Impact of the Inclusion of an Aminoglycoside to the Initial Empirical Antibiotic Therapy for Gram-Negative Bloodstream Infections in Hematological Neutropenic Patients: a Propensity-Matched Cohort Study (AMINOLACTAM Study).
To test the hypothesis that the addition of an aminoglycoside to a β-lactam antibiotic could provide better outcomes than β-lactam monotherapy for the initial empirical treatment of hematological neutropenic patients with subsequently documented Gram-negative bacillus (GNB) bloodstream infection (BSI), a multinational, retrospective, cohort study of GNB BSI episodes in hematological neutropenic patients in six centers (2010 to 2017) was conducted. Combination therapy (β-lactam plus aminoglycoside) was compared to β-lactam monotherapy. The primary endpoint was the case fatality rate, assessed at 7 and 30 days from BSI onset. Secondary endpoints were nephrotoxicity and persistent BSI. Propensity score (PS) matching was performed. Among 542 GNB BSI episodes, 304 (56%) were initially treated with combination therapy, with cefepime plus amikacin being most common (158/304 [52%]). Overall, Escherichia coli (273/304 [50.4%]) was the main etiological agent, followed by Pseudomonas aeruginosa, which predominated in the combination group (76/304 [25%] versus 28/238 [11.8%]; P < 0.001). Multidrug resistance rates were similar between groups (83/294 [28.2%] versus 63/233 [27%]; P = 0.95). In the multivariate analysis, combination therapy was associated with a lower 7-day case fatality rate (odds ratio [OR], 0.37; 95% CI, 0.14 to 0.91; P = 0.035) with a tendency toward lower mortality at 30 days (OR, 0.56; 95% CI, 0.29 to 1.08; P = 0.084). After PS matching, these differences remained for the 7-day case fatality rate (OR, 0.33; 95% CI, 0.13 to 0.82; P = 0.017). In addition, aminoglycoside use was not significantly associated with renal function impairment (OR, 1.12; 95% CI, 0.26 to 4.87; P = 0.9). The addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered.


Cometary particles: thin sectioning and electron beam analysis.
Thin sections (500 to 1000 angstroms thick) of individual micrometeorites (5 to 15 micrometers) have been prepared with an ultramicrotome equipped with a diamond knife. Electron microscopic examination of these sections has revealed the internal structures of chondritic micrometeorites, and a subset of highly porous, fragile particles has been identified. Delicate meteoritic materials such as these are characteristic of debris from cometary meteors.


A nonsemen copulatory fluid influences the outcome of sperm competition in Japanese quail.
Sperm competition is a powerful and widespread evolutionary force that drives the divergence of behavioural, physiological and morphological traits. Elucidating the mechanisms governing differential fertilization success is a fundamental question of sperm competition. Both sperm and nonsperm ejaculate components can influence sperm competition outcomes. Here, we investigate the role of a nonsemen copulatory fluid in sperm competition. Male Japanese quail possess a gland that makes meringue-like foam. Males produce and store foam independent of sperm and seminal fluid, yet transfer foam to females during copulation. We tested whether foam influenced the outcome of sperm competition by varying foam state and mating order in competitive matings. We found that the presence of foam from one male decreased the relative fertilization success of a rival, and that foam from a given male increased the probability he obtained any fertilizations. Mating order also affected competitive success. Males mated first fertilized proportionally more eggs in a clutch and had more matings with any fertilizations than subsequent males. We conclude that the function of foam in sperm competition is mediated through the positive interaction of foam with a male's sperm, and we speculate whether the benefit is achieved through improving sperm storage, fertilizing efficiency or retention. Our results suggest males can evolve complex strategies to gain fertilizations at the expense of rivals as foam, a copulatory fluid not required for fertilization, nevertheless, has important effects on reproductive performance under competition.


Protective effects of dietary PUFA against chronic disease: evidence from epidemiological studies and intervention trials.
This review considers evidence for a protective effect of PUFA on chronic disease. Estimates of PUFA intakes in prospective cohort studies are usually based on FFQ or biomarkers of intake. Cohort studies suggest that both linoleic and linolenic acid intake are associated with a lower risk of CHD. The intake of fish, the major source of long-chain n-3 PUFA is associated with a lower risk of both stroke and CHD, particularly sudden cardiac death. No relationship with common sites of cancer (breast and colon) and PUFA has been found. However, some recent studies suggest an association of high intakes of n-3 PUFA with risk of prostate cancer. An updated Cochrane review of dietary fat modification (replacing SFA with PUFA) randomised controlled trials to prevent CHD found a 14% lower incidence and a non-significant 7% lower mortality from CHD. The effects of an increased intake of n-3 PUFA on CHD incidence mortality have been tested in patients with pre-existing CHD in randomised controlled trials. Meta-analysis of these trials showed no overall benefit on total mortality or CVD incidence but a trend for lower risk of cardiac death was 0·91 (95% CI 0·85, 0·98). At present, there is little evidence from other trials demonstrating the clear benefits or harm from increased intakes of PUFA. In conclusion, present evidence intakes benefit from partial replacement of SFA with a balanced mixture of n-6 and n-3 PUFA which may contribute to CVD prevention.


Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression.
The breast cancer susceptibility protein, BRCA2, preserves chromosomal stability through roles in the repair of DNA double-strand breaks, and possibly, cell division. Post-translational modifications that may coordinate these functions remain poorly characterized. Here, we report that BRCA2 is a substrate for the mitotic Polo-like kinase, Plk1. BRCA2 undergoes phosphorylation in cells synchronously passing through the G2/M phases of cell cycle, when Plk1 expression and activity are maximal. Depletion of Plk1 by RNA interference suppresses BRCA2 modification. BRCA2 and Plk1 interact with one another in cell lysates, through a conserved region in BRCA2, which spans the eight BRC repeat motifs essential for its function in DNA repair. Within this region, residues positioned between BRC repeats--but not the repeat motifs themselves--are phosphorylated by Plk1. Interestingly, Plk1-mediated modification of BRCA2 during the G2/M phases is inhibited by treatment with the radiomimetic agent, adriamycin. Thus, our findings define a regulatory circuit for BRCA2 phosphorylation by Plk1 that is responsive to DNA damage as well as mitotic progression.


Fibroadenoma masquerading carcinoma on fine-needle aspiration of the breast.
Benign and malignant lesions of the breast may have similar appearances on fine-needle aspiration cytology. We report a case of fibroadenoma that was diagnosed as carcinoma by cytology. Breast fine-needle aspiration biopsy was highly cellular and composed of bland-appearing spindle/columnar cells that could represent either epithelial or stromal cells; the case was reported as positive and the patient had subsequent excisional biopsy taken. On microscopic examination, smears were hypercellular and had many single cells and clusters of columnar/ elongate cells No obvious bipolar cells of myoepithelial origin were seen. Significant atypia was noted. Immunocytochemistry for smooth muscle actin was not performed due to insufficient material. Some cases of fibroadenoma and carcinoma can be very difficult to distinguish on fine needle aspiration cytology smears. Immunocytochemistry may be of help if sufficient material is provided. To avoid false positive diagnosis on cytology, it is best to report such a case as intermediate (atypical/suspicious) with final interpretation pending excisional biopsy.


Social selection and professional regulation for Master's degrees for nurses.
This paper is a report of a study to understand the perspectives of two sets of stakeholders, namely clinical nursing providers and nursing academics, on how registered nurses should be selected for Master's degree programmes. The proliferation of taught Master's programmes has led to concerns about a lowering of standards. Even with the expansion of professional Master's programmes, they remain one of the least researched areas of higher education. The sampling strategy was a combination of convenience and snowball sampling. In-depth interviews were conducted in 2006-07 with 15 stakeholders and data were subjected to thematic content analysis. There were differences in service providers' and academics' perceptions of access to Master's level education for nurses. Service providers engaged in regulatory practices, as evidenced in the way in which potential candidates were judged to be suitable or not to undertake a Master's-level education. Academic participants, in contrast, tended to have far fewer concerns about the career plans of applicants and were more likely to invoke discourses of academic educational admission practices. The health services need highly skilled, educated workers whose abilities and knowledge make an impact on the provision of effective patient and client care. This level of education can be achieved through continuing education of the professions by taught Master's degrees. It is imperative that an effective partnerships between clinical service providers and academics are developed to promote understanding of their respective perceptions of admission to the degree.


Death receptor signaling giving life to ectodermal organs.
A new tumor necrosis factor (TNF) pathway has been identified that has an important function in the regulation of embryonic development. Three key components of this pathway are previously unknown proteins: the TNF ligand ectodysplasin (also known as EDA), its death domain-containing receptor EDAR, and the death domain adapter molecule EDARADD. This pathway was discovered and delineated through the cloning of genes that cause human hypohidrotic ectodermal dysplasia (HED) syndromes and by analysis of the corresponding mouse mutants (Tabby, downless, and crinkled) showing defects in hair, teeth, and several exocrine glands. EDAR signaling is mediated by the activation of nuclear factor kappa B, but other downstream targets are not known. Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth. It is also necessary for the development of fish scales, indicating that this pathway and its function have been conserved during the evolution of ectodermal organs.


Learning-based attacks for detecting the vulnerability of computer-generated hologram based optical encryption.
Optical encryption has attracted wide attention for its remarkable characteristics. Inspired by the development of double random phase encoding, many researchers have developed a number of optical encryption systems for practical applications. It has also been found that computer-generated hologram (CGH) is highly promising for optical encryption, and the CGH-based optical encryption possesses remarkable advantages of simplicity and high feasibility for practical implementations. An input image, i.e., plaintext, can be iteratively or non-iteratively encoded into one or several phase-only masks via phase retrieval algorithms. Without security keys, it is impossible for unauthorized receivers to correctly extract the input image from ciphertext. However, cryptoanalysis of CGH-based optical encryption systems has not been effectively carried out before, and it is also concerned whether CGH-based optical encryption is sufficiently secure for practical applications. In this paper, learning-based attack is proposed to demonstrate the vulnerability of CGH-based optical security system without the direct retrieval of optical encryption keys for the first time to our knowledge. Many pairs of the extracted CGH patterns and their corresponding input images (i.e., ciphertext-plaintext pairs) are used to train a designed learning model. After training, it is straightforward to directly retrieve unknown plaintexts from the given ciphertexts (i.e., phase-only masks) by using the trained learning model without subsidiary conditions. Moreover, the proposed learning-based attacks are also feasible and effective for the cryptoanalysis of CGH-based optical security systems with multiple cascaded phase-only masks. The proposed learning-based attacking method paves the way for the cryptoanalysis of CGH-based optical encryption.


Effect of verapamil on the hydroosmotic response to antidiuretic hormone in toad urinary bladder.
To investigate the role of the calcium ion in the hydroosmotic response to antidiuretic hormone (ADH), the effects of verapamil, an inhibitor of calcium ion entry into cells, on stimulated water flow was examined in vitro in the toad urinary bladder. Verapamil, 50 micro M, decreased ADH-stimulated osmotic water flow from 23.4 +/- 4.1 to 9.9 +/- 3.3 mg . min-1 . hemibladder-1 (mean +/- SE, n = 12, P < 0.001). That this inhibitory effect was due to a verapamil-induced alteration in cellular calcium metabolism is suggested by the findings that 45Ca2+ uptake by isolated toad bladder epithelial cells was reduced nearly 50% in the presence of verapamil and that reversibility of verapamil's inhibitory action was calcium dependent. Additionally, verapamil reduced theophylline- (20 mM) stimulated water flow from 22.8 +/- 2.7 to 9.5 +/- 2.9 mg . min-1 . hemibladder-1 (n = 7, P < 0.001) but enhanced cAMP- (10 mM) induced water flow from 12.8 +/- 2.5 to 21.6 +/- 1.1 ng . min-1 . hemibladder-1 (n = 7, P < 0.001). The latter effect was due, at least in part, to a direct inhibitory effect by verapamil on phosphodiesterase activity of toad bladder homogenates. These results, therefore, suggest that the calcium ion is an important coupling factor at the level of the adenylate cyclase enzyme complex for the stimulus-reabsorption coupling between ADH and the transporting epithelia of the toad urinary bladder.


Avian and Mammalian Facilitative Glucose Transporters.
The GLUT members belong to a family of glucose transporter proteins that facilitate glucose transport across the cell membrane. The mammalian GLUT family consists of thirteen members (GLUTs 1-12 and H⁺-myo-inositol transporter (HMIT)). Humans have a recently duplicated GLUT member, GLUT14. Avians express the majority of GLUT members. The arrangement of multiple GLUTs across all somatic tissues signifies the important role of glucose across all organisms. Defects in glucose transport have been linked to metabolic disorders, insulin resistance and diabetes. Despite the essential importance of these transporters, our knowledge regarding GLUT members in avians is fragmented. It is clear that there are no chicken orthologs of mammalian GLUT4 and GLUT7. Our examination of GLUT members in the chicken revealed that some chicken GLUT members do not have corresponding orthologs in mammals. We review the information regarding GLUT orthologs and their function and expression in mammals and birds, with emphasis on chickens and humans.


Proximity to Industrial Food Animal Production and Asthma Exacerbations in Pennsylvania, 2005-2012.
The research on industrial food animal production (IFAP) and asthma exacerbations in the United States has relied on small sample sizes and/or self-reported outcomes. We assessed associations of proximity to large-scale and densely stocked swine and dairy/veal IFAP with three types of asthma exacerbations: hospitalizations, emergency encounters, and oral corticosteroid (OCS) medication orders from Geisinger Clinic in Pennsylvania. We used a diagnosis code (International Classification of Diseases, 9th Revision, Clinical Modification code 493.x) and medication orders from electronic health records to identify these exacerbations among asthma patients (n = 35,269) from 2005-2012. We compared residential proximity to swine or dairy/veal IFAP (dichotomized as <3 miles (4.8 km) or ≥3 miles) among asthma patients with and without exacerbations and estimated odds ratios using multilevel logistic regression. In adjusted models, proximity to IFAP was associated (odds ratio (95% confidence interval)) with OCS orders (1.11 (1.04-1.19)) and hospitalizations (1.29 (1.15-1.46)), but not emergency encounters (1.12 (0.91-1.37)). This study contributes to growing evidence that IFAP may impact health, in this case clinically-documented asthma exacerbations. No prior study has evaluated the association of IFAP and clinically-documented asthma exacerbations in the United States.


Quality evaluation of spaceborne SiC mirrors (II): evaluation technology for mirror accuracy using actual measurement data of samples cut out from a mirror surface.
The authors studied the quality evaluation technology of a spaceborne large-scale lightweight mirror that was made of silicon carbide (SiC)-based material. To correlate the material property of a mirror body and the mirror accuracy, the authors evaluated the mirror surface deviation of a prototype mirror by inputting actually measured coefficient of thermal expansion (CTE) data into a finite element analysis model. The CTE data were obtained by thermodilatometry using a commercial grade thermal dilatometer for the samples cut from all over the mirror surface. The computationally simulated contour diagrams well reproduced the mirror accuracy profile that the actual mirror showed in cryogenic testing. Density data were also useful for evaluating the mirror surface deviation because they had a close relationship with the CTE.


Imipramine and desipramine in plasma and spinal fluid: relationship to clinical response and serotonin metabolism.
In a double-blind study of depressed patients treated with imipramine hydrochloride, levels of imipramine and desipramine were measured in plasma and in CSF. Levels of both drugs in CSF were approximately 10% of plasma levels, but the levels in the two body fluids were highly correlated. The levels of both drugs were approximately equal in plasma, but desipramine predominated in CSF (imipramine/desipramine ratio of 0.8). The imipramine-induced alteration in CSF levels of the serotonin metabolite (5-hydroxy-indoleacetic acid [5HIAA]) correlated with imipramine levels but not with desipramine. For the group of patients showing a clear antidepressant response, the mean drug levels were nearly double those of the nonresponder group, a difference that did not quite reach statistical significance in this relatively small sample. The desipramine levels showed no responder-nonresponder difference, while the ratio of imipramine/desipramine was significantly higher among the responders. On the average this particular patient group had relatively low pretreatment levels of 5HIAA in CSF, an observation that may partially account for the relatively low overall response rate to imipramine.


Clinical Course and Prognosis of Non-Secretory Multiple Myeloma.
To determine the prognosis of patients with non-secretory myeloma. Methods: We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow up testing (non-secretory myeloma). The overall survival (OS) of patients with non-secretory myeloma was compared with 7075 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis. One hundred and twenty four patients met criteria for non-secretory multiple myeloma. The median follow-up was 102 months (range, 1-204 months). The median progression free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 99.2 versus 43.8 months (prior to 2001) versus 99.2 months (2001-2012), P<0.001. OS was superior in patients with a normal baseline FLC ratio (n=10) compared to patients with an abnormal ratio (n=19), medians not reached in both groups. Prior to 2001, OS was similar in non-secretory myeloma (n=86) and secretory myeloma (n=4011), median 3.6 versus 3.5 years, respectively, P=0.63. However, among patients diagnosed between 2001-2012, OS was superior in non-secretory myeloma (n=36) compared to secretory myeloma (n=2942), median 8.3 versus 5.4 years, respectively, P=0.03. Non-secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non-secretory myeloma, and appears superior to secretory myeloma. This article is protected by copyright. All rights reserved.


Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9.
14-3-3ζ promotes cell survival via dynamic interactions with a vast network of binding partners, many of which are involved in stress regulation. We show here that hypoxia (low glucose and oxygen) triggers a rearrangement of the 14-3-3ζ interactome to favor an interaction with the core autophagy regulator Atg9A. Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. However, upon induction of hypoxic stress, activated AMPK bypasses the requirement for ULK1 and mediates S761 phosphorylation directly, resulting in an increase in 14-3-3ζ interactions, recruitment of Atg9A to LC3-positive autophagosomes, and enhanced autophagosome production. These data suggest a novel mechanism whereby the level of autophagy induction can be modulated by AMPK/ULK1-mediated phosphorylation of mammalian Atg9A.


Analysis of clinical pharmacist interventions in the COVID-19 units of a French university hospital.
The objectives were to compare clinical pharmacist interventions between two care groups: COVID-19-positive and COVID-19-negative patients, and to identify drugs that require particular attention, especially those involved in COVID-19 management. A prospective cohort study was conducted on patients with positive and negative COVID-19 statuses admitted to Lille University Hospital over 1 month. Pharmaceutical analysis instigated interventions to rectify drug-related errors. For each pharmaceutical intervention (PI), the anatomical therapeutic chemical classification of the drug and the outcome of such an intervention were specified. The study included 438 patients. Prescription analysis led to 188 PIs performed on 118 patients (64 COVID-19-positive patients and 54 COVID-19-negative patients). Most drug-related problems were incorrect dosage representing 36.7% (69/188) of all interventions: 27.9% (29/104) for the COVID-19-positive group and 47.6% (40/84) for the COVID-19-negative group. The most frequent PI in 34% (64/188) of cases was terminating a drug: 27.9% (29/104) for the COVID-19-positive group and 47.6% (40/84) for the COVID-19-negative group. The main drug classes involved were antithrombotic agents (20.7%, 39/188), antibacterials for systemic use (13.8%, 26/188) and drugs for gastric acid-related disorders (6.4%, 12/188). Study population was limited to a single centre over 1 month. No difference in PI was noted between the two groups. The presence of pharmacists led to a reduction in drug-related prescription problems, especially for antithrombotic and antibacterial drugs for both groups. Clinical pharmacy commitment in such a pandemic is therefore important.


A multi-layer energy-based fragment method for excited states and nonadiabatic dynamics.
We developed a multi-layer energy-based fragment (MLEBF) method within the many-body energy expansion framework. It supplies accurate energies and gradients, and accurately reproduces excited-state topological structures. Moreover, MLEBF-based nonadiabatic dynamics simulations give nearly the same results compared with full ab initio ones. The present work could stimulate developing energy-based fragment methods for photochemistry of large systems.


Prevalence and predictors of sexual inexperience in adulthood.
The emergence of partnered sexual behavior represents an important developmental transition. However, little is known about individuals who remain sexually inexperienced well into adulthood. We used data from 2,857 individuals who participated in Waves I-IV of the National Longitudinal Study of Adolescent Health (Add Health) and reported no sexual activity (i.e., oral-genital, vaginal, or anal sex) by age 18 to identify, using discrete-time survival models, adolescent sociodemographic, biosocial, and behavioral characteristics that predicted adult sexual inexperience. The mean age of participants at Wave IV was 28.5 years (SD = 1.92). Over one out of eight participants who did not initiate sexual activity during adolescence remained abstinent as young adults. Sexual non-attraction significantly predicted sexual inexperience among both males (aOR = 0.5) and females (aOR = 0.6). Males also had lower odds of initiating sexual activity after age 18 if they were non-Hispanic Asian, reported later than average pubertal development, or were rated as physically unattractive (aORs = 0.6-0.7). Females who were overweight, had lower cognitive performance, or reported frequent religious attendance had lower odds of sexual experience (aORs = 0.7-0.8) while those who were rated by the interviewers as very attractive or whose parents had lower educational attainment had higher odds of sexual experience (aORs = 1.4-1.8). Our findings underscore the heterogeneity of this unique population and suggest that there are a number of different pathways that may lead to either voluntary or involuntary adult sexual inexperience. Understanding the meaning of sexual inexperience in young adulthood may have important implications for the study of sexuality development across the life course.


Molecularly cloned bovine papillomavirus DNA transforms mouse fibroblasts in vitro.
NIH 3T3 mouse fibroblasts were transformed in vitro by transfection with viral DNA from bovine papillomavirus (BPV) types 4, 2 and 1. The viral DNAs were molecularly cloned in pAT153 to construct pBV4, a recombinant plasmid containing the whole genome of BPV4, pBV2 containing the entire genome of BPV2, and pBV1-D1 which contains the 69% transforming DNA fragments of BPV1. The transformed cells lost contact inhibition, were anchorage-independent, required low serum and were tumourigenic in nude mice. This is the first report of cell transformation in vitro by BPV4 DNA. The recombinant plasmids transformed NIH 3T3 cells with an efficiency of 200 to 300 foci/micrograms DNA. Cleavage of the recombinant plasmids with enzymes that separate the viral DNA from pAT153 DNA did not significantly alter the efficiency of transformation. In all the transformed cells analysed, the recombinant plasmids were found as multiple copies of non-integrated monomers.


A TCP domain transcription factor controls flower type specification along the radial axis of the Gerbera (Asteraceae) inflorescence.
Several key processes in plant development are regulated by TCP transcription factors. CYCLOIDEA-like (CYC-like) TCP domain proteins have been shown to control flower symmetry in distantly related plant lineages. Gerbera hybrida, a member of one of the largest clades of angiosperms, the sunflower family (Asteraceae), is an interesting model for developmental studies because its elaborate inflorescence comprises different types of flowers that have specialized structures and functions. The morphological differentiation of flower types involves gradual changes in flower size and symmetry that follow the radial organization of the densely packed inflorescence. Differences in the degree of petal fusion further define the distinct shapes of the Gerbera flower types. To study the role of TCP transcription factors during specification of this complex inflorescence organization, we characterized the CYC-like homolog GhCYC2 from Gerbera. The expression of GhCYC2 follows a gradient along the radial axis of the inflorescence. GhCYC2 is expressed in the marginal, bilaterally symmetrical ray flowers but not in the centermost disk flowers, which are nearly radially symmetrical and have significantly less fused petals. Overexpression of GhCYC2 causes disk flowers to obtain morphologies similar to ray flowers. Both expression patterns and transgenic phenotypes suggest that GhCYC2 is involved in differentiation among Gerbera flower types, providing the first molecular evidence that CYC-like TCP factors take part in defining the complex inflorescence structure of the Asteraceae, a major determinant of the family's evolutionary success.


Conserved high-affinity NF-kappa B binding site in the interferon regulatory factor-1 promoter is not occupied by NF-kappa B in vivo and is transcriptionally inactive.
The promoter of the interferon regulatory factor-1 (IRF-1) gene contains at position -47 to -38 an evolutionary conserved binding sequence for the inducible transcription factor NF-kappa B. This site is highly homologous to a transcriptionally active site from the MHC class I enhancer. In this study, we show by in vitro assays using purified NF-kappa B that the kappa B motif in the IRF-1 promoter binds the factor specifically and with high affinity, comparable to various other cis-acting kappa B elements. Two copies of the IRF-1 kappa B site fused to the heterologous c-fos promoter conferred induction of a chloramphenicol acetyl transferase (CAT) reported gene in response to stimulation of L929 fibroblasts with various NF-kappa B inducers, such as tumor necrosis factor alpha (TNF alpha) or phorbol 12-myristate 13-acetate (PMA). Mutation of the binding site completely abolished transcriptional inducibility of the heterologous promoter. Surprisingly, the same IRF-1 kappa B motif in context of the homologous IRF-1 promoter was transcriptionally inactive in CAT assays. The very weak induction of the IRF-1 promoter in response to TNF treatment or infection of fibroblasts with Newcastle disease virus (NDV) was barely affected by point mutation of the kappa B site or loss of the site by truncation of the promoter. Analysis of the occupational state of the chromosomal IRF-1 kappa B site by in vivo foot-printing revealed that no footprint was induced over the kappa B motif in the IRF-1 promoter after PMA treatment of L929 fibroblast cells, despite the simultaneous induction of IRF-1 mRNA and NF-kappa B binding activity. Constitutive footprints were detected at a CCAAT and GC-rich region in the promoter. This is the first example of a high-affinity NF-kappa B binding site within a promoter which may not participate in transcriptional regulation under conditions activating NF-kappa B DNA binding and gene expression.


Lung compliance changes on high-frequency ventilation in normal dogs.
To test the hypothesis that high-frequency ventilation (HFV) promotes lung stability we compared the temporal course of dynamic lung compliance changes after two inflations on HFV with those occurring on conventional mechanical ventilation (CMV) at two different lung volumes, specifically with and without 5 cmH2O positive end-expiratory pressure (PEEP). In our first set of experiments we ventilated six anesthetized paralyzed dogs first with CMV, then with HFV, then again with CMV using tidal volumes of 15 ml/kg at rates of 16-18 times/min for CMV and less than 90 ml and a rate of 15 Hz for HFV. In our second set of experiments we ventilated six dogs for 4 h, the 1st h with CMV at 0 cmH2O end-expiratory pressure, the 2nd h with CMV with 5 cmH2O PEEP, the 3rd h with HFV at the same mean pleural pressure, and the 4th h again with CMV with 5 cmH2O PEEP. We found the decreases in dynamic compliance with time following hyperinflations were similar on HFV and CMV (P greater than 0.5) at both lung volumes. With the lower lung volume the initial dynamic compliance following hyperinflation also tended to fall progressively from one hour to the next despite the inflations. However, with PEEP the initial dynamic compliance over successive hours tended to rise from one hour to the next. We found that changes in dynamic compliance were not necessarily reflected in the venous admixture or alveolar to arterial O2 partial pressure gradients. We thus conclude that lung stability in normal dogs is not improved during HFV, and blood gases cannot be used to predict compliance changes.


Antimicrobial consumption in a tertiary children's hospital in Finland (2003-2013).
Numbers of resistant pathogens are constantly increasing, and prudent use of antimicrobials is of paramount importance. In order to see whether any changes in the use of antimicrobials in recent years have occurred, we decided to monitor the consumption of these drugs at a single tertiary paediatric hospital. This single-centre retrospective study investigated the consumption of antimicrobials in defined daily doses (DDDs according to the Anatomical Therapeutical Chemical /DDD index) in a 130-bed paediatric tertiary hospital. The data on the consumption of antimicrobials were collected from years 2003-2013 by using electronic surveillance records provided by the local pharmacy. The consumption was related to days of hospital care. During 2003-2013, the use of penicillins, cephalosporins and carbapenems increased by 28%, 46% and 110%, respectively. The consumption of both aminoglycosides and vancomycin decreased by 61% and 41%, respectively. Amphotericin B use clearly decreased by 39% while the use of novel azoles and echinocandins increased. Increased use of carbapenems was the most significant finding of our study. The year-to-year consumption of antibacterials was in general relatively stable and new antibacterials were taken into use conservatively. In contrast to antibacterials, novel antifungals were rapidly adopted into use despite scarce evidence on their safety in children.


Multimodal Imaging Features of Optic Disc Drusen.
To identify key en face multimodal imaging features of optic disc drusen (ODD). Retrospective cross-sectional study. Setting: a single academic center. Patient orStudyPopulation: 786 patients (10-82 years of age) with diagnostic codes for optic disc drusen (ODD) in clinical notes extracted using natural language processing. Intervention orObservationProcedures: color fundus imaging, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT). MainOutcomeMeasurements: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT. A total of 38 patients (61 eyes) had high-quality EDI-OCT scans and en face multimodal imaging. Green-light FAF imaging had the highest diagnostic sensitivity (96.8%) for ODD and showed homogeneous hyperautofluorescence, whereas blue-light FAF imaging had heterogeneous brightness, which helped differentiate superficial from deep ODD. Blue-light FAF (93.5%) and NIR (91.8%) imaging were also sensitive tests and revealed papillary and peripapillary features that were not well seen on green-light FAF, including the size and depth of ODD, morphology of the optic disc, and common ODD-associated structures such as horizontal hyper-reflective lines and peripapillary hyper-reflective ovoid mass-like structures (PHOMS). Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all). In en face imaging, green-light FAF had the highest sensitivity for the diagnosis of ODD, whereas blue-light FAF and NIR images provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT should be performed and provides the highest-resolution characterization of the entire optic disc to assess or rule out ODD.


The accumulation of 111In-eosinophils induced by inflammatory mediators, in vivo.
Eosinophils are implicated in the pathogenesis of a variety of allergic inflammatory diseases such as asthma. Several substances have been shown to be chemotactic for eosinophils in vitro, but the inflammatory mediators involved in the accumulation of eosinophils in vivo are as yet unidentified. In this study we have developed a system to measure the accumulation of 111In-eosinophils in guinea-pig skin in vivo. Horse serum-induced guinea-pig peritoneal eosinophils were radiolabelled with 111In and injected intravenously into recipient animals. 125I-albumin was also injected intravenously in order to measure local oedema formation simultaneously. A range of putative mediators was injected intradermally and responses measured for up to 2 hr. Of the mediators tested, guinea-pig C5a des Arg in zymosan-activated plasma was the most active. Recombinant human C5a (rHC5a) was also highly active, but less than the guinea-pig material. C5a des Arg in maximally activated plasma induced a 1500% increase in eosinophil accumulation, while rHC5a (10(-10) mol dose) induced a 600% increase. Platelet-activating factor (PAF) and leukotriene B4 (LTB4) were also tested for comparison. With respect to 111In-eosinophil accumulation, the order of potency of the mediators tested was as follows: guinea-pig C5a des Arg greater than LTB4 greater than PAF. In contrast, the order of potency of the mediators with respect to oedema formation was: PAF greater than guinea-pig C5a des Arg greater than LTB4. The techniques described will facilitate analysis of the mechanisms involved in eosinophil accumulation in defined inflammatory reactions.


Oral administration of neomycin to chickens experimentally infected with Salmonella typhimurium.
Groups of healthy chickens with a light experimental Salmonella typhimurium infection were fed on a diet containing 225 g per ton (1016 kg) of neomycin for two days. This brought about only a slight reduction in the incidence of chickens that were excreting S typhimurium in their faeces. Examination of caecal contents two days after the cessation of treatment revealed the neomycin had not had any effect in eliminating infection. In one experiment, the neomycin administration resulted in the emergence of enormous populations of Escherichia coli in the alimentary tract of treated chickens that possessed multiple antibiotic resistance of the transmissible type. For these reasons the practice of feeding broiler chickens on diets containing neomycin immediately before slaughter should be actively discouraged.


Head and neck cancer as a model for advances in imaging prognosis, early assessment, and posttherapy evaluation.
Novel noninvasive functional imaging methods are necessary to predict therapeutic outcome and thereby improve the ability to properly select patients for treatment with both conventional and targeted therapies, to better evaluate therapeutic effectiveness during the early phases of treatment, and to enhance a priori risk assessment for treatment induced toxicity. Functional metabolic imaging typically involves pretreatment baseline magnetic resonance imaging (MRI) and/or positron emission tomographic (PET) scans and performance of subsequent scans during and/or after treatment. Imaging parameter changes are routinely attributed to the intervening therapy and clinical outcomes subsequently correlated with these changes. The physiologic parameter(s) that best correlate with clinical outcome and the relative utility of MRI versus PET are unknown, however. Furthermore, tumor vascular physiology and metabolic parameters are heterogeneous and dynamic processes. Large daily fluctuations often occur in the absence of treatment. The magnitude of this temporal variability is not established for MRI or for PET. Routine and meaningful clinical application of functional imaging requires understanding and quantification of the intrinsic variability of the underlying biologic processes and a demonstration that treatment-induced changes exceed intrinsic temporal variation.


[Thermography in the diagnosis of retinoblastoma in children].
The authors presented the results of thermographic examination of children with suspected retinoblastoma (30 primary examined patients and 30 patients examined to assess therapeutic efficacy). The results of the examination showed the relationship of the intensity and extent of the hyperthermia zone with tumor stage. The usefulness of the thermographic method for efficacy assessment was shown.


Microencapsulated choroid plexus epithelial cell transplants for repair of the brain.
The choroid plexuses (CPs) play pivotal roles in basic aspects of neural function including maintaining the extracellular milieu of the brain by actively modulating chemical exchange between the CSF and brain parenchyma, surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive "cocktail" of polypeptides and participating in repair processes following trauma. Even modest changes in the CP can have far reaching effects and changes in the anatomy and physiology of the CP have been linked to several CNS diseases. It is also possible that replacing diseased or transplanting healthy CP might be useful for treating acute and chronic brain diseases. Here we describe the wide-ranging functions of the CP, alterations of these functions in aging and neurodegeneration and recent demonstrations of the therapeutic potential of transplanted microencapsulated CP for neural trauma.


How has confocal microscopy helped us in refractive surgery?
To summarize the known uses of in-vivo confocal microscopy in refractive surgery, highlighting the current developments in the field. Examination of the cornea after laser in-situ keratomileusis demonstrated that the keratocyte density within the laser in-situ keratomileusis flap and anterior residual corneal bed continued to decline during the entire 3-year period of the study. The progressive loss of keratocytes in the flap and anterior portion of the residual corneal bed could have long-term implications in terms of corneal stability, refractive stability and cellular integrity after laser in-situ keratomileusis. Additional studies showed that the density of sub-basal nerves decreased by 90% 1 month after laser in-situ keratomileusis. At some point between 3 and 6 months after laser in-situ keratomileusis, the sub-basal nerves began to recover and by 2 years they had reached approximately 50% of their original preoperative density. Analysis of sub-basal nerve density after photorefractive keratectomy reported that the nerve density completely recovered to preoperative levels by 2 years. Other confocal microscopic studies demonstrated that the microscope can detect infectious organisms in vivo, without stains or dyes. The confocal microscope is a unique diagnostic instrument that can be used to evaluate corneal healing, long-term stability and to assess complications after refractive surgery. The ability of the device to view in-vivo cellular detail, microorganisms, inflammatory cells, epitheliod cells, fibrosis and measure the postoperative thickness of the residual corneal bed after laser in-situ keratomileusis, in a noninvasive manner, highlights the unique capabilities of this instrument.


Mind and action.
The author argues that Cutting's Principles of psychopathology (1997) is a remarkable compendium of ideas on psychopathology and philosophy, and offers a valuable resource for those interested in this area. There is, however, a marked contrast between the way in which Cutting views philosophy (as a source of ideas) and the way contemporary philosophy views itself (as being about the skills of deepening understanding and arriving at original ideas through the application of analytical and critical thinking skills). In addition, Cutting's survey of the philosophy literature is highly selective and is concentrated largely on pre-World War II philosophy. As a result of both these features, the book underemphasises the potential value of philosophy for psychopathology. It is argued in this paper that philosophy provides strategies for inquiry into the nature of the mind and its pathologies, rather than being merely a source of ideas. This point is made in more detail by exploring the contrast between the approach Cutting adopts and the approach used by both Karl Jaspers and in recent work on the philosophy of psychopathology, specifically K.W.M. Fulford (1989). Although the author of this paper is entirely in agreement with Cutting's general view (that psychopathology is underpinned by philosophy), it is argued that he does not take his exploration far enough to extract from his survey the fundamental underlying implications for psychopathology-that psychopathology is inherently evaluative and normative in its stance, but that this aspect is rendered opaque, currently, by psychopathology's status as an empirical science.


Gastro-retentive dosage form for improving bioavailability of Cefpodoxime proxetil in rats.
Cefpodoxime proxetil (CP) is a prodrug with poor oral bioavailability because of its metabolism to Cefpodoxime acid (CA) in luminal contents and intestinal epithelial cells. In the present investigation, regional variability in different segments of the gastrointestinal tract vis-à-vis solubility and metabolism were investigated, and the results indicated potential for a gastro retentive (GR) dosage form. Suitability of a GR dosage from for CP and finally in vivo efficacy were investigated. Thereafter, an effervescent floating GR dosage form was developed for CP and evaluated in rats. The GR dosage form improved the oral bioavailability of CP significantly by about 75%, hence providing a proof-of-concept. The Tmax value increased to 1.43+/-0.24 h from 0.91+/-0.23 h of pure drug, while Cmax values of 4735+/-802 ng/ml and 3094+/-567 ng/ml were obtained for the GR dosage form and pure drug respectively.


CONUT: a tool for controlling nutritional status. First validation in a hospital population.
The serious problem of hospital undernutrition is still being underestimated, despite its impact on clinical evolution and costs. The screening methods developed so far are not useful for daily clinical practice due to their low effectiveness/cost ratio. We present an screening tool for CONtrolling NUTritional status (CONUT) that allows an automatic daily assessment of nutritional status of all inpatients that undergo routine analysis. The system is based on a computer application that compiles daily all useful patient information available in hospital databases, through the internal network. It automatically assesses the nutritional status taking into account laboratory information including serum albumin, total cholesterol level and total lymphocyte count. We have studied the association between the results of the Subjective Global Assessment (SGA) and Full Nutritional Assessment (FNA) with those from CONUT, in a sample of 53 individuals. The agreement degree between CONUT and FNA as measured by kappa index is 0.669 (p = 0.003), and between CONUT and SGA is 0.488 (p = 0.034). Considering FNA as "gold standard" we obtain a sensitivity of 92.3 and a specificity of 85.0. CONUT seems to be an efficient tool for early detection and continuous control of hospital undernutrition, with the suitable characteristics for these screening functions.


Age-dependent effects of oxytocin in brain regions enriched with oxytocin receptors.
Although intranasal oxytocin administration to tap into central functions is the most commonly used non-invasive means for exploring oxytocin's role in human cognition and behavior, the way by which intranasal oxytocin acts on the brain is not yet fully understood. Recent research suggests that brain regions densely populated with oxytocin receptors may play a central role in intranasal oxytocin's action mechanisms in the brain. In particular, intranasal oxytocin may act directly on (subcortical) regions rich in oxytocin receptors via binding to these receptors while only indirectly affecting other (cortical) regions via their neural connections to oxytocin receptor-enriched regions. Aligned with this notion, the current study adopted a novel approach to test 1) whether the connections between oxytocin receptor-enriched regions (i.e., the thalamus, pallidum, caudate nucleus, putamen, and olfactory bulbs) and other regions in the brain were responsive to intranasal oxytocin administration, and 2) whether oxytocin-induced effects varied as a function of age. Forty-six young (24.96 ± 3.06 years) and 44 older (69.89 ± 2.99 years) participants were randomized, in a double-blind procedure, to self-administer either intranasal oxytocin or placebo before resting-state fMRI. Results supported age-dependency in the effects of intranasal oxytocin administration on connectivity between oxytocin receptor-enriched regions and other regions in the brain. Specifically, compared to placebo, oxytocin decreased both connectivity density and connectivity strength of the thalamus for young participants while it increased connectivity density and connectivity strength of the caudate for older participants. These findings inform the mechanisms underlying the effects of exogenous oxytocin on brain function and highlight the importance of age in these processes.


Immunoperoxidase localization of colonic mucoprotein antigen in neoplastic tissues.
The distribution of colonic mucoprotein antigen in various types of cancer was examined to determine whether the antigen might have a role as a tissue marker. An antiserum prepared against normal colon-derived colonic mucoprotein antigen and appropriately absorbed with mucinous ovarian cystadenocarcinoma fluid had reactivity limited to the colon and cecum when tested by immunoperoxidase against various normal adult tissue specimens. Among colon carcinomas, 60% of the tumors were stained, and a correlation with tumor differentiation was noted: seven of seven tumors were well differentiated; 21 of 35 tumors were moderately differentiated; and one of seven poorly differentiated tumors expressed the determinants. Of note was the absence of staining with gastric, pancreatic, lung, and endometrial mucin-producing carcinomas. Only one of five mucinous ovarian cystadenocarcinomas was positive for colonic mucoprotein antigen. The potential role of the mucin as a marker for colon carcinoma is discussed.


Principal component analysis and blind separation of sources for optical imaging of intrinsic signals.
The analysis of data sets from optical imaging of intrinsic signals requires the separation of signals, which accurately reflect stimulated neuronal activity (mapping signal), from signals related to background activity. Here we show that blind separation of sources by extended spatial decorrelation (ESD) is a powerful method for the extraction of the mapping signal from the total recorded signal. ESD is based on the assumptions (i) that each signal component varies smoothly across space and (ii) that every component has zero cross-correlation functions with the other components. In contrast to the standard analysis of optical imaging data, the proposed method (i) is applicable to nonorthogonal stimulus-conditions, (ii) can remove the global signal, blood-vessel patterns, and movement artifacts, (iii) works without ad hoc assumptions about the data structure in the frequency domain, and (iv) provides a confidence measure for the signals (Z score). We first demonstrate on orientation maps from cat and ferret visual cortex, that principal component analysis, which acts as a preprocessing step to ESD, can already remove global signals from image stacks, as long as data stacks for at least two-not necessarily orthogonal-stimulus conditions are available. We then show that the full ESD analysis can further reduce global signal components and-finally-concentrate the mapping signal within a single component both for differential image stacks and for image stacks recorded during presentation of a single stimulus.