Effect of cloretazine (VNP40101M) on acute myeloid leukaemia blast cells in vitro as a single agent and combined with cytarabine and daunorubicin.
We have investigated the effect of cloretazine (VNP40101M or Laromustine), a novel sulfonylhydrazine alkylating agent with significant antileukaemic activity, alone, or combined with cytarabine or daunorubicin, on the proliferation, viability and apoptosis of cell lines and acute myeloid leukaemia blast cells in vitro. Cloretazine alone induced a concentration-dependent inhibition of proliferation, reduction in cell viability and an increase in apoptosis in all samples tested. Combinations of cloretazine with varying concentrations of cytarabine or daunorubicin further enhanced these inhibitory effects, suggesting VNP40101M may have a role in combined low dose chemotherapy regimes especially in the elderly.


Congenital and acquired developmental problems of the upper airway in newborns and infants.
To review the current knowledge on congenital and acquired developmental problems of the upper airway in newborns and infants. Causes of airway obstruction include problems with the nasal airway (choanal atresia), craniofacial syndromes (Apert syndrome, Crouzon syndrome), problems with facial/tongue anatomy (Pierre-Robin syndrome), the tongue (Down syndrome), or the larynx (laryngomalacia, vocal cord palsy, subglottic stenosis, subglottic hemangioma), along with lower developmental problems (tracheo/bronchomalacia). After establishing a safe airway, a detailed assessment and appropriate management are necessary. Treatment may involve simple observation, conservative management, chest physiotherapy, CPAP ventilation, and surgery, urgently or in a second phase. Upper airway diseases in neonates and infants may be life threatening, or challenging regarding diagnosis and management. There should be a very low threshold for referring these children, after establishing a safe airway, for a specialist opinion and care in a tertiary unit, if local facilities are limited or unavailable.


Albendazole for the treatment of human gnathostomiasis.
The efficacy of albendazole was investigated in 112 patients with symptomatic gnathostomiasis; 49 received 400 mg twice daily, 51 received 400 mg once daily, and 12 patients received placebo, all for 21 d. Subsequent follow-up was for 6 months. Cure (no further swelling) was seen in 93.9% and 94.1% of the treatment groups but in none of the placebo group. Additionally, reductions in eosinophil counts and in immunoglobulin G antibody were observed after treatment. Side effects were minimal. Albendazole may be an effective compound for the treatment of gnathostomiasis.


Newly approved integrase inhibitors for clinical treatment of AIDS.
The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized.


Who Is to Blame? Framing HPV to Influence Vaccination Intentions among College Students.
Human papillomavirus (HPV) is a prevalent sexually transmitted infection (STI) among college students. Although previous research has studied HPV-related health communication strategies using various framing techniques, the goal of this study is to test how two unique message frames-whether mentioning HPV as an STI and whether to attribute the cause of infection as external or internal-would influence young adults' intentions to receive the recommended HPV vaccine. Results indicate that gender and causal attribution framing influenced participants' intentions to receive the HPV vaccine.


Immunotherapy with standardized extract of Dermatophagoides pteronyssinus in bronchial asthma: a dose-titration study.
According to the maximum tolerated dose (MTD) achieved, we assessed the changes in clinical and laboratory parameters, induced by specific immunotherapy (SIT), in a group of 43 asthmatic patients sensitized to Dermatophagoides pteronyssinus, over a period of 18 months. A standardized extract (100 Bu/ml; 40 micrograms/ml of Der p 1; 20 micrograms/ml of Der p 2) was used. The patients were divided into two groups: the high-dose immunotherapy (HDI) group (MTD > or = 4 micrograms Der p I) and the conventional immunotherapy (CI) group (MTD < 4 micrograms Der p 1). Changes in clinical severity index, medication, and symptom scores; in cutaneous and conjunctival reactivity; and in the levels of specific IgE, IgG, IgG1, and IgG4 to D. pteronyssinus (Der p 1 and Der p 2) were measured (ELISA monoclonal antibodies). Safety was monitored according to the EAACI guidelines. The range of the MTD was 0.8-16 micrograms of Der p 1. Ninety percent of the patients tolerated a dose of 3.2 micrograms, but only 18% of the patients reached a maintenance dose of 16 micrograms. The medians of the accumulated dose were 197 micrograms of Der p 1 for the HDI group, and 50 micrograms for the CI group. Conjunctival and cutaneous reactivity was significantly lowered (P < 0.001) after SIT, as were the clinical severity score and medication score in both groups, without significant differences between the groups, except for cutaneous reactivity. Levels of specific IgE decreased significantly (P < 0.01) in both groups, again without significant differences between the groups. The range of the increase in medians of specific IgG, IgG1, and IgG4 was 4.4-120-fold for the HDI group and 3-24-fold for the CI group (P < 0.01). The increase in the levels of Der p 1 and Der p 2 IgG4 were correlated to the changes in cutaneous and conjunctival reactivity (P < 0.01). These results show that a maintenance dose of 3.2 micrograms Der p 1 (8 BU) can induce pronounced clinical and immunologic changes with an excellent safety profile.


Sidestepping Darwin: horizontal gene transfer from plants to insects.
Horizontal transfer of genetic material (HT) is the passage of DNA between organisms by means other than reproduction. Increasing numbers of HT are reported in insects, with bacteria, fungi, plants, and insects acting as the main sources of these transfers. Here, we provide a detailed account of plant-to-insect HT events. At least 14 insect species belonging to 6 orders are known to have received plant genetic material through HT. One of them, the whitefly Bemisia tabaci (Middle East Asia Minor 1), concentrates most of these transfers, with no less than 28 HT events yielding 55 plant-derived genes in this species. Several plant-to-insect HT events reported so far involve gene families known to play a role in plant-parasite interactions. We highlight methodological approaches that may further help characterize these transfers. We argue that plant-to-insect HT is likely more frequent than currently appreciated and that in-depth studies of these transfers will shed new light on plant-insect interactions.


Setting research driven duck-welfare standards: a systematic review of Pekin duck welfare research.
Globally, the production of Pekin ducks for meat and eggs is considerable, with an estimated >200 million ducks slaughtered yearly for their meat in the United States and the European Union alone. However, despite the size of the Pekin duck industries, there is a lack of research-based guidance regarding the welfare of the ducks. The purpose of this systematic review is to examine and summarize available scientific literature related to the welfare of Pekin ducks raised on commercial farms for meat and eggs. Specifically, we aimed to identify topics where sufficient literature exists to support best-practice duck welfare recommendations, as well as further research needs. The literature search targeted original research papers and review articles published in English. Six pre-establish inclusion/exclusion criteria were applied, yielding 63 publications. We summarized their content based their main topic of focus. For all original studies, we additionally recorded the country where the study was executed, scale of the project (commercial or experimental barns), general information about the housing system and management (waterers, flooring, ventilation, group size, and space allowance), and the types of outcome variables collected. We begin with an overview of key publication trends. We then synthesize and discuss welfare outcomes related to key housing/management decisions: bathing water, flooring and litter, stocking density and space availability, ventilation/air quality, lighting, outdoor access, and for egg laying birds the availability of nest boxes. Throughout, we outline specific research gaps, as well as overarching research needs.


Does play shape hand use skill in rats?
Hand use is a widespread act in many vertebrate lineages and subserves behaviors including locomotion, predation, feeding, nest construction, and grooming. In order to determine whether hand use is similarly used in social behavior, the present paper describes hand use in the social play of rats. In the course of rough and tumble play sessions, rats are found to make as many as twenty different movements a minute with each hand for the purposes of manipulating a partner into a subordinate position or defending against a partner's attack. The hand movements comprise signaling movements of touching, offensive manipulating of a partner to control a play engagement, and defensive hand movements directed toward blocking, pushing and pulling to parry an attack. For signaling, attack and defense, hand movements have a structure that is similar to the structure of hand movements used for other purposes including eating, but in their contact points on an opponent, they are tailored for partner control. Given the time devoted to play by rats, play likely features the social rat behavior with the most extensive use of hand movements. This extensive use of hand movements for social play is discussed in relation to the ubiquity of hand use in adaptive behavior, the evolution of hand use in the play of mammals, and in relation to extending the multifunctional theory of the purposes of play to include the education of skilled hand movements for various adult functions including as feeding.


Ectyoplasin, a novel cytotoxic cyclic peptide from Ectyoplasia ferox sponge.
A new cyclic heptapeptide, ectyoplasin (1), was isolated from a methanol extract of the sponge Ectyoplasia ferox. The planar structure of 1, cyclo(-Leu1-Asn2-Ala3-Val4-Thr5-Pro6-Gly7-), was determined by one and two-dimensional NMR spectroscopy and high-resolution tandem mass spectrometry. Its absolute stereochemistry was solved by Marfey's method. The in vitro assays show that ectyoplasin (1) possess significant cytotoxic activity (2.9 - 23.5 µM) against the cell lines, DU-145 (human prostate cancer), Jurkat (human T-cell acute leukaemia), MM144 (human multiple myeloma), HeLa (human cervical carcinoma) and CADO-ES1 (human Ewing's sarcoma). The DU-145 cell line showed apoptotic cell death in response to ectyoplasin (1) treatment.


Lithographically defined three-dimensional pore-patterned carbon with nitrogen doping for high-performance ultrathin supercapacitor applications.
Supercapacitors that exhibit long cycle lives and fast charge/discharge rates are a promising energy-storage technology for next-generation mobile or wearable electronic systems. A great challenge facing the fabrication of ultrathin supercapacitor components, specifically their porous electrodes, is whether such components can be integrated with the fabrication of electronic devices, i.e., semiconductor fabrication processes. Here, we introduce the lithographic fabrication of micrometre-thick, submicrometre-pore-patterned carbon for supercapacitor electrodes. The pore patterns designed by multi-beam interference lithography and direct carbonisation of the photoresist pattern produced pore-patterned carbon films. A facile doping process was subsequently employed to introduce nitrogen atoms into the carbon, which was intended to further enhance the carbon's capacitive properties. Specifically, during these fabrication steps, we developed an approach that uses a supporting shell on the surface of the pore patterns to maintain their structural integrity. The nitrogen-doped, pore-patterned carbon electrodes exhibited an areal specific capacitance of 32.7 mF/cm(2) at 0.5 mA/cm(2) when used as supercapacitor electrodes, which is approximately 20 times greater than that of commercially available MWCNT films measured under the same conditions.


Proton relaxation enhancement of albumin, immunoglobulin G, and fibrinogen labeled with Gd-DTPA.
Bovine serum albumin, immunoglobulin G, and fibrinogen were labeled with Gd-DTPA using a bifunctional chelating agent DTPA anhydride. The protein-(Gd-DTPA) conjugates had 1.4- to 2.0-fold greater longitudinal relaxivities at 0.02 and 0.44 T than the relaxivity of plain Gd-DTPA. The increase of longitudinal relaxivity was not directly related to the size of carrier protein. Up to 50 Gd-DTPA chelates per protein, longitudinal relaxivity of the conjugates was proportional to the concentration of Gd and independent of the Gd/protein ratio.


Effects of adapting lights on the time course of the receptor potential of the anuran retinal rod.
1. The intracellular receptor potential of the retinal rod cell was recorded in the unperfused, isolated retina of Rana catesbiana and in the perfused, isolated retina of Bufo marinus. Qualitatively, the responses from the two preparations were similar. 2. The rate at which the receptor potential returned to the dark level at the termination of a pulse of light (Voff) was measured at a fixed potential chosen to be about 0-6 of the way from the dark level to the peak of the response. 3. When the light intensity was such that less than about 10-minus 5 of the photopigment was bleached per second, Voff increased as the duration of the pulse was increased, reaching a maximum in 50-100 s. 4. When a brief test flash was presented at various intervals after an adapting pulse lasting about 50 s, Voff for the test flash was greater than the value in the dark adapted state for times up to about 80 s after the adapting pulse. 5. It has been hypothesized that in the vertebrate rod light causes release from the disk sacs of particles which block conducting channels in the surface membrane (Yoshikami & Hagins, 1971, 1973). A modification is proposed in which the blocking particles are converted to an inactive state can be increased by light adaptation. 6. This modified hypothesis will account qualitatively for the further observations that (a) during the response to illumination lasting several seconds the membrane potential recovers part of the way to the dark level and (b) if a second light pulse is superimposed on this background illumination then after the superimposed pulse the depolarization is increased.


Identification of molecular initiating events (MIE) using chemical database analysis and nuclear receptor activity assays for screening potential inhalation toxicants.
An adverse outcome pathway (AOP) framework can facilitate the use of alternative assays in chemical regulations by providing scientific evidence. Previously, an AOP, peroxisome proliferative-activating receptor gamma (PPARγ) antagonism that leads to pulmonary fibrosis, was developed. Based on a literature search, PPARγ inactivation has been proposed as a molecular initiating event (MIE). In addition, a list of candidate chemicals that could be used in the experimental validation was proposed using toxicity database and deep learning models. In this study, the screening of environmental chemicals for MIE was conducted using in silico and in vitro tests to maximize the applicability of this AOP for screening inhalation toxicants. Initially, potential inhalation exposure chemicals that are active in three or more key events were selected, and in silico molecular docking was performed. Among the chemicals with low binding energy to PPARγ, nine chemicals were selected for validation of the AOP using in vitro PPARγ activity assay. As a result, rotenone, triorthocresyl phosphate, and castor oil were proposed as PPARγ antagonists and stressor chemicals of the AOP. Overall, the proposed tiered approach of the database-in silico-in vitro can help identify the regulatory applicability and assist in the development and experimental validation of AOP.


Sensitive neutralization test for virus antibody. 1. Mumps antibody.
A sensitive mumps virus plaque neutralization test has been developed based on the potentiation of virus-antibody complexes by heterologous anti-immunoglobulins (AIG). The enhanced neutralization test was approximately 100 times more sensitive than the conventional neutralization test or the hemagglutination-inhibition test. Using AIG against human immunoglobulin G (IgG) or human IgM permitted determination of the relative titers of the two classes of mumps antibody. The test does not require special equipment or expertise and can be readily introduced in virological laboratories.


Screening of specific internalization Fab fragment from human naive phage library by combinational bio-panning.
Phage display is a powerful tool in identifying specific antibody fragment binding to the target. Several strategies can be used to screen out a specific Fab from the phage library that binds to an antigen; it may be performed on immobilized targeted molecule, on the intact cells, or by other strategies. Antibodies with properties of recognizing tumor cell surface receptors in native conformation and ability to internalize to tumor cells through receptor binding are ideal carriers for targeted immuno-chemo and/or immuno-radiation therapy. This chapter describes a unique bio-panning method to screen out a Fab fragment against human epithelial growth factor receptor (EGFR) from a naive human Fab phage library for potential targeted therapeutic application on EGFR overexpressed cancers.


Plasma renin activity in oedematous and marasmic children with protein energy malnutrition.
Plasma renin activity was measured by bio-assay in 52 children with kwashiorkor, in 28 with marasmus and in 21 healthy children. Plasma renin activity was significantly increased in children with kwashiorkor and marasmus, compared with healthy children, and in children who died, compared with survivors. No strict causal relationship could be found between plasma renin activity and the degree of oedema in kwashiorkor. Increased renin activity probably results from a terminal change in cardiovascular function.


Quantitative detection of acyclovir by surface enhanced Raman spectroscopy using a portable Raman spectrometer coupled with multivariate data analysis.
Acyclovir (ACV) is a synthetic antiviral agent with serious side effect, particularly its nephrotoxicity, so this study was to explore the ultrasensitive detection of ACV by surface-enhanced Raman scattering (SERS). The enhancement capability of nanoparticles prepared by different chemical reduction were compared, and Ag nanoparticles reduced by citrate are the most propriate enhanced substrate for acyclovir. In addition, comparison between prominent SERS-enhanced bands and the precise mode descriptions predicted through density functional theory (DFT) simulations is used to understand the mechanisms between ACV and metallic surface. 130 different levels of ACV concentrations in a range from 10-1∼10-7 were used to build quantitative prediction models by two different modeling methods, partial least-squares (PLS) regression and artificial neural network (ANN). Under the optimal conditions, the performance of the PLS model was much better than ANN. The results demonstrated that SERS imaging with multivariate analysis holds great potential for the sensitive and cost effective clinic test of ACV and its metabolites in biological fluids.


Motion fading is driven by perceived, not actual angular velocity.
After prolonged viewing of a slowly drifting or rotating pattern under strict fixation, the pattern appears to slow down and then momentarily stop. Here we examine the relationship between such 'motion fading' and perceived angular velocity. Using several different dot patterns that generate emergent virtual contours, we demonstrate that whenever there is a difference in the perceived angular velocity of two patterns of dots that are in fact rotating at the same angular velocity, there is also a difference in the time to undergo motion fading for those two patterns. Conversely, whenever two patterns show no difference in perceived angular velocity, even if in fact rotating at different angular velocities, we find no difference in the time to undergo motion fading. Thus, motion fading is driven by the perceived rather than actual angular velocity of a rotating stimulus.


Vaxfectin enhances immunogenicity and protective efficacy of P. yoelii circumsporozoite DNA vaccines.
We evaluated the capacity of the cationic lipid based formulation, Vaxfectin, to enhance the immunogenicity and protective efficacy of DNA-based vaccine regimens in the Plasmodium yoelii murine malaria model. We immunized Balb/c mice with varying doses (0.4-50 microg) of plasmid DNA (pDNA) encoding the P. yoelii circumsporozoite protein (PyCSP), either in a homologous DNA/DNA regimen (D-D) or a heterologous prime-boost DNA-poxvirus regimen (D-V). At the lowest pDNA doses, Vaxfectin substantially enhanced IFA titers, ELISPOT frequencies, and protective efficacy. Clinical trials of pDNA vaccines have often used low pDNA doses based on a per kilogram weight basis. Formulation of pDNA vaccines in Vaxfectin may improve their potency in human clinical trials.


The distinctive role of positron emission tomography/computed tomography in breast carcinoma with brown adipose tissue 2-fluoro-2-deoxy-d-glucose uptake.
The diagnostic power of an integrated positron emission tomography/computed tomography (PET/CT) system for whole-body 2-fluoro-2-deoxy-d-glucose (FDG) imaging is clearly demonstrated in this case report. The precise anatomic localization of FDG uptake with CT in a PET/CT scan of a patient with known breast carcinoma helped identify a contralateral breast tumor with axillary lymph node metastasis despite the presence of extensive physiologic brown fat FDG uptake. Accordingly, the patient received appropriate surgical management and pathologic confirmation of the disease.


Lymphatic transport of dietary cholesterol oxidation products, cholesterol and triacylglycerols in rats.
Rats were fed on a diet containing 0.5% cholesterol oxidation products (oxysterols) or 0.5% cholesterol for 30 min, and their lymph was collected for 7 h. The amount of each of the individual oxysterols absorbed in the lymph depended on the ingested amounts, but the recovery was the highest for 5alpha,6alpha-epoxycholesterol (10.5%), this being followed by 7-ketocholesterol (5.8%), cholestanetriol (5.2%), 7beta-hydroxycholesterol (4.8%), 7alpha-hydroxycholesterol (3.4%), 5beta,6beta-epoxycholesterol (2.2%), and 25-hydroxycholesterol (1.8%). A diet enriched with oxysterol, but not cholesterol, resulted in increased transport of triacylglycerols in the lymph. These results suggest that the absorption rate of oxysterols depends on the type, and indicate that the effect of dietary oxysterols on the lymphatic transport of triacylglycerols differs from that of dietary cholesterol. It therefore remains to be determined which oxysterol was responsible for the triacyglycerol transport.


Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors.
Targeting DNA methyltransferase 1 (DNMT1) has immunomodulatory and anti-neoplastic activity, especially when paired with cancer immunotherapies. Here we explore the immunoregulatory functions of DNMT1 in the tumor vasculature of female mice. Dnmt1 deletion in endothelial cells (ECs) impairs tumor growth while priming expression of cytokine-driven cell adhesion molecules and chemokines important for CD8+ T-cell trafficking across the vasculature; consequently, the efficacy of immune checkpoint blockade (ICB) is enhanced. We find that the proangiogenic factor FGF2 promotes ERK-mediated DNMT1 phosphorylation and nuclear translocation to repress transcription of the chemokines Cxcl9/Cxcl10 in ECs. Targeting Dnmt1 in ECs reduces proliferation but augments Th1 chemokine production and extravasation of CD8+ T-cells, suggesting DNMT1 programs immunologically anergic tumor vasculature. Our study is in good accord with preclinical observations that pharmacologically disrupting DNMT1 enhances the activity of ICB but suggests an epigenetic pathway presumed to be targeted in cancer cells is also operative in the tumor vasculature.


Isolation, expression, and evolution of the gene encoding mitochondrial elongation factor Tu in Arabidopsis thaliana.
We have characterized a second nuclear gene (tufM) in Arabidopsis thaliana that encodes a eubacterial-like protein synthesis elongation factor Tu (EF-Tu). This gene does not closely resemble the previously described Arabidopsis nuclear tufA gene, which encodes the plastid EF-Tu, and does not contain sequence elements found in all cyanobacterial and plastid tufA genes. However, the predicted amino acid sequence includes an N-terminal extension which resembles an organellar targeting sequence and shares three unique sequence elements with mitochondrial EF-Tu's, from Saccharomyces cerevisiae and Homo sapiens, suggesting that this gene encodes the Arabidopsis mitochondrial EF-Tu. Consistent with this interpretation, the gene is expressed at a higher level in flowers than in leaves. Phylogenetic analysis confirms the mitochondrial character of the sequence and indicates that the human, yeast, and Arabidopsis tufM genes have undergone considerably more sequence divergence than their cytoplasmic counterparts, perhaps reflecting a cross-compartmental acceleration of gene evolution for components of the mitochondrial translation apparatus. As previously observed for tufA, the tufM gene is present in one copy in Arabidopsis but in several copies in other species of crucifers.


[An active approach to music therapy through percussion instruments].
Percussion instruments, creativity and the helping relationship are at the heart of the evolution of a rhythmic expression workshop towards a structure designed for the practice of active music therapy. Thanks to instruments within everyone's reach, the therapy based on sound production, improvisation and creativity enables patients to express themselves, communicate and create links, while constructing an identity.


Identification of differentially expressed genes associated with aluminum resistance in the soybean plant.
Aluminum (Al) toxicity is a major limitation to crop production in countries where acidic soil is abundant. In China, soybean production is constrained by Al stress-induced toxicity. As such, there is growing interest to develop Al-resistant varieties. In the present study, we sought to determine potential genes, functions and pathways for screening and breeding of Al-resistant varieties of soybean. First, we mined the E-GEOD-18517 dataset and identified 729 differentially expressed genes (DEGs) between untreated and Al-treated groups. Next, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathways enrichment analysis and observed that most of the screened genes were mainly enriched in defense response, plasma membrane and molecular transducer activity. They were also enriched in three important pathways, the phenylpropanoid biosynthesis, plant-pathogen interaction, and cutin, suberine and wax biosynthesis. Utilizing weighted gene co-expression network analysis of 815 DEGs screened by Venn diagram, we identified DEGs that were the most disparate between treated and untreated groups. LOC100793667 (probable protein phosphatase 2C 60, GLYMA_17G223800), LOC100780576 (ethylene-responsive transcription factor 1B, GLYMA_02G006200), and LOC100785578 (protein ESKIMO 1, GLYMA_02G258000) were the most differentially expressed, which were consistent with the qRT-PCR results. As these genes are known to participate in essential functions, such as cell junction and phenylpropanoid biosynthesis, these genes may be important for breeding Al-resistant varieties. The online version contains supplementary material available at 10.1007/s12298-021-01018-x.


KIF18A knockdown reduces proliferation, migration, invasion and enhances radiosensitivity of esophageal cancer.
Kinesin family member 18A (KIF18A) is significantly overexpressed and is related to the poor prognosis of human cancers. However, the function of KIF18A in esophageal cancer (EC) is still unclear. Human EC cell lines were used in this study. KIF18A expression in human tissues was assessed using Gene Expression Profiling Interactive Analysis 2.0 (GEPIA2). The expressions of KIF18A or IGF2BP3 in EC cells were detected using qRT-PCR or WB. Cells were transfected using si-KIF18A, si-IGF2BP3, and plasmid IGF2BP3. The abilities of proliferation, migration, and invasion were detected by EdU, wound-healing, and transwell assay. The interaction between KIF18A and IGF2BP3 was predicted by starBase v3.0 and studied by RIP and RNA stability assay. Colony formation assay was used to reflect the changes of radiosensitivity in EC cells. KIF18A was upregulated in EC, and KIF18A knockdown inhibited EC cell proliferation, migration, invasion, and radioresistance. The prediction in starBase and RIP assay results showed that KIF18A mRNA could bind to IGF2BP3 protein in EC cells. RNA stability assay was performed to confirm that IGF2BP3 affects mRNA stability of KIF18A. Further studies also showed that IGF2BP3 could positively regulate KIF18A on proliferation, migration, invasion, and radioresistance. Our findings first revealed an oncogenic effect of KIF18A in human EC progression. KIF18A expression was associated with radioresistance of EC cells. The binding relationship between KIF18A and IGF2BP3 might influence the mRNA stability of KIF18A in EC cell lines.


Hypomyelination and Congenital Cataract: Identification of a Novel likely pathogenic c.414+1G>A in FAM126A gene Variant.
It is key to expand the differential diagnosis and consider possible genetic etiologies on a patient with congenital cataracts associated with clinical features, such as leukodystrophy or polyneuropathy.


Selective adaptation of internally triggered saccades made to visual targets.
We examined whether internally triggered saccades made to a nonjumping target (I-saccades) could be adapted independently from externally triggered saccades induced by a jumping target (E-saccades). Five subjects made I-saccades between two fixed targets, one placed straight ahead and the other one positioned at an eccentricity of 17.5 degrees. The peripheral target was displaced to an eccentricity of 8.75 degrees during the saccadic movements toward this target. Amplitudes of the I-saccades made from the central to the peripheral target before and after adaptation were compared with each other. Saccadic amplitudes after adaptation were between 10% and 42% smaller than those before adaptation. E-saccades induced by a single target which jumped from straight ahead to the same peripheral target position as was used for the I-saccades were also measured before and after the adaptation of I-saccades. Amplitudes of E-saccades before and after adaptation were hardly different from each other except in one subject. The mean decreases in amplitude of the two types of saccades, averaged over all subjects, were 21% for I-saccades and 5% for E-saccades. These results show that I-saccades can be adapted to changed visual conditions while E-saccades remain unadapted. We conclude from this finding that I-saccades and E-saccades are generated by at least partially different neural mechanisms.


Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice.
Type 2 diabetes and obesity have emerged as global public health crises. Adipose tissue expansion in obesity promotes accumulation of classically activated macrophages that perpetuate chronic inflammation and sustain insulin resistance. Acute inflammation normally resolves in an actively orchestrated series of molecular and cellular events that ensures return to homeostasis after an inflammatory insult, a process regulated in part by endogenous lipid mediators such as the resolvins. In this study, we sought to determine whether stimulating resolution with resolvin D1 (RvD1) improves insulin sensitivity by resolving chronic inflammation associated with obesity. In male leptin receptor-deficient (db/db) mice, treatment with RvD1 (2 μg/kg) improved glucose tolerance, decreased fasting blood glucose, and increased insulin-stimulated Akt phosphorylation in adipose tissue relative to vehicle-treated mice. Treatment with RvD1 increased adiponectin production, while expression of IL-6 in adipose tissue was decreased. The formation of crown-like structures rich in inflammatory F4/80(+)CD11c(+) macrophages was reduced by >50% in adipose tissue by RvD1 and was associated with an increased percentage of F4/80(+) cells expressing macrophage galactose-type C-type lectin 1 (MGL-1), a marker of alternatively activated macrophages. These results suggest that stimulating resolution with the endogenous proresolving mediator RvD1 could provide a novel therapeutic strategy for treating obesity-induced diabetes.


Inhalation toxicity of hexafluoroisobutylene.
An acute study of hexafluoroisobutylene (HFIB) determined its 4-hr LC50 in rats to be 1425 ppm. In a 2-week study, all animals exposed to 215 ppm for 4 days died or were sacrificed in extremis, while those exposed to the lowest level tested, 53 ppm, showed respiratory and renal effects. Based on the results of these studies, Fischer-344 rats were exposed 6 hr a day, 5 days a week, for 13 weeks to average HFIB concentrations of 3, 10, 30, and 90 ppm. No animals died due to the HFIB exposures. However, at the highest exposure level tested there were numerous marked signs of systemic toxicity in males and females. At all exposure levels, males were more affected than females. The lungs and kidneys were clearly target organs for HFIB, the kidneys being more sensitive in this study (having increased absolute and relative weights, alterations in relevant clinical chemistry parameters, and alterations in microscopic structure). A clear dose-response pattern for the above toxic effects was evident with 10 ppm in the males being an effect level. Male rats exposed to 30 ppm of HFIB had decreased body weights and significantly increased kidney weights. A satellite group of animals was maintained for 2 weeks after the completion of exposure. These animals showed some remission from the observed toxic effects, indicating recovery could be expected in rats from at least most of the toxic effects associated with exposure to HFIB. All effects observed in 3 ppm males disappeared by the end of the recovery period.


SYBR Green I-based real-time PCR targeting the rpoX gene for sensitive and rapid detection of Vibrio alginolyticus.
rpoX, a Vibrio alginolyticus specific stress regulating gene, was used to detect this fish pathogen by SYBR Green I-based real-time PCR. The specificity of the detection was confirmed in different samples. The minimum level of detection was 10(3) cells from pure culture and 10(2) cells from seawater.


Endovascular treatment of an anastomotic outflow graft pseudoaneurysm of the descending aorta after implantation of a left ventricular assist device.
Outflow graft (OG) obstruction is a dangerous complication that may occur for various reasons after the implantation of the left ventricular assist device (LVAD). In this study, we describe the case of a 67-year-old patient on LVAD support who developed a late pseudoaneurysm of the OG anastomosis (to the descending aorta) causing OG stenosis at the level of the anastomosis. The patient was treated with a customized fenestrated endovascular stent graft placed into the descending aorta and stent implantation into the OG.


Density-Matrix Based Extended Lagrangian Born-Oppenheimer Molecular Dynamics.
Extended Lagrangian Born-Oppenheimer molecular dynamics [ Phys. Rev. Lett. 2008, 100, 123004] is presented for Hartree-Fock theory, where the extended electronic degrees of freedom are represented by a density matrix, including fractional occupation numbers at elevated electronic temperatures. In contrast to regular direct Born-Oppenheimer molecular dynamics simulations, no iterative self-consistent field optimization is required prior to the force evaluations. To sample regions of the potential energy landscape where the gap is small or vanishing, which leads to particular convergence problems in regular direct Born-Oppenheimer molecular dynamics simulations, an adaptive integration scheme for the extended electronic degrees of freedom is presented. The integration scheme is based on a tunable, low-rank approximation of a fourth-order kernel, [Formula: see text], that determines the metric tensor, [Formula: see text], used in the extended harmonic oscillator of the Lagrangian that generates the dynamics of the electronic degrees of freedom. The formulation and algorithms provide a general guide to implement extended Lagrangian Born-Oppenheimer molecular dynamics for quantum chemistry, density functional theory, and semiempirical methods using a density matrix formalism.


Electron beam pretreatment of sewage sludge before anaerobic digestion.
The pretreatment of waste-activated sludge (WAS) by electron beam irradiation was studied in order to improve anaerobic sludge digestion. The irradiation dose of the electron beam was varied from 0.5 to 10 kGy. Batch and continuous-flow stirred tank reactors (CFSTRs) were operated to evaluate the effect of the electron beam pretreatment on anaerobic sludge digestion. Approximately 30-52% of the total chemical oxygen demand (COD) content of the WAS was solubilized within 24 h after electron beam irradiation. A large quantity of soluble COD, protein, and carbohydrates leached out from cell ruptures caused by the electron beam irradiation. Volatile fatty acids production from the irradiated sludge was approx 90% higher than that of the unirradiated sludge. The degradation of irradiated sewage sludge was described by two distinct first-order decay rates (k1 and k2). Most initial decay reaction accelerated within 10 d, with an average k1 of 0.06/d for sewage sludge irradiated at all dosages. The mean values for the long-term batch first-order decay coefficient (k2) were 0.025/d for irradiated sewage sludge and 0.007/d for unirradiated sludge. Volatile solids removal efficiency of the control reactor fed with unirradiated sewage sludge at a hydraulic retention time (HRT) of 20 d was almost the same as that of the CFSTRs fed with irradiated sludge at an HRT of 10 d. Therefore, disintegration of sewage sludge cells using electron beam pretreatment could reduce the reactor solid retention time by half.


Effect of experimental orthodontic pain on gray and white matter functional connectivity.
Over 90% of patients receiving orthodontic treatment experience clinically significant pain. However, little is known about the neural correlates of orthodontic pain and which has therefore been investigated in the present study of healthy subjects using an experimental paradigm. Resting-state functional magnetic resonance imaging (rsfMRI) was performed in 44 healthy subjects 24 hours after an elastic separator had been introduced between the first and the second molar on the right side of the lower jaw and in 49 age- and sex-matched healthy control (HC) subjects. A K-means clustering algorithm was used to identify functional gray matter (GM) and white matter (WM) resting-state networks, and differences in functional connectivity (FC) of GM and WM between the group of subjects with experimental orthodontic pain and HC were analyzed. Twelve GM networks and 14 WM networks with high stability were identified. Compared with HC, subjects with orthodontic pain showed significantly increased FC between WM12, which includes posterior thalamic radiation and posterior cingulum bundle, and most GM networks. Besides, the WM12 network showed significant differences in FC with three GM-WM loops involving the default mode network, dorsal attention network, and salience network, respectively. Orthodontic pain is shown to produce an alteration of FC in networks relevant to pain processing, which may be mediated by a WM network relevant to emotion perception and cognitive processing.


Dolutegravir-based regimens in treatment-naive and treatment-experienced aging populations: analyses of 6 phase III clinical trials.
Background: Older adults living with HIV (OALWH) are a growing population facing unique challenges to successful antiretroviral therapy.Objective: To assess efficacy and safety profiles of antiretroviral regimens, including those containing dolutegravir, in OALWH.Methods: Combined data from 6 phase III/IIIb trials in treatment-naive (ARIA, FLAMINGO, SINGLE, SPRING-2; N = 2634) and treatment-experienced (DAWNING, SAILING; N = 1339) participants receiving dolutegravir- or non-dolutegravir-based regimens were analyzed by age (<50, ≥50 to <65, and ≥65 years). Baseline data included comorbidities and numbers of concomitant medications. Week 48 efficacy outcomes included virologic response (HIV-1 RNA <50 copies/mL) and CD4+ cell count change from baseline. Safety outcomes included incidence of adverse events (AEs), serious AEs, and AE-related withdrawals.Results: Use of ≥5 concomitant medications was more frequently reported among treatment-naive and treatment-experienced participants aged ≥50 to <65 (30% [90/296] and 25% [57/227], respectively) and ≥65 years (43% [10/23] and 29% [4/14]) than among those aged <50 years (13% [310/2315] and 11% [118/1098]). Comorbidities were more prevalent in the older age groups. For dolutegravir-based regimens, Week 48 rates of virologic response and change in CD4+ cell count were similar across age groups (treatment naive, 80-87% and 234-251 cells/mm3; treatment experienced, 70-100% and 105-156 cells/mm3, respectively). There were no major differences in safety outcomes in each age group.Conclusions: In these analyses of combined phase III/IIIb trial data, efficacy and safety of dolutegravir-based regimens were generally similar across age groups in treatment-naive or treatment-experienced participants. Polypharmacy and comorbidities were more common among OALWH than those aged <50 years.


Neutral endopeptidase (EC 220.127.116.11) in cirrhotic liver: a new target to treat portal hypertension?
In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis. Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers. In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P<0.01), decreased portal pressure (P<0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P<0.05) and urinary excretions (P<0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P<0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa. Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.


From the Transcriptome to Electrophysiology: Searching for the Underlying Cause of Diabetes.
Cells within the islet of Langerhans are heterogeneous. Camunas-Soler et al. (2020) implement a patch-seq technique to collect both transcriptomic and electrophysiological data from the same cell. By doing so, they discover new genes that correlate with functional heterogeneity and find that shifts in these correlations indicate β cell compensation in type 2 diabetes.


Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism.
To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.


Development of a new standard reference material: SRM 1955 (homocysteine and folate in human serum).
Total homocysteine (tHCY) and folate are interrelated biomarkers for arteriosclerosis and coronary heart disease. Although many different methods for both tHCY and folate are clinically available, the intermethod and interlaboratory results are often poor, resulting in the need for a matrix reference material and reference methods. The National Institute of Standards and Technology (NIST) has developed isotope dilution liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/ tandem mass spectrometry (LC/MS/MS) methods for determination of tHCY and several folate forms including 5-methyltetrahydrofolic acid (5MT) and folic acid (FA). Additionally, a method for simultaneous measurement of tHCY, 5MT, and FA has been developed and validated. In collaboration with the Centers for Disease Control and Prevention (CDC), mass spectrometric methods and methods used in clinical laboratories have been applied to characterize a new Standard Reference Material (SRM), SRM 1955, "Homocysteine and Folate in Human Serum," containing low, medium, and high levels of tHCY and 5MT. Additionally, FA, 5-formyltetrahydrofolic acid (5FT), vitamin B12, and total folate values are provided. Use of the new SRM should improve clinical measurements and will permit traceability to internationally recognized certified reference materials, as described by European Directive 98/79/EC on in vitro diagnostic medical devices.


Iron-containing superoxide dismutase from Crithidia fasciculata. Purification, characterization, and similarity to Leishmanial and trypanosomal enzymes.
Leishmania tropica, Trypanosoma brucei, Trypanosoma cruzi, and Crithidia fasciculata have superoxide dismutases which are insensitive to cyanide and sensitive to peroxide and azide, properties characteristic of iron-containing superoxide dismutase. Studies on the superoxide dismutase of C. fasciculata have revealed that: 1) the enzyme is located in the cytosol; 2) isozymes exist; 3) the major superoxide dismutase isozyme (superoxide dismutase 2) has Mr approximately equal to 43,000 and consists of two equal-sized subunits, each of which contains 1.4 atoms of iron. Comparisons of the amino acid content of this crithidial superoxide dismutase with those of superoxide dismutases from other sources suggests that the crithidial enzyme is closely related to bacterial Fe-containing superoxide dismutases, and only distantly related to human Mn- and Cu,Zn-containing superoxide dismutases and to Euglena Fe-containing superoxide dismutase. Attempts are now underway to develop specific inhibitors of the trypanosomatid superoxide dismutase which may be of use in the treatment of leishmaniasis or trypanosomiasis.


Optimization of a hybrid chromatography-crystallization process for the separation of Tröger's base enantiomers.
This paper presents an analysis of a hybrid process consisting of simulated moving bed (SMB) chromatography and crystallization and studies its performance for the separation of the Tröger's base enantiomers. The SMB is simulated using a detailed model including column efficiency, thus, implying a proper evaluation of the effect of column size on column efficiency and separation performance. The crystallization operations are accounted for through material balances, assuming equilibrium between enantiopure crystals and mother liquor. A genetic algorithm is used to optimize the combined process, using proper definitions of objective functions. Multi-objective optimization of this hybrid process for productivity and evaporation cost in terms of operating parameters, column length, and SMB feed concentration shows an optimum SMB purity value as a trade off between increased SMB performance and recycle of the mother liquor.


Rod and cone sensitivity in destriate monkeys.
Photopic and scotopic spectral sensitivity of rhesus monkeys was determined before and after complete removal of the striate cortex. The monkeys were required to choose between a white and a series of monochromatic stimuli distributed throughout the visible spectrum. A modified method of limits was used to determine the psychophysical point of subjective equality at which the colored and white lights were perceived as being equally bright. The preoperative results indicated that the method of testing was appropriate to determine spectral sensitivity since the curves obtained compared favorably to the theoretical sensitivity curves. Postoperatively, the scotopic sensitivity curve was normal whereas the photopic curve was completely displaced towards the scotopic curve. The results as indicating that cone information is processed by the geniculo-striate visual system whereas the extra-striate structures receive their input mainly from the rod receptors of the retina.


Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant.
Hairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR. This trial is registered at www.clinicaltrials.gov as #NCT00923013.


Social jetlag, sleep-related parameters, and glycemic control in adults with type 1 diabetes: Results of a cross-sectional study.
Social jetlag (SJL) is a small recurrent circadian rhythm disruption and the most frequent form of circadian rhythm misalignment. The main aim of this study was to investigate the effect of SJL on glycemic control, as assessed by HbA1c, in real-life settings. In all, 115 consecutive patients with type 1 diabetes (T1D) were analyzed cross-sectionally. Data on bedtime, sleep onset latency, and wake up time on weekdays and weekends during the previous month were collected from all participants and used to calculate SJL, chronotype, and sleep duration. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). A PSQI score > 5 was considered as an indicator of poor sleep quality. Patients with SJL ≥ 1 hour had significantly higher adjusted values of HbA1c than those with SJL <1 hour (8.7% vs 8.0%; P = 0.029). In unadjusted multivariate regression analysis, SJL ≥ 1 hour and poor sleep quality were significant predictors of HbA1c values, explaining 22.7% and 23.5%, respectively, of the increase in HbA1c. After adjusting for age, sex, diabetes duration, insulin dose (kg/d), insulin regimen and body mass index, only SJL ≥ 1 hour remained associated with HbA1c (β = 0.253; P = 0.026). There was no significant interaction between SJL ≥ 1 hour and poor sleep quality in either the unadjusted or adjusted models (Pinteraction = 0.914). In patients with T1D, SJL is associated with poor glycemic control, acting independently of sleep quality, sleep duration, and chronotype to exert a deleterious effect on glycemic control.


Hinge-loop mutation can be used to control 3D domain swapping and amyloidogenesis of human cystatin C.
Cystatins are natural inhibitors of cysteine proteases, enzymes that are widely distributed in animals, plants, and microorganisms. Human cystatin C (hCC) has been also recognized as an aggregating protein directly involved in the formation of pathological amyloid fibrils, and these amyloidogenic properties greatly increase in a naturally occurring L68Q hCC variant. For a long time only dimeric structure of wild-type hCC has been known. The dimer is created through 3D domain swapping process, in which two parts of the cystatin structure become separated from each other and next exchanged between two molecules. Important role in the domain swapping plays the L1 loop, which connects the exchanging segments and, upon dimerization, transforms from a β-turn into a part of a long β-strand. In the very recently published first monomeric structure of human cystatin C (hCC-stab1), dimerization was abrogated due to clasping of the β-strands from the swapping domains by an engineered disulfide bridge. We have designed and constructed another mutated cystatin C with the smallest possible structural intervention, that is a single-point mutation replacing hydrophobic V57 from the L1 loop by polar asparagine, known as a stabilizer of a β-turn motif. V57N hCC mutant occurred to be stable in its monomeric form and crystallized as a monomer, revealing typical cystatin fold with a five-stranded antiparallel β-sheet wrapped around an α-helix. Here we report a 2.04 Å resolution crystal structure of V57N hCC and discuss the architecture of the protein in comparison to chicken cystatin, hCC-stab1 and dimeric hCC.


Making a Sustainable Difference to People, Processes and Systems: Whole-Systems Approaches to Process Improvement in Health Systems.
The eighteen papers in this Special Issue, 'Whole-Systems Approaches to Process Improvement in Health Systems', address an enduring challenge in healthcare: to improve efficiency with existing or reduced resources, while maintaining safe and effective care [...].


Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.
To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.


An unusual case of deafness with speech impairment: lesson in diagnosis and management.
Hearing impairment can be the cause of significant disability and handicap. This medico-legal case demonstrates the need for accurate assessment of both the severity and type of hearing loss if the best clinical management is to be provided. In particular, the case identifies the critical role of additional, objective auditory testing when pure tone audiometry, which depends on the subjective response of the individual, is inconsistent or indicates severe hearing impairment.


Sequential hemibody irradiation integrated into a chemotherapy-local radiotherapy program for limited disease small cell lung cancer.
Twenty-four patients with limited disease small cell lung cancer (SCLC) were treated with sequential hemibody irradiation (SHB) integrated into a conventional chemotherapy-local radiotherapy (LRT) program. Among 23 evaluable patients, 12 (52%) attained a complete response (CR) and 8 (35%) attained a partial response for an overall major response rate of 87%. The median time since study entry is 29 months. Durations of response are 9.9 months for all patients and 16.5 months for patients who achieved a CR. The primary site was the predominant area of recurrence. The median survival is 13.2 months for all patients and 23.2 months for the 12 patients who attained a CR. Myelosuppression, especially thrombocytopenia, was the major toxicity. Acute radiation toxicities and subacute pneumonitis previously associated with hemibody radiotherapy were well controlled or prevented using the current dose, premedication, and shielding techniques. This integrated program of systemic therapies with SHB and combination chemotherapy plus LRT is feasible for limited disease SCLC; it may prolong survival in patients who attain a CR but compared to similar programs without hemibody irradiation, there was no improvement in overall response rate, response duration, or survival.


Effect of acute hyperglycemia and/or hyperinsulinemia on polymorphonuclear functions in healthy subjects.
Abnormal immune functions of polymorphonuclear (PMN) cells occur in a variety of pathophysiological conditions. There exists a close link between glucose metabolism and PMN functions. The aim of this study was to assess the effect of short-term hyperglycemia and/or hyperinsulinemia on phagocytosis and respiratory burst of PMN cells in healthy subjects in vivo. The study was performed on 12 healthy subjects (mean age, 26.9+/-1.6 years; body mass index, 24.4+/-0.84 kg/m(2)). Acute hyperglycemia and/or hyperinsulinemia was induced by three 4-hour-long clamp studies-hyperglycemic hyperinsulinemic clamp (HHC), hyperinsulinemic euglycemic clamp (HEC), and isolated hyperglycemic clamp with insulin secretion blockade (HGC). Polymorphonuclear cell phagocytosis and PMN cell respiratory burst (mean percentage and mean fluorescent intensity of phagocyting/activated PMN cells, phagocytic, and respiratory burst indexes) were evaluated by flow cytometry under basal and stimulated conditions. Results detected during clamp studies were compared with those found during a control study with saline infusion. Significant reductions in the mean percentage of phagocyting cells measured under basal conditions after the HHC (6.7%+/-1.3% vs 12.1%+/-4.3%; P<.05) and HGC (4.5% +/-1.8% vs 9.9%+/-2.1%; P<.05) were found in comparison with the pre-clamp study period; however, these results did not differ significantly from those detected during the control clamp (CC) study. Significantly higher phagocytic (115.1+/-65 vs 35.8 +/-18.6; P<.05) and respiratory burst indexes (16.5+/-3 vs 10.1+/-1.4; P<.05) measured under basal conditions were found after HEC in comparison with the pre-clamp data. However, these data did not differ significantly from those found after the CC study. No significant differences in other parameters of detected PMN cell immune functions were found after HHC, HEC, and HGC. In conclusion, immune functions of PMN cells were not significantly influenced by short-lasting hyperglycemia and/or hyperinsulinemia induced in vivo by clamp techniques in healthy subjects compared to changes induced by the CC study. Further studies on the short-term effect of glucose metabolism on PMN functions in diabetic patients should be considered necessary.


A rapid evidence assessment of recent therapeutic touch research.
To synthesize the most recent evidence investigating the effectiveness and safety of therapeutic touch as a complementary therapy in clinical health applications. A rapid evidence assessment (REA) approach was used to review recent TT research adopting PRISMA 2009 guidelines. CINAHL, PubMed, MEDLINE, Cochrane databases, Web of Science, PsychINFO and Google Scholar were screened between January 2009-March 2020 for studies exploring TT therapies as an intervention. The main outcome measures were for pain, anxiety, sleep, nausea and functional improvement. Twenty-one studies covering a range of clinical issues were identified, including 15 randomized-controlled trials, four quasi-experimental studies, one chart review study and one mixed methods study including 1,302 patients. Eighteen of the studies reported positive outcomes. Only four exhibited a low risk of bias. All others had serious methodological flaws, bias issues, were statistically underpowered and scored as low-quality studies. No high-quality evidence was found for any of the benefits claimed.


Prenatal adherence to the Mediterranean diet decreases the risk of having a small-for-gestational-age baby, ECLIPSES study.
There is little evidence regarding the role that consuming a Mediterranean diet (MedDiet) during pregnancy plays in foetal growth. We therefore examined the relationship between maternal MedDiet adherence during pregnancy and anthropometric measures and small-for-gestational-age (SGA) at birth in a Spanish population on the north-eastern Mediterranean coast of Spain. Prospective analysis involved 614 mother-newborn pairs from the ECLIPSES study. Diet during pregnancy was assessed using a validated food frequency questionnaire, and a relative MedDiet score (rMedDiet) was calculated. Neonatal information, including weight, length, head circumference and SGA (< 10th percentile) at birth, was recorded. Multivariable logistic regression analyses were performed. The mean rMedDiet score was 9.8 (SD 2.1), ranging from 5 to 16 points. In the sample, 45% of the women had low (≤ 9 points), 32% had medium (10-11 points), and 22% had high (≥ 12 points) adherence to the rMedDiet. There was no association between rMedDiet and birth weight, length, head circumference or anthropometric indices (weight/length ratio and ponderal index). Pregnant women with a high rMedDiet score had a lower risk of delivering a SGA baby for weight (high vs low, OR = 0.36; 95% CI 0.16-0.79) and head circumference (high vs low, OR = 0.39; 95% CI 0.18-0.86), and a nonsignificant decrease in risk of SGA for length (high vs low, OR = 0.57; 95% CI 0.28-1.17). In conclusion, closer adherence to the MedDiet during pregnancy may have beneficial effects on foetal growth.


Understanding quality perception gaps among executives, frontline employees, and patients: the outpatient services in Taiwan hospitals.
The purpose of this study was to identify and evaluate service quality gaps among 3 roles (ie, hospital executives, frontline employees, and outpatients). A modified Chinese SERVQUAL scale was used to pinpoint dimension-specific quality gaps. A total of 1556 subjects (including 685 outpatients, 787 frontline employees, and 84 executives) were randomly selected from 12 middle-sized hospitals across Taiwan. Significant quality gaps among the 3 roles for 5 dimensions were found. Accordingly, strategies and tactics for improving service quality of hospitals are discussed.


KCNIP3 silence promotes proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma through activating Wnt/β-catenin pathway.
Papillary thyroid carcinoma (PTC) is the common endocrine malignancy. Kv channel interacting protein 3 (KCNIP3) has been investigated in a variety of diseases, but its role and underlying mechanism in PTC are not fully delineated. Based on this, this study mainly explored the possible mechanism of KCNIP3 in PTC. KCNIP3 expression in PTC tissues was analyzed by ENCORI and validated by quantitative real-time PCR (qRT-PCR). KCNIP3 overexpression (oe-KCNIP3) or KCNIP3 silence (si-KCNIP3) was transfected into IHH4 and FTC-133 cells, respectively. Then cell biological behaviors were detected by cell function assays. The expressions of epithelial-mesenchymal transition (EMT)- and Wnt/β-catenin pathway-related proteins were quantified by qRT-PCR and western blot. Lastly, IHH4 cells were treated with LiCl and the above assays were performed again. The expression of KCNIP3 was decreased in PTC. After transfection, oe-KCNIP3 inhibited the PTC cell viability, cloning, migration and invasion but promoted apoptosis, and meanwhile, oe-KCNIP3 reduced the EMT and Wnt pathway activation. In contrast, si-KCNIP3 had the opposite effect. Moreover, LiCl, a Wnt signaling pathway activator, could reverse the above effects of oe-KCNIP3. KCNIP3 might play an anticarcinogenic role in PTC via inhibiting the activation of Wnt/β-catenin signaling pathway.


How to grow a bud: an importin acts in asymmetric division.
The growth of daughter cells in budding yeast is a classic model for investigating mechanisms involved in asymmetric cell division. An unexpected collaboration between the DEAD-box protein Dbp5 and the nuclear transport receptor Kap104 controls localized protein synthesis at the bud tip during mitosis.


Distribution of heavy-chain variable-region (Vh) subgroups on human lymphocytes.
Lymphocytes from 20 normal blood donors were stained with fluorescein isothiocyanate (FITC)-conjugated anti--F(ab')2, anti-VHI, anti-VHII, and anti-VHIII subgroup antisera. The means of the percentages of staining were 2.9%, 5.0% and 5.5% for the VHI, VHII, VHIII subgroups, respectively. The sum of the percentages of the lymphocytes stained with each of the VH subgroup-specific antisera corresponded well with the percentages of lymphocytes stained with an anti-F(ab')2 antiserum. In addition, it was shown by double immunofluorescence staining and in various depletion experiments and tests with thymocytes and lymphocytes from patients with hypogammaglobulinemia that the cells staining with anti-Vh antisera corresponded to the membrane Ig-positive cells--that is, the B-lymphocyte population.


Emerging Preclinical and Clinical Applications of Theranostics for Nononcological Disorders.
Studies in nuclear medicine have shed light on molecular imaging and therapeutic approaches for oncological and nononcological conditions. Using the same radiopharmaceuticals for diagnosis and therapeutics of malignancies, the theranostics approach, has improved clinical management of patients. Theranostic approaches for nononcological conditions are recognized as emerging topics of research. This review focuses on preclinical and clinical studies of nononcological disorders that include theranostic strategies. Theranostic approaches are demonstrated as possible in the clinical management of infections and inflammations. There is an emerging need for randomized trials to specify the factors affecting validity and efficacy of theranostic approaches in nononcological diseases.


Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.
The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.


Looking at the endometrial biopsy with evidence-based medicine.
The results of the study of endometrial biopsy for the diagnosis of infertility, which appear in this issue, are valid. Likelihood ratios and the receiver operating characteristic curves indicate that an out-of-phase test result is worse than useless; it is misleading.


Initial phase of Pu-238 production in Idaho National Laboratory.
The initial phase of Plutonium-238 (Pu-238) production for radioisotope thermal generation is described here in detail. Two dosimeters with/without cadmium sleeve containing Neptunium-237 (Np-237) and other neutron sensors were inserted into the low power Advanced Test Reactor Critical (ATRC) for Pu-238 production testing. The gamma-ray energy measurements from Np-238, the short-lived intermediate product, confirmed that sizable amount of Pu-238 can be produced in the full power Advanced Test Reactor (ATR). The Pu-238 production determined from the irradiation experiment was in accord with the modelling predictions. Detailed studies of the Au/Cu sensors for thermal and epithermal flux analysis and their consistency for sensors in different locations, bare and in Cd-sleeve, provided confidence in the Pu-238 production data.


Hypothalamic hypopituitarism following external radiotherapy for tumours distant from the adenohypophysis.
Three cases of panhypopituitarism and five of isolated growth hormone deficiency which occurred following previous external irradiation of tumours distant from the adenohypophysis are described. The hypothalamic pituitary region received between 2800 and 12 000 rads in each case, 1-9 years before endocrine deficiency was recognized. Evidence is presented that the site of damage is in the region of the hypothalamus rather than the pituitary gland itself. Individuals treated with X-ray therapy in whom the hypothalamic-pituitary region is exposed to irradiation would appear to be at risk of developing some degree of delayed hypothalamic-pituitary dysfunction.


Credentialing study. An AAOHN report.
This article is third in a series of three articles addressing credentialing to appear in AAOHN Journal. The first article, "Credentialing: Concerns and Issues Affecting Occupational Health Nursing," by Olson, Verrall, and Lundvall, appeared in the May 1997 issue [45(5):231-238]. The second article, "Certification and Occupational Health Nursing: An Historical Perspective," by Verrall appeared in the June 1997 issue [45(6):283-289].


Does carbon dioxide, methane, nitrous oxide, and GHG emissions influence the agriculture? Evidence from China.
Carbon dioxide emission and greenhouse gas emissions are considered core issue in the world that influence agricultural production and also cause climate change. The present study seeks to investigate the linkage of methane emissions, nitrous oxide emissions, carbon dioxide emission, and greenhouse gas emissions with agricultural gross domestic product in China. The long-term association was checked by using an autoregressive distributed lag (ARDL) bounds testing approach, fully modified least squares method, and canonical cointegrating regression analysis. The results from long-run analysis exposed that carbon dioxide emission and greenhouse gas emissions have positive coefficients that demonstrate the long-run linkage with the agricultural gross domestic product having p values of 0.5709 and 0.3751, respectively. Similarly, results also revealed that agricultural methane emissions and agricultural nitrous oxide emissions have a negative association with the agricultural gross domestic product having p values of 0.1737 and 0.0559. China is a huge emitter of CO2 emission and greenhouse gas emissions. Possible conservative policies are required to form the Chinese government to tackle this challenge to decrease CO2 emission in order to increase agricultural production.


Albendazole in treatment of human cystic echinococcosis: 12 years of experience.
This review paper examines the evidence from published and previously unpublished sources for the efficacy and safety of albendazole (ABZ) obtained in the last 12 years. Benzimidazole treatment alone is not ideal, requiring prolonged administration over many weeks, with an unpredictable outcome in terms of response rates in individuals. However, studies have shown that treatment with albendazole in E. granulosus infection can result in an apparent cure in up to 30% of cases, with a further 40-50% showing objective evidence of response when followed in the short term. Some studies have demonstrated that even patients who do not show obvious initial evidence of response may be found to be cured when followed up over several years. Duration of therapy and dose are also important, and with ABZ, efficacy seems to increase with exposure up to 3 months in the commoner cyst sites. Formal dose ranging and minimal effective dose studies have not been performed, but the current dose of 800 mg daily appears to be adequate. The issue of cyclical versus continuous treatment still has to be resolved. Data on ABZ safety has been accumulated over the past 12 years of marketing. The profile shows that liver function abnormalities are common although rarely treatment limiting, while occasional hematological changes affecting the white cells may be more serious. The safety data supplies the rationale for monitoring of patients during treatment. On balance ABZ has been shown to be a useful advance in the management of cystic echinococcosis both when used as sole treatment or as an adjunct to surgery or other treatments.


Pyoderma gangrenosum treated with cyclosporin A.
A 49-year-old woman with a 14-year history of pyoderma gangrenosum unresponsive to a variety of systemic and topical treatments was given oral cyclosporin A (CyA), a potent immunosuppressive agent widely used in organ transplantation for the prophylaxis of acute graft-versus-host disease. Improvement and subsequent healing of the lesions was evident within 3 weeks of starting treatment and has continued for the duration of treatment (12 months).


Extracellular hemoglobin combined with an O2 -generating material overcomes O2 limitation in the bioartificial pancreas.
The bioartificial pancreas encapsulating pancreatic islets in immunoprotective hydrogel is a promising therapy for Type 1 diabetes. As pancreatic islets are highly metabolically active and exquisitely sensitive to hypoxia, maintaining O2 supply after transplantation remains a major challenge. In this study, we address the O2 limitation by combining silicone-encapsulated CaO2 (silicone-CaO2 ) to generate O2 with an extracellular hemoglobin O2 -carrier coencapsulated with islets. We showed that the hemoglobin improved by 37% the O2 -diffusivity through an alginate hydrogel and displayed antioxidant properties neutralizing deleterious reactive O2 species produced by silicone-CaO2 . While the hemoglobin alone failed to maintain alginate macroencapsulated neonate pig islets under hypoxia, silicone-CaO2 alone or combined to the hemoglobin restored islet viability and insulin secretion and prevented proinflammatory metabolism (PTGS2 expression). Interestingly, the combination took the advantages of the two individual strategies, improved neonate pig islet viability and insulin secretion in normoxia, and VEGF secretion and PDK1 normalization in hypoxia. Moreover, we confirmed the specific benefits of the combination compared to silicone-CaO2 alone on murine pseudo-islet viability in normoxia and hypoxia. For the first time, our results show the interest of combining an O2 provider with hemoglobin as an effective strategy to overcome O2 limitations in tissue engineering.


Cation specificity and modes of the Na+:CO3(2-):HCO3- cotransporter in renal basolateral membrane vesicles.
The cation specificity and possible exchange modes of the Na+:CO3(2-):HCO3- cotransporter were evaluated by use of basolateral membrane vesicles isolated from rabbit renal cortex. External Li+ inhibited HCO3- gradient-stimulated 22Na uptake, indicating that Li+ interacts with the Na+:CO3(2-):HCO3- cotransporter. No interaction with K+, choline, Rb+, Cs+, or NH4+ could be similarly detected. Imposing an outward Li+ gradient caused quenching of acridine orange fluorescence in the presence but not in the absence of HCO3-, suggesting that Li+:base cotransport takes place via the Na+:CO3(2-):HCO3- cotransporter. Imposing an outward gradient of unlabeled Na+ stimulated the initial rate of 22Na uptake and induced its transient uphill accumulation, indicating Na(+)-Na+ exchange. Na(+)-Na+ exchange was observed in the presence but not in the absence of HCO3- and was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), suggesting that it occurs via the Na+:CO3(2-):HCO3- cotransporter. Similarly, an outward Li+ gradient stimulated uphill 22Na accumulation, indicating Na(+)-Li+ exchange. Na(+)-Li+ exchange was observed in the presence but not in the absence of HCO3-, and was inhibited by DIDS, suggesting that it also occurs via the Na+:CO3(2-):HCO3- cotransporter. Both Na(+)-Na+ and Li(+)-Na+ exchange modes were sensitive to inhibition by harmaline but not by amiloride. We conclude that Li+ is an alternative substrate for the renal Na+:CO3(2-):HCO3- cotransporter. Transport modes of the system include cation:base cotransport and HCO3-dependent cation-cation exchange.


[Serious cerebral malformations (corpus callosum aplasia, prosencephalic cyst), internal carotid canal and facial malformations due to neural crest abnormalities, associated with choleosteatoma].
The authors report an original case of malformative spectrum, which includes cerebral (corpus callosum aplasia, prosencephalic cyst) facial, otic and basi-cranial dysplasias associated with cholesteatoma. Cephalic neural crest cells migrate to different regions in the head and neck, where they contribute to the development of mainly the first and second branchial arches and of many structures as the anterior skull base, the face, the ear and the forebrain. Data suggest that the link between these rare malformations is abnormal neural crest development, perhaps due to defective Hh signal.


Purification and characterization of the entomocidal protoxin of Bacillus thuringiensis.
A procedure for purifying the insecticidal parasporal protoxin of Bacillus thuringiensis and a description of its biochemical and biophysical properties is provided. Mild alkali titration was necessary to generate a functional protoxin in a soluble form, and anion-exchange chromatography was used to remove contaminating cytoplasmic proteases that are nonspecifically bound to whole native parasporal crystals. Polyacrylamide gel electrophoresis, gel filtration chromatography, and meniscus depletion sedimentation equilibrium analysis revealed an apparent molecular weight for the protoxin of 1.34 x 10(5). The only NH2-terminal residue found was methionine. The soluble protoxin was 2.5 times more toxic to insect larvae than was the parasporal crystal. At alkaline pH the protoxin slowly converted to a low molecular weight toxin (apparent Mr = 6.8 x 10(4)). The molar specific toxicities of the protoxin and toxin were identical.


2-Methylacetoacetyl-coenzyme A reductase from Ascaris muscle: purification and properties.
2-Methylacetoacetyl-CoA and 3-keto-2-methyl pentanoyl-CoA have been proposed to be intermediates in the synthesis of 2-methylbutyrate and 2-methylvalerate, respectively, by Ascaris lumbricoides muscle. These volatile acids are major fermentation products of Ascaris metabolism. 2-Methylacetoacetyl-CoA reductase has been purified 532-fold from Ascaris muscle to yield a homogeneous preparation which contained a single protein species as observed on discontinuous polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The purification procedure utilized subcellular fractionation, affinity chromatography on NAD+ agarose, and ion-exchange chromatography on DEAE-cellulose. A constant activity ratio for ethyl 2-methylacetoacetate and acetoacetyl-CoA was observed during purification, indicating that the same enzyme catalyzed both reactions. In addition, the purified protein catalyzed the NADH-dependent reduction of ethyl-3-keto-2-methyl pentanoate at essentially the same rate as it did ethyl 2-methylacetoacetate. The purified enzyme is a basic protein with an isoelectric point of 8.45 at 4 degrees C. The molecular weight of the native protein (Mr = 64,000 by exclusion chromatography) and the size of the subunit (Mr = 30,000 by dodecyl sulfate-polyacrylamide electrophoresis) indicate that the enzyme is composed of two subunits of the same molecular weight. Substrate-specificity studies, undertaken with the purified protein, demonstrated that the ethyl esters can substitute for the coenzyme A derivatives but this substitution results in an active substrate only when a branched 2-methyl group is present. The straight-chain ethyl ester is inactive. Kinetic constants for the substrates and nucleotides were determined. The role of the CoA esters as the physiological substrates for the Ascaris enzyme is substantiated. When assayed in the reductive direction with ethyl 2-methylacetoacetate as substrate, the activity of the purified enzyme was inhibited not only by coenzyme A as previously reported, but also by acetyl-CoA. The physiological implications of these inhibitions are discussed.


Aluminum-induced suppression of testosterone through nitric oxide production in male mice.
Excessive nitric oxide (NO) production in mice serum and testis due to aluminum (Al) exposure has been shown in previous studies. The aim of this study was to further investigate the role of NO on aluminum-suppressed testosterone level in male CD-1 mice. Each animal in six groups, was given intraperitoneal injections of either saline, aluminum chloride (AlCl(3)), l-N(6)-(1-iminoethyl) lysine (NO synthase inhibitor, l-NIL), or Al chloride along with l-NIL for a period of 12 days. These groups were denoted as C (control, saline), AL (35mg Al/kg/day, saline), NIL240 (total 240mg l-NIL/kg, saline), ALNIL240 (35mg Al/kg/day, total 240mg l-NIL/kg), ALNIL60 (35mg Al/kg/day, total 60mg l-NIL/kg), and NIL60 (total 60mg l-NIL/kg, saline). Results indicated that serum/testicular aluminum levels increased significantly in aluminum-treated animals compared to the controls, whereas the values observed from groups ALNIL240 than AL/ALNIL60 were markedly lower. Aluminum administration significantly increased NO production and decreased both testicular adenosine 3',5'-cyclic monophosphate (cAMP) and testosterone levels. A lower level of NO and higher concentrations of cAMP and testosterone observed in the ALNIL240 group indicated that the protective effect of NO synthase blockage was significant, although incomplete. In addition, aluminum induction significantly elevated the testicular cholesterol, but the values were lower in the ALNIL240 group than the AL or the ALNIL60 group. Finally, it was suggested that aluminum compounds exerted a significant adverse effects on the steroidogenesis and cAMP, which aided in the transport of cholesterol to the inner mitochondrial membrane. Furthermore, nitric oxide synthase blockage prevented aluminum-induced reproductive toxicity.


Studies on the effects of non-steroidal and disease modifying agents on cartilage soft tissue interaction in vivo.
The present study reports the effects of certain non-steroidal anti-inflammatory (NSAID) and rheumatoid-disease-modifying drugs on a novel animal model of cartilage degradation in vivo. Air pouches were induced on the dorsal surface of rats, and femoral-head cartilage was implanted. The proteoglycan content of the implanted cartilage was then used to assess cartilage degradation. Indomethacin, D-penicillamine, levamisole and dexamethasone all have some cartilage-protective activity. These observations are discussed.


Comparative study on the gas-phase adsorption of hexane over zeolites by calorimetry and inverse gas chromatography.
The scope of this work is to carry out a systematic comparison of inverse gas chromatography (IGC) and microcalorimetry as tools for the study of the gas-phase adsorption of organic vapours (using hexane as model compound) on zeolitic materials (using different Mn, Co and Fe-exchanged NaX and CaA zeolites). Adsorption isotherms were recorded using both techniques in the temperature range of 150-250 degrees C, being observed that the shape of the isotherms obtained with the dynamic (IGC) and static (microcalorimetry) techniques was surprisingly similar in the pressure range at which both techniques are applicable (low surface coverages). Concerning to the measurement of the strength of the adsorption, calorimetric data provide two parameters related to the adsorption enthalpy: the initial differential heat and the isosteric adsorption enthalpy. A great coincidence was found between the last one and the adsorption enthalpy determined by IGC (4-20% of difference, depending on the studied material). The behaviour of the initial differential heat depends strongly on the studied material, being in some cases closely related to the other two parameters and temperature-independent (in the case on Mn-exchanged zeolites), whereas for the Co-CaA and Fe-CaA zeolites, it is temperature-dependent, being not correlated with the other parameters in this case. The main conclusion of this work is that IGC is an attractive alternative to the static microcalorimetric data for obtaining information on the adsorption of organic compounds on microporous materials.


First insight into genetic diversity of the Mycobacterium tuberculosis complex in Albania obtained by multilocus variable-number tandem-repeat analysis and spoligotyping reveals the presence of beijing multidrug-resistant isolates.
We characterized a set of 100 Mycobacterium tuberculosis complex clinical isolates from tuberculosis (TB) patients in Albania, typing them with a 24-locus variable-number tandem-repeat-spoligotyping scheme. Depending on the cluster definition, 43 to 49 patients were distributed into 15 to 16 clusters which were likely to be epidemiologically linked, indicative of a recent transmission rate of 28 to 34%. This result suggests that TB is under control in Albania. However, two multidrug-resistant (MDR) Beijing genotypes harboring the same S531A mutation on the rpoB gene were also found, suggesting a potential recent transmission of MDR TB. Three brand new genotypes, Albania-1 to Albania-3, are also described.


Laser capture microdissection and single-cell RT-PCR without RNA purification.
Chronic infectious diseases of the central nervous system (CNS) are characterized by intrathecal synthesis of increased amounts of immunoglobulin G (IgG) directed against the agent that causes disease. In other inflammatory CNS diseases such as multiple sclerosis and CNS sarcoid, the targets of the humoral immune response are uncertain. To identify the IgGs expressed by individual CD38(+) plasma cells seen in human brain sections, we merged the techniques of laser capture microdissection (LCM) and single-cell RT-PCR. Frozen brain sections from a patient who died of subacute sclerosing panencephalitis (SSPE), were rapidly immunostained and examined by LCM to dissect individual CD38(+) cells. After cell lysis, we developed two techniques for reverse-transcription (RT) of unpurified total RNA in the cell lysates. The first method performed repeated and rapid freeze-thawing, followed by centrifugation of the cell lysate into tubes for subsequent RT. The second, more successful method performed RT in situ on detergent-solubilized cells directly on the cap surface; subsequent nested PCR identified heavy and light chain sequences expressed by two-thirds of individually isolated plasma cells. These techniques will streamline the identification of gene expression products in single cells from complex tissues and have the potential to identify IgGs expressed in the CNS of inflammatory diseases of unknown etiology.


Day case laparoscopy. A comparison of two anaesthetic techniques using the laryngeal mask during spontaneous breathing.
Forty women undergoing day case laparoscopy were randomly allocated to receive either an inhalational or total intravenous anaesthetic. All patients breathed spontaneously through a Brain laryngeal mask. There were no clinically significant cardiovascular or respiratory differences between the two techniques. No episodes of clinical aspiration occurred and there were no peri-operative arrhythmias. We conclude that spontaneous respiration with a laryngeal mask is a safe and effective method of anaesthesia for laparoscopy provided certain guidelines are followed.


Inactivation of acrolein by sodium 2-mercaptoethanesulfonate using headspace-solid-phase microextraction gas chromatography and mass spectrometry.
Acrolein, the metabolite of cyclophosphamide and ifosphamide, is an irritant of mucous membranes and seems to play an important role in hemorrhagic cystitis. Several methods are available to reduce the risk of hemorrhagic cystitis. Mesna is a regional detoxificant which inactivates acrolein. However, the interaction of mesna and acrolein has never been reported because no available method can detect acrolein. In this study, we measured acrolein to evaluate the effect of mesna in urine or phosphate-buffered saline using a headspace-solid-phase microextraction gas chromatography and mass spectrometry method which we had previously established. We also investigated the effect of mesna at different conditions of pH. Mesna was effective in a dose-dependent (10 microM to 20 mM) fashion in both urine and phosphate-buffered saline and completely inactivated acrolein at concentrations over 10 mM. Furthermore, mesna was more effective in alkaline conditions than in acid.


The microRNA-23b/27b/24 cluster promotes breast cancer lung metastasis by targeting metastasis-suppressive gene prosaposin.
MicroRNAs (miRNAs) have been shown to function as key regulators of tumor progression and metastasis. Recent studies have indicated that the miRNAs comprising the miR-23b/27b/24 cluster might influence tumor metastasis, although the precise nature of this regulation remains unclear. Here, expression of the miR-23b/27b/24 cluster is found to correlate with metastatic potential in mouse and human breast cancer cell lines and is elevated in metastatic lung lesions in human breast cancer patients. Ectopic expression of the miRNAs in the weakly metastatic mouse 4TO7 mammary tumor cell line had no effect on proliferation or morphology of tumor cells in vitro but was found to increase lung metastasis in a mouse model of breast cancer metastasis. Furthermore, gene expression profiling analysis of miRNA overexpressing 4TO7 cells revealed the direct targeting of prosaposin (PSAP), which encodes a secreted protein found to be inversely correlated with metastatic progression in human breast cancer patients. Importantly, ectopic expression of PSAP was able to suppress the metastatic phenotype in highly metastatic 4T1 and MDA-MB-231 SCP28 cells, as well as in cells ectopically expressing miR-23b/27b/24. These findings support a metastasis-promoting function of the miR-23b/27b/24 cluster of miRNAs, which functions in part through the direct inhibition of PSAP.


Multicenter retrospective evaluation of transmural migration of subcutaneous ureteral bypass devices within the digestive tract in cats.
Placement of a subcutaneous ureteral bypass (SUB) device is an effective method to relieve all causes of ureteral obstruction in cats. Complications involving migration within the gastrointestinal tract have been seldomly described. To characterize transmural migration of SUB devices within the digestive tract in cats. Eleven migrated SUB catheters identified in 8 cats between 2017 and 2021. Retrospective review of medical records of cats with a SUB device in which migration into the gastrointestinal tract was identified. The median time from SUB device placement to implant migration was 928 days (201-2298 days). Seven cats had obstruction of the SUB device and a positive urine culture at diagnosis. The migration was identified by ultrasound in 6/11, pre-operative contrast radiography in 2/2, and only at time of surgery in 3 SUB devices. All cats underwent surgical correction. Four nephrostomy and 7 cystotomy catheters migrated. Migration occurred into the duodenum (3/11), jejunum (7/11), and colon (1/11). SUB devices were removed in 7 cats and replaced in 2 cats, with 1 cat diagnosed with 2 migration events. Gastrointestinal resection and anastomosis were performed in 7/8 cats and an enterotomy in 2 cats. Six cats survived to discharge. The median follow-up time after migration diagnosis was 365 days (range, 0-1114 days) and 2 cats are still alive. Although a rare complication, migration of SUB device should be considered in cats with SUB device obstruction and a positive urine culture.