed that a complex API-related N-nitrosamine chemically designated as (S)-2-(((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)(nitroso)amino)-3-methylbutanoic acid (named 181-14) may be generated. 181-14 was shown to be devoid of a mutagenic potential in the Non-GLP Ames test. According to ICH M7 (R1) (2018), impurities that are not mutagenic in the Ames test would be considered Class 5 impurities and limited according to ICH Q3A (R2) and B (R2) (2006) guidelines. However, certain regulatory authorities raised the concern that the Ames test may not be sufficiently sensitive to detect a mutagenic potential of nitrosamines and requested a confirmatory in vivo study using a transgenic animal genotoxicity model. Our data show that 181-14 was not mutagenic in the transgenic gene mutation assay in MutaTMMice. The data support the conclusion that the Ames test is an adequate and sensitive test system to assess a mutagenic potential of nitrosamines.


Chronic renal failure after nephrotoxic nephritis in rats: contributions to progression.
In rats dietary protein restriction decreases the rate of progressive glomerulosclerosis and the development of renal failure after subtotal nephrectomies. The present experiments were designed to see whether dietary protein had similar effects on renal failure after nephrotoxic nephritis (NTN). Groups of rats were fed isocaloric diets containing 8%, 18% and 78% casein. Irrespective of whether the diets were introduced 7 days or 30 days after induction of nephritis by a single injection of rabbit anti-rat nephrotoxic globulin, rats on 8% casein and 78% casein had significantly lower plasma creatinines than rats fed with 18% casein. Semiquantitative scoring systems were used to assess glomerular sclerosis, tubular atrophy and tubular calcification. Rats on 8% protein had significantly lower glomerular sclerosis scores than the other two groups. Tubular atrophy scores were similar in rats on 8% and 78% casein and significantly lower than those of rats on 18% casein. All rats on 8% and 18% casein diets had tubular calcification whereas rats on 78% casein did not. This suggested that the normal relation between glomerular sclerosis and tubular atrophy after NTN was altered by a 78% casein diet. This was confirmed by the slopes of the regression equation for glomerular sclerosis on tubular atrophy (0.54 +/- 0.07) for rats on 78% casein compared to the slopes of the regression equations for the other two groups which were 1.12 +/- 0.10 and 1.00 +/- 0.12, respectively. This difference is highly significant statistically, P less than 0.1 X 10(-5) (one-way analysis of variance). These results show that dietary protein has a variable effect on the development of renal failure after nephrotoxic nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)


Implications of elevated cardiac troponin T in ambulatory patients with heart failure: a prospective analysis.
Elevated concentrations of cardiac troponin T (TnT) have been reported in patients hospitalized for decompensated heart failure (HF). We assessed whether elevated TnT levels are associated with the severity, etiology, and prognosis of HF in stable, ambulatory patients. From 1998-1999, we prospectively collected data from 136 ambulatory patients with HF, New York Heart Association functional class II to IV, ejection fraction < or =35%, and no recent unstable angina, myocardial infarction, surgery, or coronary revascularization. Blood was obtained and analyzed by immunoassay for TnT, and patients were followed for 14.0 +/- 4.3 months for death or HF hospitalization (primary end point) and other adverse cardiovascular outcomes. Thirty-three patients (24%) had an elevated TnT level (> or =0.02 ng/mL). Mean TnT concentration did not differ by etiology of HF (0.002 +/- 0.03 ng/mL vs 0.02 +/- 0.04 ng/mL for ischemic and nonischemic etiologies, P =.25). Compared with patients with normal (undetectable) levels of TnT, patients with elevated TnT were significantly older, had worse functional class, and had poorer renal function. Elevated TnT concentrations were associated with increased relative risks (RR) of death or HF hospitalization (RR 2.7, 95% CI 1.7-4.3, P =.001) and death alone (RR 4.2, 95% CI 1.8-9.5, P =.001) during follow-up. Elevated TnT and New York Heart Association class were significant, independent predictors of death or HF hospitalization. Increased age and serum creatinine concentrations were significant independent predictors of death alone. Nearly one fourth of ambulatory patients with chronic HF have ongoing myocardial necrosis as shown by abnormal TnT values, which are associated with increased mortality and morbidity.


Hexameric C-alkylpyrogallol[4]arene molecular capsules sustained by metal-ion coordination and hydrogen bonds.
Large multicomponent nanospheroid arrays consisting of six C-pentylpyrogallol[4]arene molecules and 12 Ga3+ metal-ions which in turn enclose 1150 A3 of chemical space are reported.


Tuberculous peritonitis in Nigerian Igbos.
An account is given of 30 Nigerian patients of the Igbo ethnic group whose biopsies showed tuberculous peritonitis. The maximum incidence occurred in the 20-39 year age group and the female: male ratio was 2:1. The commonest clinical findings were abdominal pain and swelling and ascites. An increase in the mean age was found in Igbos suffering from tuberculous peritonitis compared with those who had tuberculous peripheral lymphadenitis.


The myogenic response in isolated rat cerebrovascular arteries: vessel model.
We develop an integrated model of isolated rat arterial resistance vessel (RV), which can simulate its major property of myogenic response. The vascular smooth muscle cell is an important component of the wall of this vessel, and serves as a vasomotor organ providing the active tension generation that underlies the myogenic response of the wall to stretch. In the previous study, we focused on the development of a smooth muscle cell model that can mimic the strain-sensing and force-generating features of the myogenic mechanism. In the current model, we embed this cell model in a larger vessel wall configuration, and couple the time course of cellular contractile activation to macroscopic changes in vessel diameter. The integrated model is used to mimic published pressure-vessel diameter data obtained from isolated RVs that are mounted in a hydraulic test apparatus. The model provides biophysically based insights into the myogenic mechanism as it responds to changes in transmural pressure, in the presence and absence of Ca2+ blockers applied to the bathing fluid.It mimics measured data very well and provides a model that is able to link events at subcellular level to macroscopic changes in vessel diameter. The model initiates a mechanistic approach to investigate myogenic response, which has not been taken previously by any other models.


Arterial Stiffness, Sugar-Sweetened Beverages and Fruits Intake in a Rural Population Sample: Data from the Brisighella Heart Study.
There is conflicting information linking fruit and fructose intake with cardiometabolic disorders. The main objective of our study was to evaluate the association between intake of fruits and sugar-sweetened beverages, and carotid-femoral pulse wave velocity (cfPWV), a non-invasive marker of arterial aging, in a large population sample. For this study, we selected four age and sex-matched subgroups from the last Brisighella Heart Study population survey, after exclusion of those in secondary prevention for cardiovascular diseases, affected by gout and moderate-to-severe chronic kidney disease (defined as eGFR < 60 mL/min), and/or actively treated with direct vasodilating drugs (calcium-antagonists, alpha-blockers, nitrates). The remaining subjects were classified into four groups: (1) low fruit and low sugar-sweetened beverage intake (LFLB), (2) high fruit and low sugar-sweetened beverage intake (HFLB), (3) low fruit and high sugar-sweetened beverage intake (LFHB), (4) high fruit and high sugar-sweetened beverage intake (HFHB). CfPWV was significantly elevated in subjects consuming a higher fructose load, particularly when it was derived from industrially sweetened beverages (pooled LFHB & HFHB: 9.6 ± 2.3 m/s; pooled LFLB & HFLB: 8.6 ± 2.3 m/s, p < 0.001). Moreover, the main predictors of cfPWV values were serum uric acid (B = 0.391, 95%CI 0.321-0.486, p = 0.001), fructose load from both fruits and sugar-sweetened beverages (B = 0.310, 95%CI 0.099-0.522, p = 0.004), triglycerides (B = 0.228, 95%CI 0.117-0.389, p = 0.018), fasting plasma glucose (B = 0.015, 95%CI 0.008-0.022, p < 0.001) and estimated Glomerular Filtration Rate (B = -0.043, 95%CI -0.052--0.035, p < 0.001). our data suggest that increased intake of fructose derived from industrial sweetened beverages, though not from fruits, is associated with higher pulse wave velocity.


[The musculo-mucosal facial artery flap: harvesting technique and indications].
Describe the anatomy and the harvesting technique of the facial artery musculo-mucosal flap (FAMM) and precise its indications in head and neck reconstruction. Retrospective review of our experience and review of the literature. Described by Pribaz et al. [Plast Reconstr Surg 90 (1992) 421-9] in 1992, the FAMM flap relies on the facial artery and can be used with a superior or inferior base depending on the deficit to be reconstructed. Venous drainage is usually assured by buccal plexus veinules instead of the facial vein. In our experience, the FAMM flap has been used mainly for limited soft tissue defects of the oral cavity following cancer ablation. Other indications were coverage of oropharyngeal, intranasal and orbital defects. The FAMM flap has also been used to treat mandibular osteoradionecrosis. Harvesting of the FAMM flap is easy and safe. This flap shows versatility in head and neck reconstruction.


A der(11)t(8;11) in two medulloblastomas. A possible nonrandom cytogenetic abnormality.
Cytogenetic analysis of tumor tissue from two patients with medulloblastoma is reported. Both showed the presence of an i(17q) and a der(11)t(8;11)(q11;p11). It is suggested that the t(8;11) may be a translocation associated with medulloblastoma.


Correlation between Ethical Sensitivity as Well as Doping Attitude and Dispositions in Taekwondo Kyorugi Athletes: Athlete Career and National Team Moderation Effect.
We aimed to examine the effect of ethical sensitivity on doping attitude and dispositions for Taekwondo athletes, as well as whether there was a difference depending on the athlete's career and national team status. Overall, 331 Korean adult Taekwondo athletes were enrolled. Data were collected using sports ethical sensitivity and Performance Enhancement Attitude Scale (PEAS) tools as the research tools. For data processing, frequency analysis was performed to confirm demographic characteristics, and the fitness index was calculated by applying the Rasch model to confirm the validity and reliability of ethical sensitivity and PEAS. An independent sample t-test was performed to confirm the difference between ethical sensitivity and doping attitude and dispositions according to demographic characteristics. Pairwise parameter comparison values were used using multi-group analysis of path analysis to confirm the effect of ethical sensitivity on PEAS and the moderating effect was calculated. First, according to the demographic characteristics of Taekwondo athletes, there were statistically significant differences in ethical sensitivity and PEAS only by gender. Second, as ethical sensitivity factors, both intentional behavior factors and intentional collusion factors had statistically significant effect on PEAS. Third, in the effect of ethical sensitivity on doping attitude and dispositions, there was no moderating effect of athlete experience and national representative status. Ethical sensitivity has a positive linear correlation with PEAS. In other words, enhancing the ethical sensitivity of sports players will enhance athletes' ethical consciousness and prevent unethical behavior, and furthermore, doping.


Activation of ternary complex factor Elk-1 by MAP kinases.
Ternary complex factors (TCFs), one of which is Elk-1, have been implicated in mediation of c-fos induction. They have been shown to be phosphorylated by mitogen-activated protein kinases (MAPKs) in vitro. We demonstrate that recombinant Elk-1 is hyperphosphorylated in vivo upon joint overexpression of MAPKs and constitutively activated Raf-1 kinase, the latter serving as an indirect in vivo activator of MAPKs. This phosphorylation is accompanied by a conformational change and results in an elevated transactivation potential of Elk-1. Mutation of mapped in vivo phosphorylation sites, which are potential targets for MAPKs, reduced Elk-1-mediated transcription. Thus, MAPKs are very probably controlling Elk-1 activity by direct phosphorylation in vivo. Furthermore, Elk-1 was shown to stimulate transcription from both the c-fos serum response element and also from an Ets binding site. While binding of TCFs to the c-fos promoter is dependent on the serum response factor, TCFs can autonomously interact with Ets binding sites. This indicates that TCFs may participate in the transcriptional regulation of two different sets of genes.


Banking of environmental samples for short-term biochemical and chemical monitoring of organic contamination in coastal marine environments: the GICBEM experience (1986-1990). Groupe Interface Chimie Biologie des Ecosystèmes, Marins.
The GICBEM (Groupe Interface Chimie Biologie des Ecosystèmes Marins) program consists of an evaluation of the ecosystem health status in the Mediterranean Sea mainly based on chemical and biochemical approaches. Specific chemical contaminants (polycyclic aromatic hydrocarbons (PAH), polychlorobiphenyls (PCB), heavy metals) in waters, sediments, and related biotransformation indicators in target organisms (mussels, fish) have been selected for a complete survey of the coastal waters. In order to provide an appropriate sampling program for standardization for each sampling cruise, various aspects have been studied: (a) parameters for the choice of the sample sites; (b) ways of collection the samples (waters, sediments, marine organisms); and (c) preparation of the samples for a short term storage on board ship and for further analyses in the ground laboratory. Methods of preparation and storage of the samples are described and could be used to initiate an environmental banking program including both possible retrospective analyses of chemical pollutants and biochemical indicators. Moreover, the correlation between chemicals (PAH) and biochemical (mixed function oxygenase activities) parameters has been studied and this demonstrates the capability of the enzyme activities as reliable pollution biomarkers.


Comparison of Empower and M-arm for One-surgeon Basketing in Ureteroscopic Lithotripsy: A Simulator Study by Non-doctors.
To compare the Empower and M-arm for stone retrieval during ureteroscopic lithotripsy in a simulator. We used flexible ureteroscopy to compare use of the Empower and use of the M-arm, both of which are one-surgeon basketing techniques. LithoVue and ZeroTip stone extraction devices were used. All participants were nurses who had never handled a ureteroscope. They retrieved 3 stones in the simulator using the Empower or M-arm. We compared the stone retrieval time, number of times the retrieval device was opened and closed, number of times the line of sight was removed from the endoscope monitor, number of times the participant lost sight of a stone, and participants' subjective evaluations. The stone retrieval time was significantly shorter with the Empower than M-arm (10.0 vs. 19.9 min, respectively; P = .02). The mean number of times the retrieval device was opened and closed and the mean number of times the line of sight was removed from the endoscope monitor were significantly lower with the Empower (24 vs. 53 times, P = .01 and 3.1 vs. 51.5 times, P < .001, respectively). The mean number of times the participant lost sight of a stone tended to be lower with the Empower (9.4 vs. 25.3, P = .06). All participants indicated that the Empower is better for stone retrieval by beginners. The Empower reduces the stone retrieval time compared with the M-arm. We consider that the Empower has the potential to be useful in ureteroscopic lithotripsy.


Age at cancer diagnosis, non-O blood group and asparaginase therapy are independently associated with deep venous thrombosis in pediatric oncology patients: A risk model.
Pediatric oncology patients are at increased risk for deep venous thrombosis (DVT). Determining the sub-population of children at increased DVT risk is critical for optimum clinical management. Therefore, the aim of the current study was to identify clinical risk factors for DVT which are easily identifiable at cancer diagnosis. A Canadian multicenter case control study in survivors of childhood cancer. Survivors who had DVT (Cases) while being treated for pediatric cancer where matched by center with a minimum of two survivors who did not experience DVT (Controls). Clinical information including age at diagnosis, type of cancer and chemotherapy were collected. Genotyping of blood group was done by single nucleotide polymorphisms analysis. 218 subjects were recruited at 4 Canadian pediatric centers. Multivariable analysis demonstrated 3 significant variables (reported as Odds Ratio (OR), (95% CI), p value): age at diagnosis p<0.001, non-O blood group OR 2.6 (1.3-5.2) p=0.005 and asparaginase treatment OR 2.4 (1.2-4.8) p=0.011. In order to optimise clinical utility, we reanalysed the study data with age at diagnosis categorised into four subgroups 0-≤2years, >2-≤7years, >7≤10years, >10years. A significant association with DVT were seen in children 0-≤2years (OR 3.1 (1.1-8.3) p=0.026) and >10years (OR 3.8, 1.7-8.5 p=0.001). Significant associations with DVT remained for non-O blood group, OR 2.2 (1.2-4.4) p=0.016 and asparaginase treatment, OR 2.1 (1.1-4.0) p=0.027. The value for the clinical risk model receiver operating characteristics curve was 0.67. We have shown 3 independent risk factors for DVT in childhood cancer.


Localization and characterization of the binding site for the regulatory subunit of type II cAMP-dependent protein kinase on MAP2.
Microtubule-associated protein 2 (MAP2) binds, and is a substrate for, type II cAMP-dependent protein kinase. The structural domain in MAP2 that binds the regulatory subunit (RII) of protein kinase II was identified by expressing fragments of a human MAP2 cDNA in E. coli using the pATH11 vector. Fusion proteins were resolved by SDS-PAGE and transferred to nitrocellulose. The filters were probed with purified bovine heart or brain RII, anti-RII monoclonal antibodies, and 125I-labeled protein A. Binding of RII was localized to a 31 amino acid sequence near the N-terminus of the MAP2 molecule. Fusion proteins containing this fragment bound both heart and brain RIIs in a concentration-dependent manner, but bound heart RII with a higher apparent affinity than brain RII. The amino acid sequence of this fragment (DRETAEEVSARIVQVVTAEAVAVLKGEQEKE) is totally conserved between human and mouse MAP2, suggesting an important role for the RII binding site of MAP2 in neuronal function.


The gut-to-brain axis for toxin-induced defensive responses.
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.


Development of a cross-artificial intelligence system for identifying intraoperative anatomical landmarks and surgical phases during laparoscopic cholecystectomy.
Attention to anatomical landmarks in the appropriate surgical phase is important to prevent bile duct injury (BDI) during laparoscopic cholecystectomy (LC). Therefore, we created a cross-AI system that works with two different AI algorithms simultaneously, landmark detection and phase recognition. We assessed whether landmark detection was activated in the appropriate phase by phase recognition during LC and the potential contribution of the cross-AI system in preventing BDI through a clinical feasibility study (J-SUMMIT-C-02). A prototype was designed to display landmarks during the preparation phase and Calot's triangle dissection. A prospective clinical feasibility study using the cross-AI system was performed in 20 LC cases. The primary endpoint of this study was the appropriateness of the detection timing of landmarks, which was assessed by an external evaluation committee (EEC). The secondary endpoint was the correctness of landmark detection and the contribution of cross-AI in preventing BDI, which were assessed based on the annotation and 4-point rubric questionnaire. Cross-AI-detected landmarks in 92% of the phases where the EEC considered landmarks necessary. In the questionnaire, each landmark detected by AI had high accuracy, especially the landmarks of the common bile duct and cystic duct, which were assessed at 3.78 and 3.67, respectively. In addition, the contribution to preventing BDI was relatively high at 3.65. The cross-AI system provided landmark detection at appropriate situations. The surgeons who previewed the model suggested that the landmark information provided by the cross-AI system may be effective in preventing BDI. Therefore, it is suggested that our system could help prevent BDI in practice. Trial registration University Hospital Medical Information Network Research Center Clinical Trial Registration System (UMIN000045731).


Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study.
This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.


Conjoint therapy: a cooperative psychotherapeutic-optometric approach to therapy.
Optometrists often see patients who have psychological problems as well as visual problems. These patients are often referred to other disciplines for appropriate care. Although it is recognized that visual problems and emotional problems affect each other, after the appropriate referral very little interdisciplinary interaction occurs. The authors believe that this interaction--Conjoint Therapy--is frequently crucial for the successful remediation of the patient's emotional problem as well as his visual problem. They present in this report, just such a case with an anecdotal abstract from the psychological as well as the visual therapy reports.


Novel insect resistance in Brassica napus developed by transformation of chitinase and scorpion toxin genes.
Transgenic plants with introduced pest-resistant gene offer an efficient alternative insect control. The novel insect-resistant gene combination, chitinase(chi) and BmkIT(Bmk), containing an insect-specific chitinase gene and a scorpion insect toxin gene was introduced into Brassica napus cultivar via Agrobacterium-mediated transformation. Fifty-seven regenerated plantlets with kanamycin-resistance were obtained. Transgenic plants were verified by Southern blot analysis. Enzyme-linked immunosorbent assay (ELISA) and bioassay of artificial inoculation with diamondback moth (Plutella maculipenis) (DBM) larvae indicated that some of the transgenic plants were high-level expression for both chitinase and scorpion toxin proteins and performed high resistance against the tested pest infestation. The genetic analysis of T(1) progeny confirmed that the inheritance of introduced genes followed the Mendelian rules.


Effect of tablet tilt positioning on ergonomic risks and respiratory function.
The static posture associated with continuous tablet use can lead to musculoskeletal disorders of the neck and upper extremities as well as respiratory function disorders. We hypothesized that 0-degree tablet placement (flat on a table) would affect ergonomic risks and respiratory function. Eighteen undergraduate students were divided into two groups (n = 9 per group). In the first group, the tablet was placed at a 0-degree angle, whereas in the second group, it was placed at a 40- to 55-degree angle on a student learning chair. The tablet was used continuously for 2 h for writing and internet use. Rapid upper-limb assessment (RULA), craniovertebral angle, and respiratory function were assessed. There was no significant difference in respiratory function, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC, between the groups (p = 0.09) or within groups. However, there was a statistically significant between-group difference in RULA (p = 0.001), with the 0-degree group having a greater ergonomic risk. There were also significant within-group differences between pre- and posttest. The CV angle differed significantly between groups (p = 0.03), whereby the 0-degree group had poor posture, as well as within the 0-degree group (p = 0.039), though not within the 40- to 55-degree group (p = 0.067). Undergraduate students who place their tablets at a 0-degree angle face increased ergonomic risks and higher potential for developing musculoskeletal disorders and poor posture. Thus, elevating the tablet and instituting rest intervals may prevent or decrease the ergonomic risks among tablet users.


Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation.
The purpose of this study was to develop Cremophor EL-free nanoparticles loaded with Paclitaxel (PTX), intended to be intravenously administered, able to improve the therapeutic index of the drug and devoid of the adverse effects of Cremophor EL. PTX-loaded PEGylated PLGA-based were prepared by simple emulsion and nanoprecipitation. The incorporation efficiency of PTX was higher with the nanoprecipitation technique. The release behavior of PTX exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous release. The in vitro anti-tumoral activity was assessed using the Human Cervix Carcinoma cells (HeLa) by the MTT test and was compared to the commercial formulation Taxol and to Cremophor EL. When exposed to 25 microg/ml of PTX, the cell viability was lower for PTX-loaded nanoparticles than for Taxol (IC(50) 5.5 vs 15.5 microg/ml). Flow cytometry studies showed that the cellular uptake of PTX-loaded nanoparticles was concentration and time dependent. Exposure of HeLa cells to Taxol and PTX-loaded nanoparticles induced the same percentage of apoptotic cells. PTX-loaded nanoparticles showed greater tumor growth inhibition effect in vivo on TLT tumor, compared with Taxol. Therefore, PTX-loaded nanoparticles may be considered as an effective anticancer drug delivery system for cancer chemotherapy.


[Age-dependent effects of flavonoids on secretory function of the rat liver].
The effects of the chamomilla recutita (1) flavonoids (chamiloflan) on bilegenesis of the adult and old white rats were investigated. Chamiloflan (20, 40 and 80 mg/kg) induced a dose-dependent increase in the bile flow and bile acid secretion in rats of both age groups. Cholesterol concentration in the liver and bile cholesterol secretion were not changed in the treated adult rats. Chamiloflan increased cholesterol bile secretion and reduced lipid content in the liver of the old rats.


TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity.
TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1alpha and TP53INP1beta), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53-/- mice and in cisplatin-treated p53-/- mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.


Mortality among workers exposed to acrylonitrile in fiber production: an update.
The investigation updates the mortality experience through 2002 for a cohort of workers exposed to acrylonitrile (AN). Standardized mortality ratios (SMR) were estimated based on two reference populations: the US population and a regional employee population. Exposure-response analyses were conducted using Cox regression models for cumulative and mean intensity exposure measures. In the cohort of 2548 workers, 839 deaths have occurred with 91 deaths due to respiratory system cancer. Most standardized mortality ratio estimates are at or near no-effects levels. Hazard ratio (HR) estimates indicate no increased mortality risk for respiratory system cancer (adjusted HR = 0.96, 95% confidence interval: 0.74, 1.25). In summary, no mortality outcome of a priori interest, principally respiratory system cancer, is associated with increased AN exposure among fiber production workers over five decades of follow-up.


Ammon's horn sclerosis on pneumoencephalotomography.
Fourteen cases with psychomotor seizure were examined by pneumoencephalotomographic technique. In all cases uni- or bilateral changes of the inferior horn were found: diverticular dilatation of subiculum, lowering and irregularity of the floor, reduction of width, and deformation of digitation. These findings correlated well with the autopsy reports. In most cases, EEG findings also correlated.


Clinical characteristics and treatment effects of astragalus injection in non-pediatric patients with acute fulminant myocarditis.
To explore the clinical characteristics of non-pediatric patients with acute fulminant myocarditis (AFM) and evaluate the treatment effects of astragalus injection on this disease.A total of 54 AFM patients were screened out from 586 patients with acute myocarditis, admitted to the department of cardiology between January 2011 to June 2018. The demographic and clinical data, investigations, treatments, and short-term outcomes were collected and retrospectively analyzed.The mean age of the 54 AFM patients was 34 ± 16.5 years old (range: 13-70 years), including 24 (44.5%) men and 30 (55.5%) women, with a high incidence in 2 age groups: 13-19 and 40-49 years old, despite an inverse trend to the increase of age. All these cases were admitted in emergency conditions: 26 (48.1%) cardiogenic shock, 18 (33.4%) malignant arrhythmias, 8 (14.8%) severe heart failure, and 2 (3.7%) acute pericardial tamponade. Apart from first-aid measures, 37 (68.5%) patients received astragalus injection. During hospitalization, 11 (20.4%) patients died, and 4 (36.3%) of them were from astragalus group while 7 (63.7%) of them from without-astragalus group (P=0.03). Furthermore, the levels of cardiac injury biomarkers, renal function and left ventricular ejection fraction of astragalus group were significantly improved compared with those of without-astragalus group at discharge (all P < .05).Middle-aged people were also prone to AFM. And cardiac shock was the most common, while acute pericardial tamponade was a rare presentation in non-pediatric AFM patients. Astragalus was a potential adjuvant medicine for the treatment of AFM.


Involvement of a guanine-nucleotide-binding protein-mediated mechanism in the enhancement of arachidonic acid liberation by phorbol 12-myristate 13-acetate and Ca2+ in saponin-permeabilized platelets.
A mechanism by which protein kinase C potentiates arachidonic acid (AA) liberation in rabbit platelets was examined using [3H]AA-labeled, saponin (7 micrograms/ml)-permeabilized rabbit platelets. Pretreatment of the [3H]AA-labeled platelets with 4 beta-phorbol 12-myristate 13-acetate (PMA, 10-40 nM) or 1,2-dioctanoylglycerol (DOG, 20 microM) enhanced [3H]AA liberation induced by an addition of Ca2+ (1 mM) after cell permeabilization, whereas 4 alpha-phorbol 12,13-didecanoate (80 nM) did not exert such an effect. The potentiating effects of PMA and DOG were inhibited by staurosporine (200 nM). PMA (40 nM) also potentiated [3H]AA liberation induced by guanosine 5'-[gamma-thio]triphosphate (GTP gamma S, 100 microM), 5'-guanylyl imidodiphosphate (200 microM) or NaF (20 mM) plus AlCl3 (10 microM) in the presence of Ca2+ (100 microM). The enhancement by PMA of the GTP gamma S-induced AA liberation was also inhibited by staurosporine (200 nM). Furthermore, guanosine 5'-[beta-thio]diphosphate (GDP beta S, 0.5-2 mM) suppressed the PMA (40 nM)- and DOG (20 microM)-enhanced, Ca2+ (1 mM)-dependent [3H]AA liberation. This inhibitory effect of GDP beta S was reversed by a further addition of GTP gamma S (200 microM). However, pertussis toxin (0.2-1 micrograms/ml) had no effect on the PMA-enhanced [3H]AA liberation. These results indicate a possibility that protein kinase C may potentiate AA liberation through a guanine-nucleotide-binding protein-mediated mechanism in saponin-permeabilized rabbit platelets.


Escherichia coli Sterilization Using a Light-Emitting Diode and Methylene Blue.
The prevalence of pathogenic Escherichia coli as well as E. coli O157 and antibiotic- resistant bacteria has increased. This study aimed to examine the effect of methylene blue (MB) with sodium bicarbonate (NaHCO3) against E. coli using photodynamic antimicrobial chemotherapy (PACT). MB was basified using NaHCO3. E. coli and basic MB were smeared on the culture media followed by irradiation using a red light-emitting diode (LED) at 660 nm. Energy densities of 5, 10, 15, and 20 J/cm2 were applied to the culture medium.After 24 h, the bactericidal effect of basic MB with LED irradiation was determined based on the bacterial growth. The basic effect was observed with 1%-6% of NaHCO3 at 5 J/cm2.This effect increased between 1% and 2% of NaHCO3 at 10 J/cm2 and 15 J/cm2, whereas decreased at the NaHCO3 concentrations of > 2%. Moreover, this effect decreased at an energy density of 20 J/cm2. The biphasic basic effect on bactericidal activity was observed between pH 8.6-9.0. Thus, PACT using basic MB may be an effective method for pathogenic E. coli sterilization.


RP2 X-LINKED RETINITIS PIGMENTOSA CARRIER STATE PRESENTING WITH VASCULAR LEAKAGE AND UNILATERAL MACULAR ATROPHY.
We describe the unusual clinical presentation of a 33-year-old woman subsequently identified as a carrier of RP2-associated X-linked retinitis pigmentosa. Case report. A 33-year-old woman without a known family history of retinal disease presented with unilateral reduced visual acuity and central scotoma in the left eye. Examination showed underlying macular atrophy in the left eye and a bilateral tapetal-like reflex. Full-field electroretinogram was abnormal in the left eye but normal in the right eye. Notable findings on wide-field imaging included bilateral peripheral vascular leakage on fluorescein angiography and a bilaterally symmetric radial pattern of hyperfluorescence on fundus autofluorescence. Genetic testing demonstrated a pathogenic variant in the gene RP2 confirming that she was a carrier of X-linked retinitis pigmentosa. We describe clinical features of the carrier state of RP2-XLRP and expand potential findings to include peripheral vascular leakage. This case highlights the importance of awareness of the carrier state, particularly if a family history cannot be provided.


Predictors of T2DM Remission after Bariatric Surgery in Patients with a BMI < 35 kg/m2: a Meta-Analysis.
Although a few studies have reported the predictors of postoperative diabetes remission in patients with body mass index (BMI) < 35 kg/m2, the conclusions are still inconsistent. This meta-analysis aimed to evaluate the preoperative clinical factors of type 2 diabetes mellitus (T2DM) remission after bariatric surgery. The PubMed, Embase, and Cochrane Library databases were systematically searched until April 2022. The Newcastle-Ottawa Scale was used for quality assessment. Statistical heterogeneity was assessed with the I2 statistic, followed by subgroup and sensitivity analyses. 16 studies involving 932 patients were selected. T2DM remission was negatively correlated with age, duration, insulin use, fasting plasma glucose, fasting insulin, and glycosylated hemoglobin levels. While BMI, body weight, waist circumference, and C-peptide levels were positive predictors of T2DM remission in patients with a BMI < 35 kg/m2. However, there was no significant association between gender, oral hypoglycemic agent, homeostasis model assessment, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, and remission rate. Patients with younger age, short diabetes duration, more obesity, better glucose control, and better β cell function were more likely to achieve T2DM remission in patients with a BMI < 35 kg/m2 after bariatric surgery.


Ultrastrong Hybrid Fibers with Tunable Macromolecular Interfaces of Graphene Oxide and Carbon Nanotube for Multifunctional Applications.
Individual carbon nanotubes (CNT) and graphene have unique mechanical and electrical properties; however, the properties of their macroscopic assemblies have not met expectations because of limited physical dimensions, the limited degree of dispersion of the components, and various structural defects. Here, a state-of-the-art assembly for a novel type of hybrid fiber possessing the properties required for a wide variety of multifunctional applications is presented. A simple and effective multidimensional nanostructure of CNT and graphene oxide (GO) assembled by solution processing improves the interfacial utilization of the components. Flexible GOs are effectively intercalated between nanotubes along the shape of CNTs, which reduces voids, enhances orientation, and maximizes the contact between elements. The microstructure is finely controlled by the elements content ratio and dimensions, and an optimal balance improves the mechanical properties. The hybrid fibers simultaneously exhibit exceptional strength (6.05 GPa), modulus (422 GPa), toughness (76.8 J g-1 ), electrical conductivity (8.43 MS m-1 ), and knot strength efficiency (92%). Furthermore, surface and electrochemical properties are significantly improved by tuning the GO content, further expanding the scope of applications. These hybrid fibers are expected to offer a strategy for overcoming the limitations of existing fibers in meeting the requirements for applications in the fiber industry.


PDDA induced step-pyramidal growth of nickel-platinum (Ni-Pt) nanoparticles for enhanced 4-nitrophenol reduction.
Herein, we report the synthesis of novel platinum-based nanoparticles with step-pyramidal growth induced by poly(diallyldimethylammonium chloride) (PDDA). The complex stepped pyramidal shape became the central point for outstanding catalytic reduction of 4-nitrophenol, overcoming the activity of bare Pt nanoparticles. These results are valuable for the catalytic degradation of reactive molecules.


Amniotic membrane implantation to reduce extraocular muscle adhesions to a titanium implant.
Amniotic membrane grafts are used extensively for ocular surface reconstruction. We describe the case of a 66-year-old man with traumatic, restrictive strabismus. Amniotic membrane was applied to resolve symblepharon between the globe and lids and also to prevent re-formation of adhesions between extraocular muscles and adjacent titanium plates placed during prior surgery.


Competing two enzymatic reactions realizing one-step preparation of cell-enclosing duplex microcapsules.
The usefulness of cell-enclosing microcapsules in biomedical and biopharmaceutical fields is widely recognized. In this study, we developed a method enabling the preparation of microcapsules with a liquid core in one step using two enzymatic reactions, both of which consume H2 O2 competitively. The microcapsule membrane prepared in this study is composed of the hydrogel obtained from an alginate derivative possessing phenolic hydroxyl moieties (Alg-Ph). The cell-enclosing microcapsules with a hollow core were obtained by extruding an aqueous solution of Alg-Ph containing horseradish peroxidase (HRP), catalase, and cells into a co-flowing stream of liquid paraffin containing H2 O2 . Formation of the microcapsule membrane progressed from the surface of the droplets through HRP-catalyzed cross-linking of Ph moieties by consuming H2 O2 supplied from the ambient liquid paraffin. A hollow core structure was induced by catalase-catalyzed decomposition of H2 O2 resulting in the center region being at an insufficient level of H2 O2 . The viability of HeLa cells was 93.1% immediately after encapsulation in the microcapsules with about 250 µm diameter obtained from an aqueous solution of 2.5% (w/v) Alg-Ph, 100 units mL(-1) HRP, 9.1 × 10(4) units mL(-1) catalase. The enclosed cells grew much faster than those in the microparticles with a solid core. In addition, the thickness of microcapsule membrane could be controlled by changing the concentrations of HRP and catalase in the range of 13-48 µm. The proposed method could be versatile for preparing the microcapsules from the other polymer derivatives of carboxymetylcellulose and gelatin.


Association between dietary inflammatory potential and the probable sarcopenia among community-dwelling older adults: a cross-sectional study.
Unlike the numerous studies concerning the role of dietary inflammatory potential in chronic diseases, limited studies focused on the association of dietary inflammatory potential with handgrip strength (HGS) and probable sarcopenia (PS). This study tends to explore the association between dietary inflammatory potential and PS among older adults in Tehran. The cross-sectional study was conducted between May and October 2019 on 201 randomly selected older adults in Tehran, Iran. A validated food frequency questionnaire was utilized for recording dietary intake. Dietary habits were evaluated through Dietary Inflammatory Index (DII) and Empirical Dietary Inflammatory Index (EDII). PS assessment was done by HGS estimation. Statistical evaluation included descriptive analyses, logistic, and linear regression. Those probably suffering from sarcopenia were older than healthy ones (p < 0.0001) and had significantly higher DII scores (p = 0.05) but not EDII (p = 0.85). Besides, PS subjects had a lower intake of anti-inflammatory nutrients. The odds of PS were doubled in people on the top tertile of DII (OR = 2.49, 95% (CI) = 1.11-5.58) and second tertile of EDII (OR = 2.29, 95% (CI) = 1.03-5.07) relative to bottom tertiles after adjusting for confounders. The relationships between index scores and HGS were simply significant in the adjusted model of EDII and HGS (B = -0.49, p = 0.04). Conclusively, participants adhering to a pro-inflammatory diet had more likelihood of PS. Findings are in line with current recommendations to reduce unhealthy foods with more inflammatory potential. These findings warrant confirmation in high-quality interventional studies.


Pyoderma gangrenosum with myelofibrosis.
Pyoderma gangrenosum is a papulovesicular skin disorder commonly associated with underlying systemic disease, but rarely with the myeloproliferative syndromes. A case of rapidly progressive pyoderma is cited in a 77-year-old white man who had no other evidence of disease aside from macrocytic anemia. Bone marrow biopsy revealed proliferation of fibroblasts and a dense reticulin network consistent with myelofibrosis. Response of the pyoderma to steroid therapy was dramatic. Although pyoderma gangrenosum is more commonly associated with inflammatory bowel disease and rheumatoid arthritis, this is the fifth reported case of its coexistence with idiopathic myelofibrosis.


Modeling the potential public health impact of different vaccination strategies with an omicron-adapted bivalent vaccine in Malaysia.
Coronavirus disease 2019 (COVID-19) case numbers have increased following the emergence of the Omicron variant. This study estimated the impact of introducing and increasing the coverage of an Omicron-adapted bivalent booster vaccine in Malaysia. A combined cohort Markov decision tree model was used to compare booster vaccination with an Omicron-adapted bivalent COVID-19 vaccine versus no booster vaccination in Malaysia. The model utilized age-specific data from January 2021 to March 2022 derived from published sources. The outcomes of interest included case numbers, hospitalizations, deaths, medical costs, and productivity losses. The population was stratified into high-risk and standard-risk subpopulations, and the study evaluated the benefits of increased coverage in different age and risk groups. Vaccinating only high-risk individuals and those aged ≥ 65 years was estimated to avert 274,313 cases, 33229 hospitalizations, 2,434 deaths, Malaysian ringgit (MYR) 576 million in direct medical costs, and MYR 579 million in indirect costs. Expanding vaccination coverage in the standard-risk population to 75% was estimated to avert more deaths (31%), hospitalizations (155%), infections (206%), direct costs (206%), and indirect costs (281%). These findings support broader population Omicron-adapted bivalent booster vaccination in Malaysia with potential for significant health and economic gains.


Brazilin plays an anti-inflammatory role with regulating Toll-like receptor 2 and TLR 2 downstream pathways in Staphylococcus aureus-induced mastitis in mice.
Mastitis, which commonly occurs during the postpartum period, is caused by the infection of the mammary glands. The most common infectious bacterial pathogen of mastitis is Staphylococcus aureus (S. aureus) in both human and animals. Brazilin, a compound isolated from the traditional herbal medicine Caesalpinia sappan L., has been shown to exhibit multiple biological properties. The present study was performed to determine the effect of brazilin on the inflammatory response in the mouse model of S. aureus mastitis and to confirm the mechanism of action involved. Brazilin treatment was applied in both a mouse model and cells. After brazilin treatment of cells, Western blotting and qPCR were performed to detect the protein levels and mRNA levels, respectively. Brazilin treatment significantly attenuated inflammatory cell infiltration and inhibited the expressions of TNF-α, IL-1β and IL-6 in a dose-dependent manner. Administration of brazilin in mice suppressed S. aureus-induced inflammatory injury and the production of proinflammatory mediators. This suppression was achieved by reducing the increased expression of TLR2 and regulating the NF-κB and MAPK signaling pathways in the mammary gland tissues and cells with S. aureus-induced mastitis. These results suggest that brazilin appears to be an effective drug for the treatment of mastitis and may be applied as a clinical therapy.


The physical mechanism of magnetic field controlled magnetocaloric effect and magnetoresistance in bulk PrGa compound.
The PrGa compound shows excellent performance on the magnetocaloric effect (MCE) and magnetoresistance (MR). The physical mechanism of MCE and MR in PrGa compound was investigated and elaborated in detail on the basis of magnetic measurement, heat capacity measurement and neutron powder diffraction (NPD) experiment. New types of magnetic structure and magnetic transition are found. The results of the NPD along with the saturation magnetic moment (MS) and magnetic entropy (SM) indicate that the magnetic moments are randomly distributed within the equivalent conical surface in the ferromagnetic (FM) temperature range. PrGa compound undergoes an FM to FM transition and an FM to paramagnetic (PM) transition as temperature increases. The magnetizing process was discussed in detail and the physical mechanism of the magnetic field controlled magnetocaloric effect (MCE) and the magnetoresistance (MR) was studied. The formation of the plateau on MCE curve was explained and MR was calculated in detail on the basis of the magnetic structure and the analysis of the magnetizing process. The experimental results are in excellent agreement with the calculations. Finally, the expression of MR = β(T)X(2) and its application conditions were discussed, where X is M(H)/Meff, and Meff is the paramagnetic effective moment.


TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain.
TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-β1 (TGF-β1), has been developed as a novel cell-based gene therapy and a candidate for disease modifying osteoarthritis drug (DMOAD). We aim to investigate analgesic mechanism of TG-C in a pre-clinical animal model with monoiodoacetate (MIA)-induced pain. We used a rat MIA model of osteoarthritis (OA) pain. We examined that TG-C can regulate pain by inhibiting the upregulation of various pain mediators in both knee joint tissue and dorsal root ganglia (DRG) (n = 112) and alleviating pain behavior (n = 41) and neuronal hyperexcitability in DRG (n = 60), afferent nerve fiber (n = 24), and spinal cord (n = 35). TG-C significantly alleviated pain-related behavior by restoring altered dynamic weight bearing and reduced mechanical threshold of the affected hindlimb. TG-C significantly suppressed the expression of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) in inflamed joint tissue. TG-C significantly suppressed the upregulation of tropomyosin receptor kinase A (TrkA) and nerve injury/regeneration protein (GAP43) and activation of Iba1-positive microglial cells in DRG. TG-C significantly recovered neuronal hyperexcitability by restoring RMP and firing threshold and frequency of DRG neurons, attenuating firing rates of mechanosensitive C- or Aδ-nerve fiber innervating knee joint, and lowering increased miniature and evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) in the spinal cord. Our results demonstrated that TG-C exerted potent analgesic effects in a rat MIA model of OA pain by inhibiting the upregulation of pain mediators and modulating neuronal sensitization.


Development of Glypican-2 Targeting Single-Domain Antibody CAR T Cells for Neuroblastoma.
Chimeric antigen receptors (CARs) are engineered fusion proteins constructed from antigen-recognition, signaling, and costimulatory domains. CARs can be expressed in T cells with the purpose of reprogramming the T cells to specifically target tumor cells. This strategy thereby avoids the requirement for antigen processing and presentation by the target cell. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan with highly tumor-specific expression in neuroblastoma compared with nonmalignant cells. Therefore, GPC2 is an attractive target candidate for CAR T-cell therapy. Single-domain antibodies (sdAbs) can access epitopes different from those targeted by single-chain variable fragments and, because of their stability and modularity, could serve as ideal antigen-recognition domains in CAR T cells. Here, we describe a protocol for generating GPC2-targeted sdAb CAR T cells. We also present a methodology for assessing the efficiency of CAR expression on human T cells and their ability to kill GPC2-positive neuroblastoma cells in vitro and in vivo. The method described here is applicable to the production of CAR T cells derived from all types of sdAbs including VHHs and VNARs.


Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16).
The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. ClinicalTrials.gov number NCT01730677.


Selenium nanoparticles inhibit the growth of HeLa and MDA-MB-231 cells through induction of S phase arrest.
In vitro antiproliferative effects of selenium nanoparticles (nanoSe(0), 10-40 μmol/L) on HeLa (human cervical carcinoma) cells and MDA-MB-231 (human breast carcinoma) cells were examined by optical microscopic inspection and MTT assay in the present study. The nanoSe(0) effectively inhibited the growth of MDA-MB-231 cells and HeLa cells in a dose-dependent manner. The morphology analysis with atomic force microscope showed that the HeLa cells treated with 10 μmol/L nanoSe(0) were rough and shrunken with truncated lamellipodia at terminal part of the cells. Flow cytometric analysis demonstrated that HeLa cells were arrested at S phase of the cell cycle after exposed to nanoSe(0) (10 μmol/L). Taken together, our results suggested that nanoSe(0) may be more helpful in cancer chemoprevention as a potential anticancer drug.


A cross-validation study of clustering of schizotypy using a non-clinical Chinese sample.
This study aimed to examine whether the same clusters of individuals with schizotypy as reported in Western samples are present in a Chinese sample. Cluster analysis was conducted on the responses of 418 individuals to the Chapman Psychosis-Proneness Scales. Results revealed that similar clusters of schizotypy exist in Chinese and Western samples, and that the emotional and neuropsychological symptoms they manifest are consistent with their cluster type.


Effects of puromycin on rat embryos in vitro.
Somite-staged rat embryos were exposed to varying concentrations of puromycin for 48 h in vitro. Medium concentrations below 0.92 microM had no significant effects, while concentrations above 1.84 microM were lethal. Between these extremes, there were concentration dependent increases in the incidence of malformations in a close relationship to growth retardation.


MYRbase: analysis of genome-wide glycine myristoylation enlarges the functional spectrum of eukaryotic myristoylated proteins.
We evaluated the evolutionary conservation of glycine myristoylation within eukaryotic sequences. Our large-scale cross-genome analyses, available as MYRbase, show that the functional spectrum of myristoylated proteins is currently largely underestimated. We give experimental evidence for in vitro myristoylation of selected predictions. Furthermore, we classify five membrane-attachment factors that occur most frequently in combination with, or even replacing, myristoyl anchors, as some protein family examples show.


Du13 encodes a C2 H2 zinc-finger protein that regulates Wxb pre-mRNA splicing and microRNA biogenesis in rice endosperm.
Amylose content is a crucial physicochemical property responsible for the eating and cooking quality of rice (Oryza sativa L.) grain and is mainly controlled by the Waxy (Wx) gene. Previous studies have identified several Dull genes that modulate the expression of the Wxb allele in japonica rice by affecting the splicing efficiency of the Wxb pre-mRNA. Here, we uncover dual roles for a novel Dull gene in pre-mRNA splicing and microRNA processing. We isolated the dull mutant, du13, with a dull endosperm and low amylose content. Map-based cloning showed that Du13 encodes a C2 H2 zinc-finger protein. Du13 coordinates with the nuclear cap-binding complex to regulate the splicing of Wxb transcripts in rice endosperm. Moreover, Du13 also regulates alternative splicing of other protein-coding transcripts and affects the biogenesis of a subset of microRNAs. Our results reveal an evolutionarily conserved link between pre-mRNA splicing and microRNA biogenesis in rice endosperm. Our findings also provide new insights into the functions of Dull genes in rice and expand our knowledge of microRNA biogenesis in monocots.


IL-4-induced apoptosis in peripheral blood eosinophils.
The regulation of eosinophil survival and apoptosis may play a major role in diseases demonstrating increased numbers of circulating and tissue eosinophils such as allergic reactions. Because few promoters of eosinophil apoptosis have been described so far, the objective of this study was to elucidate the role of endogenous factors on eosinophil survival and apoptosis. Highly purified peripheral blood eosinophils were analyzed in the time course from 24 up to 144 hours in culture. Eosinophil survival was assessed with trypan blue dye exclusion and apoptosis was determined by DNA fragmentation gel analysis and ELISA technique with anti-histone antibodies. We confirmed previous results demonstrating prolonged eosinophil survival and inhibited apoptosis by IL-3, IL-5, and GM-CSF. In contrast, eosinophil apoptosis was significantly enhanced by corticosteroids, particularly dexamethasone and hydrocortisone. However, IL-1beta, IL-8, IL-12, platelet-activating factor, TNF-alpha, and eotaxin had no effect on eosinophil survival or apoptosis when compared with culture medium alone. In contrast, IL-4 at concentrations of 100 U/mL or more inhibited eosinophil survival and induced apoptosis. This effect was time dependent and abrogated by preincubation with neutralizing anti-IL-4 antibodies. However, after 96 hours in coincubation, IL-4 did overcome the survival-prolonging effect of IL-3, IL-5, and GM-CSF. IL-4 did not enhance eosinophil surface expression of APO-1/Fas antigen (CD95). In assessing IL-4-mediated effects on eosinophil function, we found no response by means of the release of eosinophil cationic protein or reactive oxygen species. Taken together, our data present direct evidence for the presence of functional IL-4 receptors on human eosinophils and indicate that IL-4 may lead to resolution of chronic inflammation by induction of eosinophil apoptosis.


Impotence caused by pudendal arteriovenous fistula.
Partial impotence in a twenty-year-old was found, on angiography, to be the result of an arteriovenous fistula of the internal pudendal artery. This condition was corrected by corpus cavernosum revascularization.


Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma.
We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n=24, or HLA-haploidentical related, n=28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P=.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P=.01) and unrelated (P=.03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.


Adsorption of dissolved organic matter onto activated carbon--the influence of temperature, absorption wavelength, and molecular size.
In this study, batch and column adsorption experiments with granular activated carbon (GAC) were carried out for removing dissolved organic matter (DOM) of a pond water at different water temperatures (5, 20, and 35 degrees C). The water was characterized before and after the adsorption step using UV/VIS spectroscopy and size-exclusion chromatography (SEC) combined with diode array detection (DAD). DOM breakthrough of GAC filters has been found to be slower at higher water temperatures, the DOM removal being most effective at 35 degrees C. UV/VIS spectra and SEC chromatograms of water samples treated at different water temperatures indicate that an increase in temperature especially supports the adsorption of small DOM molecules as well as molecules absorbing at higher wavelengths, specifying aromatic structures of DOM. SEC-DAD has been demonstrated to be an efficient method for characterizing DOM of natural waters and for detecting relative changes of DOM during the water treatment process.