Risk Factors for Asparaginase-associated Pancreatitis: A Systematic Review.
To evaluate potential risk factors for the development of asparaginase-associated pancreatitis (AAP), we performed a systematic review of the current literature from January 1946 through May 2015. Asparaginase, a primary treatment for the most common childhood cancer, acute lymphoblastic leukemia (ALL), is a well-described cause of pancreatitis. Further, pancreatitis is among the most burdensome and common complications of asparaginase treatment and represents a major reason for early-drug termination and inferior outcomes. The literature lacks clarity about the risk factors for AAP, and this knowledge gap has hampered the ability to reliably predict which patients are likely to develop AAP. In an expansive screen, 1842 citations were funneled into a review of 59 full articles, of which 10 were deemed eligible based on predetermined inclusion criteria. Of the 10 identified studies, only 2 studies showed that children above 10 years of age had a >2-fold risk of AAP compared with younger children. Patients placed in high-risk ALL categories had a greater incidence of pancreatitis in 2 studies. In addition, use of pegylated asparaginase resulted in a higher incidence of AAP in 1 study. In this systematic review, older age, asparaginase formulation, higher ALL risk stratification, and higher asparaginase dosing appear to play a limited role in the development of AAP. Further studies are needed to probe the underlying mechanisms contributing to the development of pancreatitis in patients receiving asparaginase.


Role of conserved prolines in the structure and function of the Na+/dicarboxylate cotransporter 1, NaDC1.
The Na+/dicarboxylate cotransporter 1 (NaDC1) is a low-affinity transporter for citric acid cycle intermediates such as succinate and citrate. The sequence of NaDC1 contains a number of conserved proline residues in predicted transmembrane helices (TMs) 7 and 10. These transmembrane domains are of particular importance because they may be involved in determining the substrate or cation-binding affinity in NaDC1. Four conserved proline residues in TMs 7 and 10 of rabbit NaDC1 were replaced with alanine to promote ideal alpha helix or glycine to promote free conformation, and the mutant transporters were expressed in the HRPE cell line. Mutations of prolines in TM 10 produced decreased protein expression and activity, whereas mutations of prolines in TM 7 completely abolished protein expression and activity. The chemical chaperone glycerol was found to improve the expression of the Pro-351 mutants in TM 7, suggesting that these mutants had defects in trafficking. The inactive mutant transporters at position 351 could also be rescued by the addition of a proline at a second site. For example, the P351A-F347P mutant had restored activity, although its substrate specificity was altered. We conclude that, in TM 7, Pro-327 may be of particular importance in the function of the transporter, whereas Pro-351 may affect protein targeting. The prolines in TM 10, at positions 523 and 524, may not be directly involved in the transporter function but may be necessary for maintaining structure.


[Music and neurology].
Music perception and output are special functions of the human brain. Investigation in this field is growing with the support of modern neuroimaging techniques (functional magnetic resonance imaging, positron emission tomography). Interest in the music phenomenon and the disorders regarding its processing has been limited. Music is not just an artistic activity but a language to communicate, evoke and reinforce several emotions. Although the subject is still under debate, processing of music is independent of common language and each one uses independent circuits. One may be seriously affected and the other practically unharmed. On the other hand, there may be separate channels within the processing of music for the temporary elements (rhythm), melodic elements (pitch, timbre, and melody), memory and emotional response. The study of subjects with absolute pitch, congenital and acquired amusias, musicogenic epilepsy and musical hallucinations has greatly contributed to the knowledge of how the brain processes music. Music training involves some changes in morphology and physiology of professional musicians' brains. Stress, chronic pain and professional dystonias constitute a special field of musicians' disturbances that concerns neurological practice. Listening to and playing music may have some educational and therapeutic benefits.


The Efficacy of Eye Masks and Earplugs Interventions for Sleep Promotion in Critically Ill Patients: A Systematic Review and Meta-Analysis.
Using physical devices such as eye masks and earplugs to improve to the quality of sleep in intensive care units (ICUs) is a very important issue. This study was conducted to assess the efficacy of eye masks and earplugs for sleep promotion in critically ill adult patients in the ICU based on various sleep quality assessment tools. PubMed, Scopus, Web of Science, and ProQuest were systematically retrieved until May 2021. Both randomized and non-randomized experimental and quasi-experimental studies were included if they evaluated the efficacy of eye masks and earplugs interventions on sleep outcomes in critically ill patients. The methodological quality was assessed by the Joanna Briggs Institute (JBI) critical appraisal tool. For the main outcome (sleep quality), a mean difference (MD) and confidence intervals (CIs) of 95% were determined. A total of 2,687 participants from 35 studies met the inclusion criteria. Twenty one studies were included in meta-analysis and 14 studies were included in the qualitative analysis. According to the results based on sleep quality assessment tools; overall scores of Pittsburgh Sleep Quality Index (PSQI) and Richards-Campbell Sleep Questionnaire (RCSQ), eye mask and/or earplug interventions have a positive effect on sleep quality. Based on Verran-Snyder-Halpern Sleep Scale (VSHSS), sleep disturbance was significantly lower in the intervention groups. In terms of polysomnography, the use of eye masks and/or earplugs resulted in a significant increase in total sleep time, sleep efficiency, rapid eye movement (REM) time, significant reduction of awaking, and sleep arousals index. The results of the present study suggest that the use of earplugs or eye masks, separately or combined affects sleep improvement in critically ill patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=145830, PROSPERO: CRD42020145830.


Immunoprofile of adenocarcinomas of the endometrium, endocervix, and ovary with mucinous differentiation.
Primary mucinous tumors of the female genital tract have morphologic features similar to primary gastrointestinal adenocarcinomas, and distinguishing these malignancies may be extremely difficult. The purpose of this study was to characterize the immunostaining patterns of tumors of the female genital tract that show mucinous differentiation using cytokeratin 7 (CK7), CK20, and CDX2 and to evaluate the usefulness of these markers in differentiating these tumors from gastrointestinal tract adenocarcinomas and also from each other. A total of 64 cases were collected, including adenocarcinomas of the ovary (n=13), endocervix (n=16), endometrium (n=34), and vagina (n=1), all of which showed predominant mucinous differentiation. Intestinal mucinous differentiation was present in 11 of the cases (6 endocervical, 4 ovarian, and 1 vaginal adenocarcinoma). All tumors were at least focally positive for CK7 with the exception of 3 cases. The majority of tumors were negative for CK20 and CDX2. However, 25% of endocervical, 24% of ovarian, and 3% of endometrial adenocarcinomas were positive for CDX2, CK20, or both. The positivity for CDX2 and CK20 correlated with intestinal differentiation: 73% of all intestinal mucinous adenocarcinomas and 4% of all Müllerian mucinous adenocarcinomas showed positivity for the hindgut markers. In 70% of the tumors positive for CK20/CDX2, the intensity of CK7 stain was stronger than the intensity of either CK20 or CDX2 stain. In conclusion, immunostaining for CK7/CK20/CDX2 is helpful in distinguishing Müllerian subtype of mucinous gynecologic tumors from lower gastrointestinal tract malignancies. In gynecologic mucinous tumors with intestinal differentiation, the overlap of staining positivity may be a limiting factor. However, a dominant CK7 staining pattern was observed.


Low incidence of de novo HLA antibodies after COVID-19 vaccination: A cohort study of patients awaiting kidney transplantation.
Antibodies against human leukocyte antigen (anti-HLA Abs) are associated with an increased risk of allograft loss. Herein, we report the prospective follow-up for anti-HLA Abs formation in 103 patients with end-stage kidney disease on the waiting list for transplantation who underwent COVID-19 vaccination. Sera were tested before and after vaccination using Luminex technology. The cohort comprised of 62 males and 41 females with a mean age of 56 ± 14 years. The patients received BNT162b2 (80.4%), mRNA-1273 (18.5%), AZD1222 (0.40%), or ChAdOx1-S (0.80%) vaccine. Patients were tested before and within 119 ± 50, 95 ± 46 and 25 ± 26 days after the first, second, and third dose of the vaccine, respectively. No significant change in calculated panel reactive antibody (cPRA) after vaccination was seen. Although 98.1% of patients had no change in anti-HLA Abs profile or cPRA after vaccination, two patients (1.9%) developed de novo anti-HLA Abs against class I or II HLA antigens. In those two patients, the cPRA changed from 0% and 63% at baseline to 9% and 90% after vaccination, respectively. Both patients received the BNT162b2 mRNA-based vaccine. The earliest detected anti-HLA Abs was 18 days after the first dose. In rare cases, new anti-HLA antibodies were observed after COVID-19 vaccination, with potential implications for transplantation. The low incidence of this phenomenon is outweighed by the clinical benefits of vaccination.


Lipid-modified, cysteinyl-containing peptides of diverse structures are efficiently S-acylated at the plasma membrane of mammalian cells.
A variety of cysteine-containing, lipid-modified peptides are found to be S-acylated by cultured mammalian cells. The acylation reaction is highly specific for cysteinyl over serinyl residues and for lipid-modified peptides over hydrophilic peptides. The S-acylation process appears by various criteria to be enzymatic and resembles the S-acylation of plasma membrane-associated proteins in various characteristics, including inhibition by tunicamycin. The substrate range of the S-acylation reaction encompasses, but is not limited to, lipopeptides incorporating the motifs myristoylGC- and -CXC(farnesyl)-OCH3, which are reversibly S-acylated in various intracellular proteins. Mass-spectrometric analysis indicates that palmitoyl residues constitute the predominant but not the only type of S-acyl group coupled to a lipopeptide carrying the myristoylGC- motif, with smaller amounts of S-stearoyl and S-oleoyl substituents also detectable. Fluorescence microscopy using NBD-labeled cysteinyl lipopeptides reveals that the products of lipopeptide S-acylation, which cannot diffuse between membranes, are in almost all cases localized preferentially to the plasma membrane. This preferential localization is found even at reduced temperatures where vesicular transport from the Golgi complex to the plasma membrane is suppressed, strongly suggesting that the plasma membrane itself is the preferred site of S-acylation of these species. Uniquely among the lipopeptides studied, species incorporating an unphysiological N-myristoylcysteinyl- motif also show substantial formation of S-acylated products in a second, intracellular compartment identified as the Golgi complex by its labeling with a fluorescent ceramide. Our results suggest that distinct S-acyltransferases exist in the Golgi complex and plasma membrane compartments and that S-acylation of motifs such as myristoylGC- occurs specifically at the plasma membrane, affording efficient targeting of cellular proteins bearing such motifs to this membrane compartment.


The correlation between peripheral leukocyte telomere length and indicators of cardiovascular aging.
To investigate the relationship between telomere length in peripheral blood white cells and cardiovascular function in a healthy, aging Han Chinese population. In 2012, peripheral blood leukocytes were obtained from 139 healthy individuals in Beijing, China, and telomere restriction fragment (TRF) length was assayed using a digoxigenin-labeled hybridization probe in Southern blot assays. Indicators of cardiovascular function were also evaluated, including electrocardiograms (ECG), (RR, P, PR, QRS, ST and T intervals); blood pressure (BP), (SBP, DBP, PP, PPI); cardiovascular ultrasound (left ventricular ejection fraction, LVEF); mitral early and late diastolic peak flow velocity (MVE and MVA); and lipid indices (TC, TG, HDL, LDL, LCI). The relationships of these cardiovascular indictors to telomere length were evaluated. No correlations were found between telomere length and ECG, BP or lipid indices even after adjustment for age. Correlations were found between TFR length and some cardiovascular ultrasound indictors (D, MVEA, MVEDT, MVES, MVEL, MVEI, IMT), but these were not seen after adjusting for age. We did not find that leukocyte TFR length was associated with cardiovascular ultrasound indictors, ECG, BP, or lipid indices in this population of healthy Han Chinese individuals. Telomere length may serve as a genetic factor in biological aging.


[Pectin production from burdock (Arctium sp.)].
The pectin complex of different morphological parts of burdock: leaf, leaf stems, main stock have been investigated. High quantity of pectic substances about 1.9% per wet mass, has been detected in the leaf stems of burdock. It has been also established that pressed leaf stems as to pectin content (about 21% of dry mass) do not give in to traditional raw material for pectin production: pressed apple, squeezed sugar-beet, citrus fruit peel, sunflower head, etc. The technological scheme of pectin production from burdock has been developed. Pectin powder obtained from burdock was of light grey colour. The total output was 17% of dry mass of raw material. Uronide component of burdock pectin was 66%, esterification rate 47%, methoxyl component 9%, equivalent weight 343, the free carboxyl group content 16%.


Psychological well-being in retirement: the effects of personal and gendered contextual resources.
Although prior research points to the gendered nature of work and private routines, surprisingly few studies have explored the influence of gender on the sources of psychological well-being in retirement. Drawing on resource theories and theories on the gendered division of labor, this study examines how preretirement resources relate to retirees' psychological well-being by using data from the Wisconsin Longitudinal Study. It is hypothesized that possessing key resources prior to retirement as well as losing or gaining resources in the transition to retirement influence retirees' well-being and that these effects are partially conditioned by gender. Results indicate that preretirement physical health, tenacity in goal pursuit, and flexibility in goal adjustment are beneficial for men's and women's well-being alike. By contrast, financial assets and job dissatisfaction are more strongly related to men's psychological well-being in retirement and preretirement social contacts to that of women. Thus, the study underscores the importance of considering gendered resources in retirement research.


Ordinary and Hot Electroluminescence from Single-Molecule Devices: Controlling the Emission Color by Chemical Engineering.
Single-molecule junctions specifically designed for their optical properties are operated as light-emitting devices using a cryogenic scanning tunneling microscope. They are composed of an emitting unit-a molecular chromophore-suspended between a Au(111) surface and the tip of the microscope by organic linkers. Tunneling electrons flowing through these junctions generate a narrow-line emission of light whose color is controlled by carefully selecting the chemical structure of the emitting unit. Besides the main emission line, red and blue-shifted vibronic features of low intensity are also detected. While the red-shifted features provide a spectroscopic fingerprint of the emitting unit, the blue-shifted ones are interpreted in terms of hot luminescence from vibrationally excited states of the molecule.


Zinc effects on hyperglycemia and hypoleptinemia in streptozotocin-induced diabetic mice.
Zinc has an antihyperglycemic effect. Zinc can also influence the production of leptin, a satiety factor that reduces appetite and blood sugar level. In this study, we investigated the effect of zinc supplementation on food intake and circulating leptin and glucose concentrations in streptozotocin-induced diabetic mice. Male diabetic mice received zinc supplementation (20 ppm) from drinking water for two weeks. The results showed that zinc treatment did not affect body weight gain, body fat content or food intake in these diabetic mice. However, zinc supplementation markedly ameliorated the hyperglycemia of diabetic mice. After zinc treatment, serum leptin concentrations tended to increase in the diabetic mice. This study suggests that zinc is a mediator of leptin production.


Hamiltonian decompositions of 4-regular Cayley graphs of infinite abelian groups.
A well-known conjecture of Alspach says that every 2 k -regular Cayley graph of a finite abelian group can be decomposed into Hamiltonian cycles. We consider an analogous question for infinite abelian groups. In this setting one natural analogue of a Hamiltonian cycle is a spanning double-ray. However, a naive generalisation of Alspach's conjecture fails to hold in this setting due to the existence of 2 k -regular Cayley graphs with finite cuts F , where ∣ F ∣ and k differ in parity, which necessarily preclude the existence of a decomposition into spanning double-rays. We show that every 4-regular Cayley graph of an infinite abelian group all of whose finite cuts are even can be decomposed into spanning double-rays, and so characterise when such decompositions exist. We also characterise when such graphs can be decomposed either into Hamiltonian circles, a more topological generalisation of a Hamiltonian cycle in infinite graphs, or into a Hamiltonian circle and a spanning double-ray.


Detection of denitrification genes by in situ rolling circle amplification-fluorescence in situ hybridization to link metabolic potential with identity inside bacterial cells.
A target-primed in situ rolling circle amplification (in situ RCA) protocol was developed for detection of single-copy genes inside bacterial cells and optimized with Pseudomonas stutzeri, targeting nitrite and nitrous oxide reductase genes (nirS and nosZ). Two padlock probes were designed per gene to target both DNA strands; the target DNA was cut by a restriction endonuclease close to the probe binding sites, which subsequently were made accessible by 5'-3' exonucleolysis. After hybridization, the padlock probe was circularized by ligation and served as template for in situ RCA, primed by the probe target site. Finally, the RCA product inside the cells was detected by standard fluorescence in situ hybridization (FISH). The optimized protocol showed high specificity and signal-to-noise ratio but low detection frequency (up to 15% for single-copy genes and up to 43% for the multi-copy 16S rRNA gene). Nevertheless, multiple genes (nirS and nosZ; nirS and the 16S rRNA gene) could be detected simultaneously in P. stutzeri. Environmental application of in situ RCA-FISH was demonstrated on activated sludge by the differential detection of two types of nirS-defined denitrifiers; one of them was identified as Candidatus Accumulibacter phosphatis by combining in situ RCA-FISH with 16S rRNA-targeted FISH. While not suitable for quantification because of its low detection frequency, in situ RCA-FISH will allow to link metabolic potential with 16S rRNA (gene)-based identification of single microbial cells.


Effect of levocarnitine on cerebral ischemia-reperfusion rats via activating Nrf2/ARE signaling pathway.
Levocarnitine plays a crucial role in the metabolism of organisms. The aim of this study was to explore the impact of Levocarnitine on cerebral ischemia-reperfusion (I/R) rats and the underlying mechanism. Cerebral I/R model was first successfully established. Two groups were set up, including drug group (I/R + Levocarnitine group) and control group (I/R group). The influences of Levocarnitine on brain injury and oxidative stress in cerebral I/R rats were evaluated. Furthermore, the impacts of Levocarnitine on the nuclear factor E2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) signaling pathway and neuronal apoptosis in rats were detected. Compared with I/R group, I/R + Levocarnitine group exhibited markedly lowered neurological deficit score and cerebral infarct volume. However, superoxide dismutase (SOD) and notably decreased malondialdehyde (MDA) were significantly up-regulated in I/R + Levocarnitine group. This suggested that Levocarnitine could relieve cerebral nerve injury and oxidative stress in cerebral I/R rats. Additionally, in I/R + Levocarnitine group, the protein expressions of Nrf2, heme oxygenase-1 (HO-1), and B-cell lymphoma 2 (Bcl-2) were significantly up-regulated, whereas cleaved Caspase-3 (c-Caspase-3) was notably down-regulated. Furthermore, neuronal apoptosis in cerebral I/R rats was remarkably inhibited. Levocarnitine alleviates brain injury and neuronal apoptosis in cerebral I/R rats by activating the Nrf2/ARE signaling pathway.


Next generation ligand binding assays-review of emerging real-time measurement technologies.
Over the last few years, numerous ligand binding assay technologies that utilize real-time measurement have been introduced; however, an assemblage and evaluation of these technologies has not previously been published. Herein, we describe six emerging real-time measurement technologies: Maverick™, MX96 SPR™, NanoDLSay™, AMMP®/ViBE®, SoPrano™, and two Lab-on-a-Chip (LoC) microfluidic devices. The development stage gate of these technologies ranges from pre-commercial to commercially available. Due to the novelty, the application and utility of some of the technologies regarding bioanalysis are likely to evolve but it is our hope that this review will provide insight into the direction the development of real-time measurement technologies is moving and the vision of those that are taking us there. Following the technology discussions, a comprehensive summary table is presented.


Oscillating intensity display of soft tissue lesions in MRI.
A new postprocessing method for improving visualization of soft tissue lesions in MR images is described. Abnormal tissues are detected by a computerized tissue characterization algorithm which is based on measurements of intensity in a spatially matched pair of T1- and T2-weighted images. Simultaneous display of information from this pair of static images is achieved by using a temporal parameter (amplitude or frequency of intensity oscillation) to encode abnormal pixels. Specifically, a movie is created in which pixel intensities of abnormal tissues are made to oscillate so that the amplitude (or frequency) of oscillation is proportional to an abnormality index which depends on the difference between intensities of normal and abnormal tissues in the original image pair. The visual effect is that of a churning motion within the lesion, while surrounding normal tissues are displayed as stable structures. This technique increases the conspicuity of the lesion by exploiting the eye's great sensitivity to motion.


A Foucauldian analysis of old age and the power of social welfare.
It is argued that the question of social welfare is a key, if often overlooked, component in the construction of power relations and identities in later life that can take its place next to debates on bioethics and consumer lifestyle. Foucault's (1977) claim, that identities are kept in place through the deployment of integrated systems of power and knowledge and a routine operation of surveillance and assessment, is critically examined in this context. Trends in social welfare in the United Kingdom are used as a case example that sheds light on wider contemporary issues associated with old age. Finally, implications for the creation of particular narratives about later life are discussed and grounded through Foucault's (1988) notion of "technologies of self."


Store-Operated Calcium Entry Increases Nuclear Calcium in Adult Rat Atrial and Ventricular Cardiomyocytes.
Store-operated calcium entry (SOCE) in cardiomyocytes may be involved in cardiac remodeling, but the underlying mechanisms remain elusive. We hypothesized that SOCE may increase nuclear calcium, which alters gene expression via calcium/calmodulin-dependent enzyme signaling, and elucidated the underlying cellular mechanisms. An experimental protocol was established in isolated adult rat cardiomyocytes to elicit SOCE by re-addition of calcium following complete depletion of sarcoplasmic reticulum (SR) calcium and to quantify SOCE in relation to the electrically stimulated calcium transient (CaT) measured in the same cell before SR depletion. Using confocal imaging, calcium changes were recorded simultaneously in the cytosol and in the nucleus of the cell. In ventricular myocytes, SOCE was observed in the cytosol and nucleus amounting to ≈15% and ≈25% of the respective CaT. There was a linear correlation between the SOCE-mediated calcium increase in the cytosol and nucleus. Inhibitors of TRPC or Orai channels reduced SOCE by ≈33-67%, whereas detubulation did not. In atrial myocytes, SOCE with similar characteristics was observed in the cytosol and nucleus. However, the SOCE amplitudes in atrial myocytes were ≈two-fold larger than in ventricular myocytes, and this was associated with ≈1.4- to 3.6-fold larger expression of putative SOCE proteins (TRPC1, 3, 6, and STIM1) in atrial tissue. The results indicated that SOCE in atrial and ventricular myocytes is able to cause robust calcium increases in the nucleus and that both TRPC and Orai channels may contribute to SOCE in adult cardiomyocytes.


Monomorphic HLA class I-(non-A, non-B) expression on Ewing's tumor cell lines, modulation by TNF-alpha and IFN-gamma.
In this study, the expression of polymorphic and non-polymorphic MHC antigens in Ewing's tumor (ET) cells was examined by surface staining, Western blots and transcriptional analysis. Cell lines derived from Ewing's tumors largely lack polymorphic HLA class Ia antigens of both the HLA-A and the HLA-B loci but binding of monomorphic HLA antibodies indicates significant expression of HLA-C locus antigens and/or HLA class Ib molecules. HLA Ib molecules encoded by the HLA-E, -F or -G loci with a molecular mass of less than 44 kDa were not detected in lysates of either constitutive or TNF-alpha plus IFN-gamma treated ET cells. Two representative ET cell lines with either detectable HLA-A, -B antigens (A673) or absolutely non-detectable HLA-A, -B antigens (SK-ES-1) were further subjected to transcriptional analysis. A673 mRNA hybridized with HLA-A, -B, -C and HLA-E-specific probes in Northern blots. By contrast, mRNA specific for HLA-A, -B, -C was negative in SK-ES-1 but TNF-alpha plus IFN-gamma reconstituted HLA-A, -B, -C transcription in this cell line. HLA-E was transcribed in A673 but not in SK-ES-1. Combining mRNA and surface expression of HLA class Ia molecules results in a highly variable pattern of defective HLA class I expression in this type of neuroectodermal tumor. The involvement of the ET-specific fusion transcript EWS/Fli-1 in modulating the HLA-A and -B locus antigens is likely to occur by the upregulation of c-myc in these tumors. The exceptionally constant expression of HLA-C or some other non-A, non-B antigens (reactive with defined monoclonal antibodies) implies important consequences on tumor-cell resistance against specific CTL and NK activity in vivo.


Penicillium chrysogenum var. halophenolicum, a new halotolerant strain with potential in the remediation of aromatic compounds in high salt environments.
A halotolerant phenylacetate-degrading fungus Penicillium CLONA2, previously isolated from a salt mine at Algarve (Portugal), was identified as a variant of P. chrysogenum using the ITS-5,8S rDNA and the D1/D2 domain of 28S rDNA sequences. The metabolic features and genetic characteristics suggest that this strain belongs to a subgroup of P. chrysogenum, named var. halophenolicum. The presence of the penicillin biosynthetic cluster was proven by Southern hybridizations using probes internal to the pcbAB and penDE genes and sequencing of the pcbAB-pcbC intergenic region. However the pcbAB-pcbC divergent promoter region contained 20 point modifications with respect to that of the wild type P. chrysogenum NRRL1951. The CLONA2 strain produced non-aromatic natural penicillins rather than benzylpenicillin in a medium containing potassium phenylacetate (the precursor of benzylpenicillin) and was able to grow well on phenylacetatic acid using it as sole carbon source. Due to the ability of P. chrysogenum CLONA2 to degrade aromatic compounds, this strain may be an interesting organism for aromatic compounds remediation in high salinity environments.


Rare earth elements as markers for rate of passage measurements of individual feedstuffs through the digestive tract of ruminants.
Rumen and in vitro abomasal fluid incubations of four feeds, soybean meal (SBM), 0.3% formaldehyde-treated SBM, cottonseed meal and ground corn, each labeled with one of two markers (Sm and La) were conducted to estimate the extent of marker movement from the feeds. Feeds were marked by spraying acidic solutions of the marker movement from the feeds. Feeds were marked by spraying acidic solutions of the markers uniformly over the feeds. Concentration of marker on the feeds, on the feed residues remaining in polyester bags after 12 hours of incubation in the rumen, and on the feed residues after 12 hours of incubation in the rumen and 3 hours of in vitro incubation in abomasal fluid were determined by neutron activation. Initial concentration of the markers on the feeds was used as a covariable in analysis of the restricted randomized block design. Marker concentration of Sm and La, for all feeds, averaged 1115 +/- 44 and 1503 +/- 44 ppm after the rumen incubation and 959 +/- 54 and 1666 +/- 54 ppm after the combined incubations and differed (P less than 0.01) from the mean initial marker concentration of 1294 +/- 42 ppm. Abomasal incubations allowed estimation of marker movement (contamination) between bags. For both markers, increases (P less than 0.01) were observed in marker contamination when compared to initial levels. Marker contamination increased from 2.5 +/- 0.8 to 20.1 +/- 0.1 and 10.7 +/- 0.8 ppm for Sm and La, respectively. Data indicate significant marker movement and suggest that Sm and La, when applied to feeds by this method, are not suitable markers for estimating passage rates of individual feedstuffs.


Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis.
Acute respiratory syncytial virus (RSV)-induced bronchiolitis is often associated with continuing respiratory symptoms following hospitalization. To date, there is no validated objective measure to evaluate symptoms of RSV-induced bronchiolitis. We report on the reliability, validity, and responsiveness of the bronchiolitis caregiver diary (BCD) of symptoms and healthcare utilization associated with postacute RSV. The BCD measures four symptoms (daytime cough, wheeze, trouble breathing, and nighttime cough), healthcare utilization, and rescue medication for worsening of lung symptoms. Data from the 4-week treatment period of the reported prospective, placebo-controlled trial of montelukast for treatment of postacute RSV were used to assess reliability (internal consistency and test-retest), construct validity (cross-sectional and longitudinal correlations), discriminant validity (known-groups analyses), and responsiveness. The primary outcome of this study was the percentage of symptom-free days (SFD). The secondary outcome was a composite symptom score (CSS; average of daytime cough, wheezing, and trouble breathing). Cronbach's alpha of 0.85 indicated that the four symptoms were internally consistent, supporting a unidimensional scale structure. Test-retest reliabilities for the percentage of SFD and CSS were above the recommended cut point of 0.70. Cross-sectional and longitudinal correlations were sizeable and statistically significant, demonstrating construct validity. Hypothesized known-group differences were statistically significant in the appropriate direction. Responsiveness analyses indicated moderate effect sizes for percentage of SFD. In conclusion, the BCD provides a valid, reliable, and responsive tool for the assessment of symptoms of postacute RSV-induced bronchiolitis, capable of measuring moderate effect sizes, and demonstrating responsiveness to therapy.


A Novel Classification of Relationship Between Nasal Septum and Inferior Turbinate Associated With Nasal Airway Obstruction in Patients With Unilateral Alveolar Cleft.
This study aims to investigate nasal morphologies associated with nasal airway obstruction in unilateral alveolar cleft patients. A total of 234 unilateral alveolar cleft cases were performed cone beam computed tomography scans. The digital imaging and communication in medicine data were imported into Simplant Pro software. The radiographic features including nasal septum deviation and inferior turbinate hypertrophy as well as nasal airway volume and sinusitis were analyzed. A new radiographic classification of relationship between nasal septum and inferior turbinate (NS-IT) on the cleft side was proposed and three types of NS-IT relationship (type I, II and III) were identified in 234 cases. The statistical analysis revealed that the nasal airway volume on non-cleft side was significantly higher than that on cleft side in each of three types (P < 0.0001), while no difference of nasal airway volume on non-cleft side was found among three types. In addition, the nasal airway volume on non-cleft side in type I and II was significantly higher than that in type III (P < 0.0001). Also, type III presented higher rate of maxillary sinusitis (P = 0.0154) and ethmoid sinusitis on cleft side (P = 0.0490) than type I and II. The other indexes including clinical variances were not significant among three types. Unilateral alveolar cleft patients with type III NS-IT relationship could have nasal airway obstruction and higher rate of maxillary and ethmoid sinusitis on cleft side, which may be taken into account at primary cleft repair and alveolar bone grafting treatment.


Who Serves Where: A Geospatial Analysis of Access to Endocrine Surgeons in the United States and Puerto Rico.
The association between surgical volume and patient outcome is well established, with higher case volume associated with a lower risk of complications. We hypothesized that the geographic distribution of endocrine/head and neck surgeons with an endocrine focus in the United States and Puerto Rico may limit access to many potential patients, particularly in rural areas. We used web-based directories from the American Association of Endocrine Surgeons, American Head and Neck Society, and the American Academy of Otolaryngology-Head and Neck Surgery to identify endocrine surgery specialists in the United States and Puerto Rico. Using geographic coordinates and OpenStreetMap and Valhalla software, we calculated the areas within a 60-, 90-, or 120-minute driving distance from specialist offices. We used 2020 U.S. Census Data to calculate census tract populations inside or outside the accessible areas. Excluding duplicate providers across organizations, we geocoded 603 specialist addresses in the United States and Puerto. We found that 23.76% (78.3 million) of Americans do not have access to a society-affiliated endocrine/head and neck surgeon with an endocrine focus within a 60-minute drive, 14.37% (47.4 million) within a 90-minute drive, and 8.38% (27.6 million) within a 120-minute drive. We observed that the areas of coverage are primarily focused on metropolitan areas. Nearly one-third of Americans do not have access to a society-affiliated endocrine/head and neck surgeon with an endocrine focus within a 1-hour drive, highlighting a concerning geographic barrier to care. Further work is needed to facilitate patient access and mitigate disparities in quality care.


The effects of time compression on the auditory processing abilities of learning disabled children.
This study measured the ability of ten 8- and ten 12-yr-old learning disabled (LD) children of normal intelligence (WISC-R) to discriminate phonemic contrasts in sentential stimuli (Subtest 13 of the Carrow Auditory Visual Abilities Test) presented at a 50% time-compression rate. Their group responses were compared statistically to similar data gathered earlier (May et al, J. Aud. Res., 1984, 24, 205-211) from 6-, 8-, and 10-yr-old normal children and young adults. LD Ss exhibited auditory processing capacities reminiscent of an earlier level of operation (e.g., the group of LD Ss with mn age of 12.8 yrs yielded group performance equivalent to that of normal 6- and 8-yr-olds), and also manifested marked differences in their feature- and frequency-processing abilities. These data indicate that contributing to the learning difficulties of LD children may very well be delays in auditory development and anomalies in auditory-feature processing.


Time-resolved spectral observations of cadmium-enriched cadmium sulfide nanoparticles and the effects of DNA oligomer binding.
We measured the steady-state and time-resolved fluorescence spectral properties of cadmium-enriched nanoparticles (CdS-Cd2+). These particles displayed two emission maxima, at 460 and 580 nm. The emission spectra were independent of excitation wavelength. Surprisingly, the intensity decays were strongly dependent on the observation wavelength, with longer decay times being observed at longer wavelengths. The mean lifetime increased from 150 to 370 ns as the emission wavelength was increased from 460 to 650 nm. The wavelength-dependent lifetimes were used to construct the time-resolved emission spectra, which showed a growth of the long-wavelength emission at longer times, and decay-associated spectra, which showed the longer wavelength emission associated with the longer decay time. These nanoparticles displayed anisotropy values as high as 0.35, depending on the excitation and emission wavelengths. Such high anisotropies are unexpected for presumably spherical nanoparticles. The anisotropy decayed with two correlation times near 5 and 370 ns, with the larger value probably due to overall rotational diffusion of the nanoparticles. Addition of a 32-base pair oligomer selectively quenched the 460-nm emission, with less quenching being observed at longer wavelengths. The time-resolved intensity decays were minimally affected by the DNA, suggesting a static quenching mechanism. The wavelength-selected quenching shown by the nanoparticles may make them useful for DNA analysis.


Pyrosequencing on nicked dsDNA generated by nicking endonucleases.
Although the pyrosequencing method is simple and fast, the step of ssDNA preparation increases the cost, labor, and cross-contamination risk. In this paper, we proposed a method enabling pyrosequencing directly on dsDNA digested by nicking endonucleases (NEases). Recognition sequence of NEases was introduced using artificially mismatched bases in a PCR primer (in the case of genotyping) or a reverse-transcription primer (in the case of gene expression analysis). PCR products were treated to remove excess amounts of primers, nucleotides, and pyrophosphate (PPi) prior to sequencing. After the nicking reaction, pyrosequencing starts at the nicked 3' end, and extension reaction occurs when the added dNTP is complementary to the non-nicked strand. Although the activity of strand displacement by Klenow is limited, approximately 10 bases are accurately sequenced; this length is long enough for genotyping and SRPP-based differential gene expression analysis. It was observed that the signals of two allele-specific bases in a pyrogram from nicked dsDNA are highly quantitative, enabling quantitative determination of allele-specific templates; thus, Down's Syndrome diagnosis as well as differential gene expression analysis was successfully executed. The results indicate that pyrosequencing using nicked dsDNA as templates is a simple, inexpensive, and reliable way in either quantitative genotyping or gene expression analysis.


The "broken heart sydrome": you're likely to have it only once!
Stress cardiomyopathy (SC) is also known as Takotsubo cardiomyopathy. The term transient left ventricular ballooning syndrome has also been used. These terms refer to the same phenomenon. The typical presentation of SC in a patient is a sudden onset of chest pain or heart failure associated with electrocardiographic changes of ST-segment elevation, which is suggestive of anterior ST-segment elevation myocardial infarction. When these patients are assessed, a bulging of the left ventricular apex with a hypercontractile base of the left ventricle is noted. It is this hallmark bulging of the apex with preserved function at the base that characterises this unique syndrome. The possible pathophysiology of its mechanism as well as the different morphological types are discussed.


Adenoviral p53 gene therapy promotes heat-induced apoptosis in a nasopharyngeal carcinoma cell line.
It has previously been demonstrated that Ad5CMV-p53 gene transfer, either used alone or delivered concomitantly with ionizing radiation, resulted in cytotoxicity mediated by apoptosis in nasopharyngeal carcinoma (NPC) cell lines. In this study, a novel approach was evaluated of combining Ad5CMV-p53 gene therapy with hyperthermia (HT), in the CNE-1 NPC cell line, which harbours a mutation in codon 249 of the p53 gene. CNE-1 cells were infected using either Ad5CMV-p53 or Ad5CMV-B-gal, followed, 24 h later, by HT (43 degrees C x 0-2 h). Protein was extracted for Western blot analysis, and apoptosis was evaluated using acridine-orange ethidium bromide staining, followed immediately by fluorescent microscopy examination for the proportion of cells displaying morphologic features of apoptosis. Ad5CMV-p53 gene therapy combined with HT resulted in a dose-dependent cytotoxicity with less than 1% clonogenic survival when 10 pfu/cell of Ad5CMV-p53 was combined with 2 h heating at 43 degrees C. Western blotting demonstrated that treatment with Ad5CMV-p53 resulted in the rapid expression of p53, which was minimally affected by HT. The inducible form of hsp70 was maximally expressed at 48 h post-HT, with minimal effect when cells were additionally treated with Ad5CMV-p53. Clonogenic cytotoxicity was associated with the development of apoptosis, with up to 70% of CNE-1 cells displaying morphologic features of apoptosis after the combination treatments. Based on the shapes of the clonogenic survival curves, Ad5CMV-p53 gene therapy and HT appear to interact in an additive manner, suggesting the therapeutic potential of this combined treatment approach for patients with NPC.


Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity.
Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial cell-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. The data suggest an endothelial cell-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.


Technique for transvaginal removal of large specimen using an Alexis Contained Extraction System during laparoscopic hysterectomy.
Transvaginal removal of large specimens during laparoscopic hysterectomy can be a complex surgical procedure that poses a risk of organ injury and tissue spillage into the abdominal cavity and is associated with extraction of the specimen and manual morcellation. Our objective was to demonstrate a technique for transvaginal removal of large specimens using the Alexis Contained Extraction System (CES) in laparoscopic hysterectomy. The technique used for transvaginal removal of large specimens using the Alexis CES was presented in this video. Surgery was performed at a tertiary hospital. Following resection of the specimen during laparoscopic hysterectomy, the Alexis CES was inserted into the abdominal cavity through the umbilical trocar wound. The specimen was placed in a bag to prevent tissue spillage. The ring retractor was guided to the vagina and pulled out transvaginally. By repeatedly turning the ring retractor, tension was applied to the specimen bag, and the vaginal wall was unfolded all around to enable a secure surgical field. During manual morcellation of the specimen in the bag, the retractor was pulled and additionally turned to roll and re-tension the specimen bag when the bag was loosened. The specimen was pushed out of the vagina and safely and effectively extracted without concerns about tissue spillage in the abdominal cavity or related organ injuries. The technique for transvaginal removal of large specimens using the Alexis CES enables simple, effective, and safe tissue extraction with contained manual morcellation during laparoscopic hysterectomy.


Arterial hypertension elicited by subpressor amounts of angiotensin.
Long-term infusion of amounts of angiotensin insufficient at the beginning to raise arterial pressure results, after several days in sustained arterial hypertension in unanesthetized dogs. This hypertension is to a large degree dependent on environmental stimuli, and results chiefly from increase in peripheral resistance. As in dogs with renal hypertension, there is increased pressor responsiveness to tyramine. This indirect action of angiotensin to increase total peripheral resistance and arterial pressure by an action on the sympathetic nervous system, along with an upward resetting of the carotid sinus buffering mechanism, might logically account for the neural component of chronic renal hypertension. Such a proposal integrates the humoral and neural elements of the mosaic describing the mechanisms of tissue perfusion.


Cryosurgical treatment of cancerous and noncancerous diseases of dogs, horses, and cats.
Cryosurgery was used to treat a variety of cancerous and noncancerous diseases in dogs, horses, and cats. Follow-up evaluation on 52 animals revealed an overall "no recurrence" rate of 61%. Among the animals with no recurrence were 12 of 17 with cutaneous lesions and 5 of 8 (horses) with sarcoids. Seven of 10 dogs with anal fistulas healed after cryosurgery, but 2 had recurrence of the disease. Treatment of invasive neoplasms of the oral and nasal cavities was not successful. Side effects and complications were minimal.


Nausea and vomiting of pregnancy and hyperemesis gravidarum.
Nausea and vomiting of pregnancy (NVP) is a common condition that affects as many as 70% of pregnant women. Although no consensus definition is available for hyperemesis gravidarum (HG), it is typically viewed as the severe form of NVP and has been reported to occur in 0.3-10.8% of pregnant women. HG can be associated with poor maternal, fetal and child outcomes. The majority of women with NVP can be managed with dietary and lifestyle changes, but more than one-third of patients experience clinically relevant symptoms that may require fluid and vitamin supplementation and/or antiemetic therapy such as, for example, combined doxylamine/pyridoxine, which is not teratogenic and may be effective in treating NVP. Ondansetron is commonly used to treat HG, but studies are urgently needed to determine whether it is safer and more effective than using first-line antiemetics. Thiamine (vitamin B1) should be introduced following protocols to prevent refeeding syndrome and Wernicke encephalopathy. Recent advances in the genetic study of NVP and HG suggest a placental component to the aetiology by implicating common variants in genes encoding placental proteins (namely GDF15 and IGFBP7) and hormone receptors (namely GFRAL and PGR). New studies on aetiology, diagnosis, management and treatment are under way. In the next decade, progress in these areas may improve maternal quality of life and limit the adverse outcomes associated with HG.


Desensitization of tumour Leydig cells by lutropin: evidence for uncoupling of the lutropin receptor from the guanine nucleotide-binding protein.
Purified rat Leydig tumour cells were pretreated with lutropin and the effect on the subsequent response to lutropin was determined. Maximal cyclic AMP production was achieved with the same concentration of lutropin in control and lutropin-pretreated cells; however, the maximum stimulated level in pretreated cells was only 30% of controls. The sensitivity to lutropin was decreased in lutropin-pretreated cells [ED(50) (dose that produces a response that is 50% of the maximum response) 60+/-5.7ng/ml and 8+/-1.8ng/ml (mean+/-s.d., n=3) for controls], as was the rate of maximal cyclic AMP production (0.58, compared with 1.89pmol/10(6) cells per min for controls). However, cholera-toxin-stimulated cyclic AMP production was not decreased by lutropin pretreatment, and a potentiation was seen at all time points studied (up to 6h). Pre-incubation with lutropin caused a decrease in specific (125)I-labelled human choriogonadotropin binding; however, this decrease was abolished if the cells were washed under acidic conditions (pH3.0 for 2min at 4 degrees C), indicating that occupation but not loss of the lutropin receptors had taken place. The effect of pretreating the cells with lutropin on adenylate cyclase activity in purified plasma membranes was also investigated. In plasma membranes from control cells both guanosine 5'-[beta,gamma-imido]triphosphate [p(NH)ppG] plus lutropin and NaF plus lutropin caused a 50-60-fold linear increase in cyclic AMP production over 40min compared with 15-fold with p(NH)ppG and 6-fold with lutropin alone. In plasma membranes isolated from lutropin-treated cells the NaF-plus-lutropin- and the p(NH)ppG-stimulated cyclic AMP production rates were unchanged but no effect of lutropin could be demonstrated with or without added p(NH)ppG. In contrast the plasma membranes from dibutyryl cyclic AMP-treated cells had similar cyclic AMP production rates to control cells with all stimulants studied. The present evidence obtained from studies both with intact cells and with isolated plasma membranes indicates that the initial lutropin-induced desensitization of the rat Leydig tumour cell is due to a lesion in the hormone-receptor coupling to the guanine nucleotide regulatory protein. This process is apparently not mediated by cyclic AMP.


[Mammography and sonography in the diagnosis of recurrence after breast-preserving therapy of breast carcinoma].
89 patients, who underwent conservative surgery for breast cancer were followed up with mammography and real-time sonography. 78 patients underwent postoperative irradiation. Depending on the time interval between irradiation and examination various alterations in mammographic and sonographic patterns were evident. Of 14 biopsy-confirmed local recurrences, 11 were diagnosed by mammography and 12 by sonography. Sonography was superior in the diagnosis of small recurrences in breasts with radiation-induced increased density, whereas mammography showed better results in the detection of tumours with microcalcifications. As a result of the different sonographic aspect of recurrent tumours and scar tissue, the number of false positive diagnoses of sonography was markedly lower compared to that of mammography (2 versus 18). Combined use of mammography and sonography should therefore lead to better results in the diagnosis of local recurrences and to a reduction of unnecessary biopsies.


[Are young Norwegian women sufficiently physically active?].
The physical activity level of girls and young women is not known in Norway, hence the aim of this survey was to study physical activity and compare it with national recommendations for physical activity. A questionnaire including the International Physical Activity Questionnaire (IPAQ) was administered to a representative sample of women aged 13-39 years (n=900). The response rate was 69%; 549 women were included in the study. The physical activity level and intensity of exercise decreased with increasing age. 52 % percent of those aged 13-19 met the recommendations for adolescents: at least one hour of activity per day, including walking or other activities of at least moderate intensity. 63% percent of women in the age group 20-39 were physically active during the last week, on average at least 30 minutes every day at moderate intensity. In the age bracket 20-29 and 30-39 years, 72%, and 57%, respectively met the recommendations. The activity level decreased with increasing age. Every second adolescent girl and four in ten young women were not as physically active as recommended.


Initial cognitive performance predicts longitudinal aviator performance.
The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age. We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise. Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age. These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.


Identification of bacteria using volatile organic compounds.
The rapid diagnosis of respiratory infections has always been an important goal for medical professionals, because rapid and accurate diagnosis leads to proper and timely treatment, and consequently, reduces the costs of incorrect and long-term treatments, and antibiotic resistance. The present study was conducted with the aim of detecting volatile organic compounds (VOCs) in three bacteria: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae. Headspace of the studied bacteria, after separately culturing in two types of liquid medium in three different time-periods, was extracted by solid phase microextraction and analysed by gas chromatography mass spectrometry The analysis results of the VOCs produced by the studied bacteria indicate that some VOCs are common and some are unique in each bacterium. 1-penten-3-ol, levomenthol, and 2-octyl-1-ol for P. aeruginosa, cyclohexene, 4-ethenyl, and cis-Dihydro-α-terpinyl acetate for A. baumannii and 1,3-butadiene, butyraldehyde, longifolene, octyl acetate, tridecanol, dodecenal, (E)-2-hexyl ester, butanoic acid, and 5,5-dodecadinyl-1 12-diol for K. pneumoniae were identified as unique VOCs for each bacterium. Finally, it can be said that an accurate and rapid bacterial detection method can be achieved by using a tool that can detect bacterial VOCs. However, more studies are needed to design a tool for which all aspects have been assessed, so that it can give us a more complete pattern for the use of these compounds as biomarkers.


A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma.
Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries. Children 6 to 17 years old with pain from a musculoskeletal injury (to extremities, neck, and back) that occurred in the preceding 48 hours before presentation in the emergency department were randomly assigned to receive orally 15 mg/kg acetaminophen, 10 mg/kg ibuprofen, or 1 mg/kg codeine. Children, parents, and the research assistants were blinded to group assignment. The primary outcome was change in pain from baseline to 60 minutes after treatment with study medication as measured by using a visual analog scale. A total of 336 patients were randomly assigned, and 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the ibuprofen group, and 100 in the codeine group). Study groups were similar in age, gender, final diagnosis, previous analgesic given, and baseline pain score. Patients in the ibuprofen group had a significantly greater improvement in pain score (mean decrease: 24 mm) than those in the codeine (mean decrease: 11 mm) and acetaminophen (mean decrease: 12 mm) groups at 60 minutes. In addition, at 60 minutes more patients in the ibuprofen group achieved adequate analgesia (as defined by a visual analog scale <30 mm) than the other 2 groups. There was no significant difference between patients in the codeine and acetaminophen groups in the change in pain score at any time period or in the number of patients achieving adequate analgesia. For the treatment of acute traumatic musculoskeletal injuries, ibuprofen provides the best analgesia among the 3 study medications.


Progression of aggressive metastatic carcinosarcoma after treatment of epithelioid osteosarcoma.
Osteosarcoma is the most common primary malignant osseous neoplasm, constituting approximately 35% of skeletal malignancies. The different subtypes of osteosarcoma are differentiated based on clinical, histologic, and radiographic data, as well as the variable amount of osteoid produced by malignant cells. The epithelioid osteosarcoma subtype accounts for only 5.7% of all osteosarcomas and portends an extremely poor prognosis. The 5-year survival rate for patients with epithelioid osteosarcoma treated with surgery (with or without chemotherapy) is 13.5%. This is in direct contrast to the >70% ten-year survival rate of conventional osteosarcoma treated with surgery and chemotherapy. This article presents a fatal case of epithelioid osteosarcoma in an 11-year-old girl with right knee pain of 6 months' duration. Biopsy demonstrated morphologic findings consistent with high-grade osteosarcoma with epithelioid features. The epithelioid component was positive for vimentin and CD99; however, fluorescent in situ hybridization for the (11;22) translocation was negative. In this case, the epithelioid cells failed to respond to conventional or subsequent experimental chemotherapy for osteosarcoma and eventual metastasized to the lymph nodes and lungs despite multiple ablative surgeries. This case report supports the concept of carcinosarcoma with malignant cells lines arising from 2 different cellular lineages or a common cellular precursor. The epithelial component was more aggressive than the cells of mesenchymal origin, highlighting the need for continued research and a more favorable outcome for this rare subset of osteosarcoma.


Quantitative analyses of antagonism: combinations of midazolam and either flunitrazepam or pregnanolone in rhesus monkeys discriminating midazolam.
Adverse effects of benzodiazepines limit their clinical use; these effects might be reduced without altering therapeutic effects by administering other positive GABA(A) modulators (i.e., neuroactive steroids) with benzodiazepines. One concern with this strategy involves reversing these combined effects in case of overdose. The current study examined whether flumazenil can attenuate the combined effects of two benzodiazepines, midazolam and flunitrazepam, and the combined effects of midazolam and the neuroactive steroid pregnanolone, in four monkeys discriminating midazolam. Each positive modulator produced ≥80% midazolam-lever responding. Interactions between midazolam and either flunitrazepam or pregnanolone were additive. Flumazenil antagonized the benzodiazepines when they were administered alone or in combination. Schild analyses yielded slopes that did not deviate from unity, regardless of whether benzodiazepines were administered alone or together; the pA(2) value for flumazenil was 7.58. In contrast, flumazenil enhanced the effects of pregnanolone with 0.32 mg/kg flumazenil shifting the pregnanolone dose-effect curve 2-fold leftward. Flumazenil attenuated the combined effects of midazolam and pregnanolone, although antagonism was not dose-dependent. Thus, the interaction between two benzodiazepines was similar to that of a benzodiazepine and a neuroactive steroid; however, flumazenil more efficiently attenuated a combination of two benzodiazepines compared with a combination of a benzodiazepine and a neuroactive steroid. Although the magnitude of antagonism of a benzodiazepine combined with a neuroactive steroid was reduced, these results support continued exploration of the use of combinations of positive modulators to enhance therapeutic effects while reducing adverse effects.


Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters.
The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties. The primary representative of this group, Re32D03, neutralizes Alpha to Delta as well as Omicron BA.2.75; other members neutralize, in addition, Omicron BA.1, BA.2, BA.4/5, and XBB.1. Crystal structures of RBD-nanobody complexes reveal how ACE2-binding is blocked and also explain the nanobodies' tolerance to immune escape mutations. Through the cryo-EM structure of the Ma16B06-BA.1 Spike complex, we demonstrated how a single nanobody molecule can neutralize a trimeric spike. We also describe a method for large-scale production of these nanobodies in Pichia pastoris, and for formulating them into aerosols. Exposing hamsters to these aerosols, before or even 24 h after infection with SARS-CoV-2, significantly reduced virus load, weight loss and pathogenicity. These results show the potential of aerosolized nanobodies for prophylaxis and therapy of coronavirus infections.


Cost-effectiveness of intensive multifactorial treatment compared with routine care for individuals with screen-detected Type 2 diabetes: analysis of the ADDITION-UK cluster-randomized controlled trial.
To examine the short- and long-term cost-effectiveness of intensive multifactorial treatment compared with routine care among people with screen-detected Type 2 diabetes. Cost-utility analysis in ADDITION-UK, a cluster-randomized controlled trial of early intensive treatment in people with screen-detected diabetes in 69 UK general practices. Unit treatment costs and utility decrement data were taken from published literature. Accumulated costs and quality-adjusted life years (QALYs) were calculated using ADDITION-UK data from 1 to 5 years (short-term analysis, n = 1024); trial data were extrapolated to 30 years using the UKPDS outcomes model (version 1.3) (long-term analysis; n = 999). All costs were transformed to the UK 2009/10 price level. Adjusted incremental costs to the NHS were £285, £935, £1190 and £1745 over a 1-, 5-, 10- and 30-year time horizon, respectively (discounted at 3.5%). Adjusted incremental QALYs were 0.0000, - 0.0040, 0.0140 and 0.0465 over the same time horizons. Point estimate incremental cost-effectiveness ratios (ICERs) suggested that the intervention was not cost-effective although the ratio improved over time: the ICER over 10 years was £82,250, falling to £37,500 over 30 years. The ICER fell below £30 000 only when the intervention cost was below £631 per patient: we estimated the cost at £981. Given conventional thresholds of cost-effectiveness, the intensive treatment delivered in ADDITION was not cost-effective compared with routine care for individuals with screen-detected diabetes in the UK. The intervention may be cost-effective if it can be delivered at reduced cost.


Intertissue flow of glutathione (GSH) as a tumor growth-promoting mechanism: interleukin 6 induces GSH release from hepatocytes in metastatic B16 melanoma-bearing mice.
B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci.


[Evaluation of the anti-emetic effectiveness of two drug formulations of Ondansetron in combined chemotherapy for children with malignant tumors].
A double-blind randomized comparison (protocol S3AB4003, Glaxo Wellcome, Great Britain) carried out in a group of 52 children showed that the 5-HT3-receptor antagonist ondansetron (in syrup) effectively prevented vomiting, nausea and loss of appetite caused in combination chemotherapy with highly- or moderately emetogenic cytostatic drugs in 92.3; 69.3 and 81.0%, respectively. Treatment was given to patients who were on dexamethasone. With intravenous injection of ondansetron plus dexamethasone, per os, said indices were 88.5; 73.2%; 73.2%, respectively, thus showing no significant differences. No side-effects were observed with either regimen.


A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q.
Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.


Renal resistive index in patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The renal resistive index (RRI) is a measure of renal arterial resistance to blood flow. The aim of this study was to investigate the renal resistive index levels of patients with PCOS. A total of 216 women were included in this cross-sectional study. The study group consisted of 109 patients with PCOS, and the control group consisted of 107 healthy subjects. The RRI of all subjects was measured using renal Doppler ultrasonography. The patients with PCOS had higher RRI levels in comparison to the healthy subjects (0.64 ± 0.06 vs. 0.57 ± 0.06, p < 0.001). The RRI levels of the patients with PCOS were correlated with systolic blood pressure (p = 0.004, r = 0.268) and with homeostasis model assessment of insulin resistance (HOMA-IR) (p = 0.02, r = 0.216). In this study, we observed higher RRI levels in patients with PCOS. High RRI levels may be an indicator of cardiovascular and/or cardiovascular-associated diseases in patients with PCOS.


eEF1A is a novel component of the mammalian nuclear protein export machinery.
The cytoplasmic translation factor eEF1A has been implicated in the nuclear export of tRNA species in lower eukaryotes. Here we demonstrate that eEF1A plays a central role in nuclear export of proteins in mammalian cells. TD-NEM (transcription-dependent nuclear export motif), a newly characterized nuclear export signal, mediates efficient nuclear export of several proteins including the von Hippel-Lindau (VHL) tumor suppressor and the poly(A)-binding protein (PABP1) in a manner that is dependent on ongoing RNA polymerase II (RNA PolII)-dependent transcription. eEF1A interacts specifically with TD-NEM of VHL and PABP1 and disrupting this interaction, by point mutations of key TD-NEM residues or treatment with actinomycin D, an inhibitor of RNA PolII-dependent transcription, prevents assembly and nuclear export. siRNA-induced knockdown or antibody-mediated depletion of eEF1A prevents in vivo and in vitro nuclear export of TD-NEM-containing proteins. Nuclear retention experiments and inhibition of the Exportin-5 pathway suggest that eEF1A stimulates nuclear export of proteins from the cytoplasmic side of the nuclear envelope, without entering the nucleus. Together, these data identify a role for eEF1A, a cytoplasmic mediator of tRNA export in yeast, in the nuclear export of proteins in mammalian cells. These results also provide a link between the translational apparatus and subcellular trafficking machinery demonstrating that these two central pathways in basic metabolism can act cooperatively.


Activation of epithelial Na channels by hormonal and autoregulatory mechanisms of action.
Methods of blocker-induced noise analysis were used to investigate the way in which forskolin and vasopressin stimulate Na transport at apical membranes of short-circuited frog skin transporting Na at spontaneous rates of transport. Experiments were done under conditions where the apical Ringer solution contained either 100 mM Na or a reduced Na concentration of 5 or 10 mM Na and buffered with either HCO3 or HEPES. Reduction of apical solution Na concentration caused a large autoregulatory increase of Na channel density (NT) similar in magnitude to that observed previously in response to blocker (amiloride) inhibition of apical membrane Na entry. Forskolin at 2.5 microM caused maximal and reversible large increases of NT, which were larger than could be elicited by 30 mU/ml vasopressin. In both the absence and presence of the autoregulatory increase of NT (caused by reduction of apical Na concentration), forskolin caused large increases of NT. Although the fractional increases of NT in response to forskolin were roughly similar, the absolute increases of NT were considerably larger in those tissues studied at reduced Na concentration and where baseline values of NT were markedly elevated by reduction of apical Na concentration. Because the effects on NT were additive, it is likely that the cAMP-dependent and autoregulatory mechanism that lead to changes of NT are distinct. We speculate that autoregulation of NT may involve change of the size of a cytosolic pool of Na-containing vesicles that are in dynamic balance with the apical membranes. cAMP-dependent regulation of NT may involve change of the dynamic balance between vesicles and the apical membranes of these epithelial cells. Alternative hypotheses cannot at present be ruled out, but will require incorporation of the idea that regulation of NT can occur both by hormonal and nonhormonal (autoregulatory) mechanisms of action.


Growth factors embedded in an agarose matrix enhance the rate of porous polyethylene implant biointegration.
Repeated injections of epidermal and basic fibroblastic growth factors have been shown to enhance the biointegration rate of implanted porous polyethylene. A study was done to determine whether agarose, introduced at the time of implant placement, might serve as an adequate "single dose" delivery system for endogenous and exogenous growth factors. Polyethylene cubes coated with agarose-containing growth factors were implanted into fat and muscle in rabbits. Factors studied included autogenous whole blood, autogenous serum, ascorbic acid, epidermal growth factor, basic fibroblast growth factor, transforming growth factor alpha, and transforming growth factor beta. The rate and character of the fibrovascular ingrowth into implants and surrounding capsule thickness were assessed. Fibroblast infiltration enhanced two- to sixfold with the use of autogenous or allogenic factors introduced in an agarose matrix at the time of cube implantation. Growth factors studied altered the thickness of the capsule surrounding implants as well as both the vascularity and stromal density within implants.


Defining the risk of elective cyclosporine withdrawal in stable kidney transplant recipients.
Although it is known that elective cyclosporine (CsA) withdrawal increases the risk for acute rejection, few studies have been large enough to identify risk factors for acute rejection after CsA withdrawal. We examined risk factors for acute rejection in 464 kidney transplant recipients who underwent elective CsA withdrawal. The incidence of acute rejection within 6 months of CsA withdrawal was 20/141 (14.2%) in the period January 1986 to May 1989, but only 14/323 (4.5%) since May 1989 (p = 0.0002). Among those transplanted since May 1989, the incidence was 5/20 (25%) for those with both 2 HLA-B and 2 HLA-DR mismatches, compared with only 9/298 (3.0%) for those with fewer mismatches (p < 0.0001). In Cox proportional hazards analysis, risk factors for acute rejection within 6 months, or at any time after elective CsA withdrawal, were date of transplant January 1986 to May 1989 (compared with more recently May 1989 to March 1999), younger age, obesity, as well as B and DR mismatches. Recipient race (83% were white), acute rejection during the first year before withdrawal (31%), mycophenolate mofetil (17%), and other variables failed to predict postwithdrawal acute rejection. We concluded that avoiding CsA withdrawal in the relatively small number of recipients with both 2 HLA-B and 2 HLA-DR mismatches could further reduce our already low incidence of acute rejection following elective CsA withdrawal.


Clinical Evaluation of a Patient With Symptoms of Colonic or Anorectal Motility Disorders.
Constipation, irritable bowel syndrome, fecal incontinence, abdominal pain, and anorectal pain are problems that affect 40% of the population. They commonly present with overlapping symptoms indicating that their pathophysiology affects multiple segments of the gut as well as brain and gut interactions. Clinically, although some conditions are readily recognized, dyssynergic defecation, fecal incontinence, and anorectal pain are often missed or misdiagnosed. Consequently, the assessment of lower gastrointestinal symptoms in patients with suspected colonic or anorectal motility disorder(s) remains challenging for most clinicians. A detailed history, use of the Bristol stool form scale, prospective stool diaries, ideally through a phone App, digital rectal examination, and judicious use of complementary diagnostic tests are essential. Additionally, it is important to evaluate the impact of these problems on quality of life and psychosocial issues, because they are intricately linked with these disorders. The Rome IV diagnostic questionnaire for functional gastrointestinal disorders can provide additional information often missed during history taking. Here, we discuss a systematic approach for the clinical evaluation of patients with suspected lower gastrointestinal problems, grouped under 4 common diagnostic categories. We describe how to take a detailed history, perform meticulous digital rectal examination, and use validated tools to supplement clinical evaluation, including assessments of quality of life and scoring systems for disease severity and digital Apps. These tools could facilitate a comprehensive plan for clinical management including diagnostic tests, and translate the patients' complaints into definable, diagnostic categories.


Transcranial direct current stimulation (tDCS) reduces postsurgical opioid consumption in total knee arthroplasty (TKA).
Although pain is often a symptom that precedes total knee arthroplasty (TKA), the procedure itself is associated with considerable postoperative pain lasting days to weeks. Postoperative pain control is an important factor in determining recovery time, hospital length of stay, and rehabilitation success. Several brain stimulation technologies including transcranial direct current stimulation (tDCS) have demonstrated promise as treatments for a variety of pain conditions. The present study examined the effects of 4 sessions of tDCS on post-TKA pain and opioid consumption. Forty patients undergoing unilateral TKA were randomly assigned to receive a total of 80 minutes of real (n=20) or sham tDCS (n=20) with the anode over the knee representation of the motor strip (C1h or C2h corresponding to the target knee) and cathode over the right dorsolateral prefrontal cortex (F3; located by the EEG 10-20 System). Patient-controlled analgesia ( hydromorphone) use was tracked during the ∼48 hours postsurgery. Patients in the real tDCS group used an average of 6.6 mg (SD=5.3) of patient-controlled analgesia hydromorphone, whereas those in the sham group used 12.3 mg (SD=6.6; t37=2.93, P=0.006). Despite using less opioid medication, participants in the real tDCS group reported no pain exacerbation or worse mood with respect to those in the sham tDCS group. Results from this pilot feasibility study suggest that tDCS may be able to reduce post-TKA opioid requirements. Although these results are preliminary, the data support further research in the area of adjunctive cortical stimulation in the management of postsurgical pain.


Exploration of significant influences of the operating conditions on the local O2 transport in proton exchange membrane fuel cells (PEMFCs).
A drastic reduction of the Pt loading in the cathode catalyst layers (CCLs) of proton exchange membrane fuel cells (PEMFCs) is much desired. However, a decrease in Pt loading inevitably leads to an unexpected increase of local O2 transport resistance (rLocal) and severely weakens the fuel cell performance, particularly at high current densities. Thus, it is both urgent and meaningful to explore the impacts of the operating conditions on rLocal in CCLs and therefore to clarify the intrinsic mechanism. Herein, we systematically explore the influences of the operating conditions, in terms of the dry O2 mole fraction, the relative humidity, the operating pressure and the temperature on rLocal using limiting current measurements combined with mathematical calculations. The results show that, in contrary to the established rules, rLocal in CCLs of PEMFCs is aggravated when the dry O2 mole fraction or the operating pressure are increased. It is also experimentally found that rLocal in CCLs is alleviated with the increase in the relative humidity or the operating temperature. Moreover, an adsorption controlled solution-diffusion model is proposed to illuminate the local O2 transport behavior in CCLs of PEMFCs, and it accounts for the influence of the dry O2 mole fraction on rLocal in CCLs.


Cystatin C Deficiency Increases LPS-Induced Sepsis and NLRP3 Inflammasome Activation in Mice.
Cystatin C is a potent cysteine protease inhibitor that plays an important role in various biological processes including cancer, cardiovascular diseases and neurodegenerative diseases. However, the role of CstC in inflammation is still unclear. In this study we demonstrated that cystatin C-deficient mice were significantly more sensitive to the lethal LPS-induced sepsis. We further showed increased caspase-11 gene expression and enhanced processing of pro-inflammatory cytokines IL-1β and IL-18 in CstC KO bone marrow-derived macrophages (BMDM) upon LPS and ATP stimulation. Pre-treatment of BMDMs with the cysteine cathepsin inhibitor E-64d did not reverse the effect of CstC deficiency on IL-1β processing and secretion, suggesting that the increased cysteine cathepsin activity determined in CstC KO BMDMs is not essential for NLRP3 inflammasome activation. The CstC deficiency had no effect on (mitochondrial) reactive oxygen species (ROS) generation, the MAPK signaling pathway or the secretion of anti-inflammatory cytokine IL-10. However, CstC-deficient BMDMs showed dysfunctional autophagy, as autophagy induction via mTOR and AMPK signaling pathways was suppressed and accumulation of SQSTM1/p62 indicated a reduced autophagic flux. Collectively, our study demonstrates that the excessive inflammatory response to the LPS-induced sepsis in CstC KO mice is dependent on increased caspase-11 expression and impaired autophagy, but is not associated with increased cysteine cathepsin activity.


Cardiac manifestations of digoxin intoxication. (Clinical correlations with serum levels).
Clinical, electrocardiographic and laboratory data were found out in 52 patients with cardiac arrhythmias and conduction defects due to digoxin intoxication. Forty six nontoxic patients were also studied for comparison. Blood urea concentration was significantly higher in toxic patients as compared to nontoxic ones (P less than 0-01). Ventricular bigeminy and trigeminy (38.6%), multifocal ventricular premature beats (25%) and second or third degree A-V blocks (25%) were very much prevalent. Fairly good correlations have been observed between different cardiac arrhythmias and serum digoxin levels. Significantly higher mean serum digoxin levels were observed in patients with A-V block and multifocal ventricular premature beats as compared to patients with supraventricular arrhythmias.


A theory of atmospheric oxygen.
Geological records of atmospheric oxygen suggest that pO2 was less than 0.001% of present atmospheric levels (PAL) during the Archean, increasing abruptly to a Proterozoic value between 0.1% and 10% PAL, and rising quickly to modern levels in the Phanerozoic. Using a simple model of the biogeochemical cycles of carbon, oxygen, sulfur, hydrogen, iron, and phosphorous, we demonstrate that there are three stable states for atmospheric oxygen, roughly corresponding to levels observed in the geological record. These stable states arise from a series of specific positive and negative feedbacks, requiring a large geochemical perturbation to the redox state to transition from one to another. In particular, we show that a very low oxygen level in the Archean (i.e., 10-7 PAL) is consistent with the presence of oxygenic photosynthesis and a robust organic carbon cycle. We show that the Snowball Earth glaciations, which immediately precede both transitions, provide an appropriate transient increase in atmospheric oxygen to drive the atmosphere either from its Archean state to its Proterozoic state, or from its Proterozoic state to its Phanerozoic state. This hypothesis provides a mechanistic explanation for the apparent synchronicity of the Proterozoic Snowball Earth events with both the Great Oxidation Event, and the Neoproterozoic oxidation.


Association of Whole Grain Consumption and Cognitive Decline: An Investigation From a Community-Based Biracial Cohort of Older Adults.
To examine the association of whole grain consumption and longitudinal change in global cognition, perceptual speed, and episodic memory by different race/ethnicity. We included 3,326 participants from the Chicago Health and Aging Project who responded to a Food Frequency Questionnaire (FFQ), with 2 or more cognitive assessments. Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the Mini Mental State Examination (MMSE). Diet was assessed by a 144-item FFQ. Linear mixed-effects models were used to estimate the association of intakes of whole grains and cognitive decline. This study involved 3,326 participants (60.1% African American [AA], 63.7% female) with a mean age of 75 years at baseline and a mean follow-up of 6.1 years. Higher consumption of whole grains was associated with a slower rate of global cognitive decline. Among AA participants, those in the highest quintile of whole grain consumption had a slower rate of decline in global cognition (β = 0.024, 95% CI [0.008-0.039], p = 0.004), perceptual speed (β = 0.023, 95% CI [0.007-0.040], p = 0.005), and episodic memory (β = 0.028, 95% CI [0.005-0.050], p = 0.01) compared with those on the lowest quintile. Regarding the amount consumed, in AA participants, those who consumed >3 servings/d vs those who consumed <1 serving/d had a slower rate of decline in global cognition (β = 0.021, 95% CI [0.005-0.036], p = 0.0093). In White participants, with >3 servings/d, we found a suggestive association of whole grains with global cognitive decline when compared with those who consumed <1 serving/d (β = 0.025, 95% CI [-0.003 to 0.053], p = 0.08). Among AA participants, individuals with higher consumption of whole grains and more frequent consumption of whole grain had slower decline in global cognition, perceptual speed, and episodic memory. We did not see a similar trend in White adults.


Episomal expression of truncated listeriolysin O in LmddA-LLO-E7 vaccine enhances antitumor efficacy by preferentially inducing expansions of CD4+FoxP3- and CD8+ T cells.
Studies have shown that Listeria monocytogenes (Lm)-based vaccine expressing a fusion protein comprising truncated listeriolysin O (LLO) and human papilloma virus (HPV) E7 protein (Lm-LLO-E7) induces a decrease in regulatory T cells (Treg) and complete regression of established, transplanted HPV-TC-1 tumors in mice. However, how the Lm-based vaccine causes a decrease in Tregs remains unclear. Using a highly attenuated Lm dal dat ΔactA strain (LmddA)-based vaccine, we report here that the vector LmddA was sufficient to induce a decrease in the proportion of Tregs by preferentially expanding CD4(+)FoxP3(-) T cells and CD8(+) T cells by a mechanism dependent on and directly mediated by LLO. Episomal expression of a nonhemolytic truncated LLO in Lm (LmddA-LLO) significantly augmented the expansion, thus further decreasing Treg frequency. Although adoptive transfer of Tregs compromised the antitumor efficacy of the LmddA-LLO-E7 vaccine, a combination of LmddA-LLO and an Lm-based vaccine expressing E7 protein (Lm-E7) induced complete regression against established TC-1 tumors. An engineered LLO-minus Lm expressing perfringolysin O (PFO) that enables the recombinant bacteria to exit from the phagolysosome without LLO confirmed that the adjuvant effect was dependent on LLO. These results suggest that LLO may serve as a promising adjuvant by preferentially inducing the expansions of CD4(+)FoxP3(-) T cells and CD8(+) T cells, thus reducing the ratio of Tregs to CD4(+)FoxP3(-) T cells and to CD8(+) T cells favoring immune responses to eradicate tumor.


Multidimensional assessment of personality in patients with psychogenic non-epileptic seizures.
To determine whether patients with psychogenic non-epileptic seizures (PNES) have evidence of maladaptive personality, and whether they have a single or several different typical pathological personality profiles. Patients were recruited from the department of epileptology, Bonn, Germany. In all, 85 patients with PNES and 63 with epilepsy completed a postal questionnaire including the dimensional assessment of personality pathology - basic questionnaire (DAPP-BQ). The DAPP-BQ was also completed by 100 healthy volunteers. The groups were compared and the PNES group was subjected to cluster analysis. Patients with PNES had a greater degree of personality abnormality than clinical and non-clinical controls. There were several clusters of personality pathology. The profile of the largest cluster (n = 43) resembled that found in borderline personality disorder, that of the second largest (n = 37) was characterised by an overly controlled personality, that of the third (n = 4) was similar to the profile in avoidant personality disorder. Outcome differed between clusters. Maladaptive personality is common in patients with PNES. PNES are associated with several distinct profiles of pathological personality. This is relevant because outcome differed between profiles.


Efficacy of sumatriptan in two pediatric cases with abdominal pain-related functional gastrointestinal disorders: does the mechanism overlap that of migraine?
We successfully treated 2 pediatric cases of abdominal pain-related functional gastrointestinal disorder with sumatriptan. When 9 years old, patient 1 developed periodic abdominal pain that was intractable to medication and remitted spontaneously. She was diagnosed with abdominal migraine, categorized as H2c in the Rome III criteria for functional gastrointestinal disorders. At age 12, intranasal sumatriptan relieved her pain, and her attacks halted 2 years later. Patient 2 was a 9-year-old girl diagnosed with attention-deficit hyperactivity disorder (ADHD), who began to have intermittent abdominal pain of variable severity, which sometimes restricted daily activity. She was diagnosed with childhood functional abdominal pain syndrome, categorized as H2d1 using the Rome III criteria. Intranasal sumatriptan also relieved her pain. These cases suggest that the mechanism of pain in abdominal pain-related functional gastrointestinal disorders is similar to that of migraine, with probable central hypersensitivity, at least in a subset of cases.


Multi-scale investigation of the formation and properties of high-grade rutile TiO2 from titanium slags using microwave heating.
In this paper, the phase transition of titanium slag under microwave heating observed through electron microscopy was systematically investigated. The phase identification and transformation as well as the morphology of samples before and after each treatment were characterized using X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy, Raman spectroscopy and scanning electron microscopy (SEM). The XRD confirmed that sodium salt roasting could modify the phase composition of titanium slag. The microwave roasting in the presence of sodium salt increased the rutile TiO2 with high crystallinity after acid leaching. The Raman spectroscopy demonstrated the phase transition of titanium slag from anosovite to rutile TiO2 after a series of treatments, and the SEM analyses showed that the surface of calcined products grew plenty of rutile TiO2 with typical characteristics. The results indicate a successful process for an effective and efficient way for the utilization of both titanium slag and preparation of rutile TiO2.


Response of the human myocardium to ischemic injury and preconditioning: The role of cardiac and comorbid conditions, medical treatment, and basal redox status.
The diseased human myocardium is highly susceptible to ischemia/reoxygenation (I/R)-induced injury but its response to protective interventions such as ischemic preconditioning (IPreC) is unclear. Cardiac and other pre-existing clinical conditions as well as previous or ongoing medical treatment may influence the myocardial response to I/R injury and protection. This study investigated the effect of both on myocardial susceptibility to I/R-induced injury and the protective effects of IPreC. Atrial myocardium from cardiac surgery patients (n = 300) was assigned to one of three groups: aerobic control, I/R alone, and IPreC. Lactate dehydrogenase leakage, as a marker of cell injury, and cell viability were measured. The basal redox status was determined in samples from 90 patients. The response to I/R varied widely. Myocardium from patients with aortic valve disease was the most susceptible to injury whereas myocardium from dyslipidemia patients was the least susceptible. Tissue from females was better protected than tissue from males. Myocardium from patients with mitral valve disease was the least responsive to IPreC. The basal redox status was altered in the myocardium from patients with mitral and aortic valve disease. The response of the myocardium to I/R and IPreC is highly variable and influenced by the underlying cardiac pathology, dyslipidemia, sex, and the basal redox status. These results should be taken into account in the design of future clinical studies on the prevention of I/R injury and protection.


Insulin receptor is phosphorylated in response to treatment of HepG2 cells with insulin-like growth factor I.
1. Binding of insulin and insulin-like growth factor I (IGF-I) to HepG2 cells was analysed with regard to competition by both insulin and IGF-I. At concentrations of insulin that caused maximal phosphorylation of the insulin receptor, virtually no displacement of IGF-I binding was observed. Similarly, at concentrations of IGF-I that caused maximal phosphorylation of the IGF-I receptor, no displacement of insulin binding was observed. 2. When the phosphorylation of both receptors was examined individually by using specific monoclonal antibodies to immunoprecipitate the receptors, phosphorylation of the insulin receptor was found to increase on both serine and tyrosine residues in cells treated with 100 ng of IGF-I/ml. In contrast, no increased phosphorylation of IGF-I receptor was observed in cells treated with 100 ng of insulin/ml. 3. The increase in phosphorylation of insulin receptor in response to IGF-I correlated with the dose-response of IGF-I-stimulated phosphorylation of the IGF-I receptor. 4. The IGF-I-stimulated phosphorylation of the insulin receptor could be blocked by preincubation with a monoclonal antibody that blocks IGF-I binding to the IGF-I receptor.


Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.
Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy.