Surgical Interventions in Infants Born Preterm with Congenital Heart Defects: An Analysis of the Kids' Inpatient Database.
To evaluate short-term outcomes in infants born preterm with congenital heart defects (CHDs) and the factors associated with surgery, survival, and length of hospitalization in this population. We analyzed data from infants born preterm (gestational age <37 weeks) enrolled in the multicenter Kids' Inpatient Database of the Healthcare Cost and Utilization Project who were admitted to the hospital within 30 days after birth. Infants with atrial septal defects were excluded. Of 1 429 762 enrolled infants born preterm, 27 434 (2.0%) with CHDs were included. Overall survival to discharge was 90.5%; 74.0% among infants with critical CHDs and 45.7% among infants with hypoplastic left heart syndrome. Cardiac surgeries were performed in 12.2% of all infants born preterm. Rates of surgical intervention for infants with critical CHDs were lower for very low birth weight (≤1.5 kg) vs larger infants >1.5 kg (27% vs 44%), and only 6.3% of infants born with very low birth weight underwent surgeries in Risk-adjustment for Congenital Heart Surgery categories 4 or greater. Greater birth weight, left-sided lesions, care at children's hospitals, and absence of trisomies were associated with a greater likelihood of surgery. Birth weight <2 kg, nonwhite race, trisomy syndromes, prematurity-related morbidities, and Risk-adjustment for Congenital Heart Surgery category 4 or greater were independent predictors of mortality. Birth weight <2 kg, Risk-adjustment for Congenital Heart Surgery category, morbidities, and sidedness of lesion predicted length of stay. The high survival rates of infants born preterm with CHDs suggests that a cautiously optimistic approach to surgery may be warranted in all but the most immature infants with the greatest-risk conditions.


Basal chloride currents in murine airway epithelial cells: modulation by CFTR.
We have isolated ciliated respiratory cells from the nasal epithelium of wild-type and cystic fibrosis (CF) null mice and used the patch-clamp technique to investigate their basal conductances. Current-clamp experiments on unstimulated cells indicated the presence of K+ and Cl- conductances and, under certain conditions, a small Na+ conductance. Voltage-clamp experiments revealed three distinct Cl- conductances. Itv-indep was time and voltage independent with a linear current-voltage (I-V) plot; Iv-act exhibited activation at potentials greater than +/- 50 mV, giving an S-shaped I-V plot; and Ihyp-act was activated by hyperpolarizing potentials and had an inwardly rectified I-V plot. The current density sequence was Ihyp-act = Iv-act >> Itv-indep. These conductances had Cl(-)-to-N-methyl-D-glucamine cation permeability ratios of between 2.8 and 10.3 and were unaffected by tamoxifen, flufenamate, glibenclamide, DIDS, and 5-nitro-2-(3-phenylpropylamino) benzoic acid but were inhibited by Zn2+ and Gd3+. Itv-indep and Iv-act were present in wild-type and CF cells at equal density and frequency. However, Ihyp-act was detected in only 3% of CF cells compared with 26% of wild-type cells, suggesting that this conductance may be modulated by cystic fibrosis transmembrane conductance regulator (CFTR).


Exercise prescription for overhead athletes with shoulder pathology: a systematic review with best evidence synthesis.
To produce a best evidence synthesis of exercise prescription used when treating shoulder pathology in the overhead athlete. A systematic review of exercises used in overhead athletes including case studies and clinical commentaries. MEDLINE, PubMed, SPORTDiscus and CINAHL from database inception through July 8, 2016. We examined data from randomised controlled trials and prospective cohort (level I-IV evidence) studies that addressed exercise intervention in the rehabilitation of the overhead athlete with shoulder pathology. Case studies and clinical commentaries (level V evidence) were examined to account for expert opinion-based research. Data were combined using best evidence synthesis and graded (A-F) recommendations (Centre for Evidence-Based Medicine). There were 33 unique exercises in six level I-IV studies that met our inclusion criteria. Most exercises were single-plane, upper extremity exercises performed below 90o of elevation. There were 102 unique exercises in 33 level V studies that met our inclusion criteria. These exercises emphasised plyometrics, kinetic chain and sport-specific training. Overall, evidence for exercise interventions in overhead athletes with shoulder pathology is dominated by expert opinion (grade D). There is great variability between exercise approaches suggested by experts and those investigated in research studies and the overall level of evidence is low. The strongest available evidence (level B) supports the use of single-plane, open chain upper extremity exercises performed below 90° of elevation and closed chain upper extremity exercises. Clinical expert pieces support a more advanced, global treatment approach consistent with the complex, multidimensional nature of sport.


Assessment of global cardiac function.
High-resolution magnetic resonance cine imaging (cine-MRI) allows for a non-invasive assessment of ventricular function and mass in normal mice and in genetically and surgically modified mouse models of cardiac disease. The assessment of myocardial mass and function by cine-MRI does not rely on geometric assumptions, as the hearts are covered from the base to the apex, typically by a stack of two-dimensional images. The MR data acquisition is then followed by image segmentation of specific cine frames in each slice to obtain geometric and functional parameters, such as end-diastolic volume (EDV), end-systolic volume (ESV) or ejection fraction (EF). This technique has been well established in clinical routine application and it is now also becoming the reference method in experimental cardiovascular MRI. The cine images are typically acquired in short- and long-axis orientations of the heart to facilitate an accurate assessment of cardiac functional parameters. These views can be difficult to identify, particularly in animals with diseased hearts. Furthermore, data analysis can be the source of a systematic error, mainly for myocardial mass measurement. We have established protocols that allow for a quick and reproducible way of obtaining the relevant cardiac views for cine-MRI, and for accurate image analysis.


Assessing nicotine dependence.
Family physicians can assess the smoking behavior of their patients in a few minutes, using carefully chosen questions. The CAGE questionnaire for smoking (modified from the familiar CAGE questionnaire for alcoholism), the "four Cs" test and the Fagerström Test for Nicotine Dependence help make the diagnosis of nicotine dependence based on standard criteria. Additional questions can be used to determine the patient's readiness to change and the nature of the reinforcement the patient receives from smoking. These tools can assist family physicians in guiding patients to quit smoking-the single most important thing smokers can do to improve their health.


Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA.
Hydroxyindole-O-methyltransferase (HIOMT) catalyzes the last step in the synthesis of the pineal hormone melatonin. In this study, an HIOMT clone was isolated from a human pineal cDNA library using synthetic oligonucleotide probes based on the bovine HIOMT sequence. The human sequence is unusual because it contains a 3' fragment (84 bp) of the LINE-1 sequence, a highly repetitive sequence in the human genome and the genome of some primates and rodents. Exclusive of this LINE-1 fragment, the human HIOMT clone is 75% and 63% homologous to bovine and avian HIOMT sequences, respectively. The deduced amino acid sequence of the human cDNA clone encodes a 41.6-kD protein. In addition, the sequence is 70% and 57% identical and 81% and 73% similar to bovine and avian HIOMT, respectively. In agreement with the results of earlier studies, it was found that vertebrate HIOMT amino acid sequences are not homologous to any other vertebrate proteins, including several methyltransferases. However, HIOMT exhibits homology with a plant O-methyltransferase and an internal 120-amino-acid region is approximately 35% identical to a region of four bacterial O-methyltransferases. The results of PCR and Southern blot analysis indicate that three species of HIOMT mRNA are typically present in the human pineal gland, only one of which contains the LINE-1 fragment. An antiserum was raised against a mixture of three synthetic peptides, corresponding to three regions of the deduced amino acid sequence of human HIOMT. This antiserum detected a single immunoreactive protein in Western blot analysis of human pineal glands. The size of the protein (approximately 42 kD) is identical to that predicted from the HIOMT clone, including the LINE-1 fragment. The human HIOMT sequence should be useful in further studies of this enzyme and will also be of special importance in evaluating the functional significance of the inclusion of a fragment of the LINE-1 in an mRNA.


AI-related BMD variation in actual practice conditions: A prospective cohort study.
The aim of the study was to evaluate the progression of bone mineral density (BMD) during 3 years of aromatase inhibitors (AI) therapy in actual practice conditions. This prospective, clinical cohort study of Barcelona-Aromatase induced Bone Loss in Early breast cancer (B-ABLE) assessed BMD changes during 3 years of AI treatment in women with breast cancer. Patients with osteoporosis (T score < -2.5 or T score ≤ -2.0) and a major risk factor and/or prevalent fragility fractures were treated with oral bisphosphonates (BPs). Of 685 women recruited, 179 (26.1%) received BP treatment. By the third year of AI therapy, this group exhibited increased BMD in the lumbar spine (LS; 2.59%) and femoral neck (FN; 2.50%), although the increase was significant only within the first year (LS: 1.99% and FN: 2.04%). Despite BP therapy, however, approximately 15% of these patients lost more than 3% of their baseline bone mass. At 3 years, patients without BP experienced BMD decreases in the LS (-3.10%) and FN (-2.79%). In this group, BMD changes occurred during the first (LS: -1.33% and FN: -1.25%), second (LS: -1.19% and FN: -0.82%), and third (LS: -0.57% and FN: -0.65%) years of AI treatment. Increased BMD (>3%) was observed in just 7.6% and 10.8% of these patients at the LS and FN, respectively. Our data confirm a clinically relevant bone loss associated with AI therapy amongst nonusers of preventative BPs. We further report on the importance of BMD monitoring as well as calcium and 25-hydroxy vitamin D supplementation in these patients.


Synthesis of aromatase inhibitors and dual aromatase steroid sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities.
4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 STS)=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg(-1), single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.


A meta-analysis of controlled research on social skills training for schizophrenia.
A meta-analysis of randomized, controlled trials of social skills training for schizophrenia was conducted. Outcome measures from 22 studies including 1,521 clients were categorized according to a proximal-distal continuum in relation to the presumed site of action of skills training interventions, with content mastery tests and performance-based measures of skills assumed to be most proximal, community functioning and negative symptoms intermediate, and general symptoms and relapse most distal. Results reveal a large weighted mean effect size for content-mastery exams (d = 1.20), a moderate mean effect size for performance-based measures of social and daily living skills (d = 0.52), moderate mean effect sizes for community functioning (d = 0.52) and negative symptoms (d = 0.40), and small mean effect sizes for other symptoms (d = 0.15) and relapse (d = 0.23). These results support the efficacy of social skills training for improving psychosocial functioning in schizophrenia.


Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance.
Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.


Impact of Different Irrigant Agitation Methods on Bacterial Elimination from Infected Root Canals.
Activation techniques are essential for root canal disinfection but may result in incomplete removal of bacteria. The aim of our study was to assess the antibacterial action of sonically, ultrasonically and laser-activated irrigation and 5.25% sodium hypochlorite (NaOCl) on Enterococcus faecalis in an infected tooth. Forty-four extracted mandibular premolars were mechanically prepared, sterilized, and inoculated with E. faecalis for 1 week. Bacterial counts after inoculation were evaluated in 4 randomly chosen teeth, remaining root canals were divided into 4 groups. Group A: laser-activated irrigation by photon-induced photoacoustic streaming, Group B: the sonic irrigation by EDDY, Group C: ultrasonic irrigation by EndoUltra, and Group D: 5.25% NaOCl. Colony forming unit (CFU) counts were measured and Kolmogorov-Smirnov, Wilcoxon, Kruskal-Wallis and Mann-Whitney tests were used to determine differences. The mean of CFU was found to significantly decrease in group D, 2110 ± 1015.93 (p < 0.001). Changes in measurement levels followed the same trend over time in groups A 27.40 ± 30.15, B 81.3 ± 85.68 and C 44.40 ± 67.12 (p = 0.141). The average CFU after irrigation in all groups was significantly greater than 0. Within the limitations of this study, all activation techniques were superior to NaOCl 5.25% in reducing E. faecalis from the infected tooth model.


What to Do If N Is Two?
The field of in vivo neurophysiology currently uses statistical standards that are based on tradition rather than formal analysis. Typically, data from two (or few) animals are pooled for one statistical test, or a significant test in a first animal is replicated in one (or few) further animals. The use of more than one animal is widely believed to allow an inference on the population. Here, we explain that a useful inference on the population would require larger numbers and a different statistical approach. The field should consider to perform studies at that standard, potentially through coordinated multicenter efforts, for selected questions of exceptional importance. Yet, for many questions, this is ethically and/or economically not justifiable. We explain why in those studies with two (or few) animals, any useful inference is limited to the sample of investigated animals, irrespective of whether it is based on few animals, two animals, or a single animal.


Insulin-regulated aminopeptidase deficiency provides protection against ischemic stroke in mice.
Recent studies have demonstrated that angiotensin IV (Ang IV) provides protection against brain injury caused by cerebral ischemia. Ang IV is a potent inhibitor of insulin-regulated aminopeptidase (IRAP). Therefore, we examined the effect of IRAP gene inactivation on neuroprotection following transient middle cerebral artery occlusion (MCAo) in mice. IRAP knockout mice and wild-type controls were subjected to 2 h of transient MCAo using the intraluminal filament technique. Twenty-four hours after reperfusion, neurological deficits of the stroke-induced mice were assessed and infarct volumes were measured by TTC staining. The cerebral infarct volume was significantly reduced in the IRAP knockout mice compared to wild-type littermates with corresponding improvement in neurological performance at 24 h post-ischemia. An increase in compensatory cerebral blood flow during MCAo was observed in the IRAP knockout animals with no differences in cerebral vascular anatomy detected. The current study demonstrates that deletion of the IRAP gene protects the brain from ischemic damage analogous to the effect of the IRAP inhibitor, Ang IV. This study indicates that IRAP is potentially a new therapeutic target for the development of treatment for ischemic stroke.


In vivo X-ray cine-tomography for tracking morphological dynamics.
Scientific cinematography using ultrafast optical imaging is a common tool to study motion. In opaque organisms or structures, X-ray radiography captures sequences of 2D projections to visualize morphological dynamics, but for many applications full four-dimensional (4D) spatiotemporal information is highly desirable. We introduce in vivo X-ray cine-tomography as a 4D imaging technique developed to study real-time dynamics in small living organisms with micrometer spatial resolution and subsecond time resolution. The method enables insights into the physiology of small animals by tracking the 4D morphological dynamics of minute anatomical features as demonstrated in this work by the analysis of fast-moving screw-and-nut-type weevil hip joints. The presented method can be applied to a broad range of biological specimens and biotechnological processes.


Perinatal mortality rate in the Netherlands compared to other European countries: a secondary analysis of Euro-PERISTAT data.
the poor perinatal mortality ranking of the Netherlands compared to other European countries has led to questioning the safety of primary care births, particularly those at home. Primary care births are only planned at term. We therefore examined to which extent the perinatal mortality rate at term in the Netherlands contributes to its poor ranking. secondary analyses using published data from the Euro-PERISTAT study. women that gave birth in 2004 in the 29 European regions and countries called 'countries' included in the Euro-PERISTAT study (4,328,441 women in total and 1,940,977 women at term). odds ratios and 95% confidence intervals were calculated for the comparison of perinatal mortality rates between European countries and the Netherlands, through logistic regression analyses using summary country data. combined perinatal mortality rates overall and at term. Perinatal deaths below 28 weeks, between 28 and 37 weeks and from 37 weeks onwards per 1000 total births. compared to the Netherlands, perinatal mortality rates at term were significantly higher for Denmark and Latvia and not significantly different compared to seven other countries. Eleven countries had a significantly lower rate, and for eight the term perinatal mortality rate could not be compared. The Netherlands had the highest number of perinatal deaths before 28 weeks per 1000 total births (4.3). the relatively high perinatal mortality rate in the Netherlands is driven more by extremely preterm births than births at term. Although the PERISTAT data cannot be used to show that the Dutch maternity care system is safe, neither should they be used to argue that the system is unsafe. The PERISTAT data alone do not support changes to the Dutch maternity care system that reduce the possibility for women to choose a home birth while benefits of these changes are uncertain.


Gastric mucosal secretion of interleukin-10: relations to histopathology, Helicobacter pylori status, and tumour necrosis factor-alpha secretion.
Interleukin-10 (IL-10) is an 18 kDa peptide with a range of anti-inflammatory and immunosuppressive properties. To determine whether this cytokine is involved in gastric mucosal inflammation in Helicobacter pylori infection. The production of IL-10 by antral mucosal biopsy specimens during short term in vitro culture was determined by measuring IL-10 content of supernatants by enzyme linked immunosorbent assay (ELISA). H pylori status was determined by serology and histology, with gastritis scored using the Sydney system. Tumour necrosis factor-alpha (TNF-alpha) content of supernatants was also determined in a subgroup of patients. IL-10 secretion was significantly greater in patients with H pylori associated chronic gastritis than in patients who were H pylori negative with normal mucosa/reactive changes, and those with H pylori negative chronic gastritis (p < 0.01 and < 0.05 respectively). There was a significant correlation overall between IL-10 secretion and chronic inflammation score (r = 0.40). Secretion of TNF-alpha, which was significantly higher in H pylori infected patients than uninfected patients with a normal mucosa (p < 0.04), correlated with scores for chronic inflammation and activity (r = 0.39 and 0.38 respectively), but was only weakly correlated with IL-10 secretion (r = 0.22, NS). Gastric mucosal production of IL-10 and TNF-alpha are increased in chronic gastritis associated with H pylori infection, and mucosal cytokine secretion varies with important histopathological aspects of gastric inflammation. Whereas the secretion of IL-10 in H pylori infection may be protective, limiting tissue damage caused by inflammation, it may also contribute towards failure of the immune response to eliminate the organism.


[Hepatic veno-occlusive disease associated with ingestion of Senecio tephrosioides].
A case of hepatic veno-occlusive disease (HVOD) in a 38 year-old woman is reported. She had occasionally consumed "Huamanrripa" (Senecio tephrosioides) as a cough remedy for many years. She was hospitalized because she had presented abdominal pain, jaundice and anasarca during 10 weeks. The histological studies of hepatic biopsy showed pronounced congestion to centrilobulillar predominance, focus of necrosis and a reversed lobulation pattern in some areas. In the next 13 months she was hospitalized four times due to complications of portal hypertension. This is the first reported case of HVOD associated with S tephrosioides ingestion. It is very probable that this plant used in peruvian traditional medicine contains pyrrolizidine alkaloids, hepatic and nephrotoxic substances that are present in other species of Senecio genus. Due to present popularity of alternative medicine, an increment in HVOD incidence is expected.


Neuroeconomics and aging: neuromodulation of economic decision making in old age.
Economic decision making is a complex process of integrating and comparing various aspects of economically relevant choice options. Neuroeconomics has made important progress in grounding these aspects of decision making in neural systems and the neurotransmitters therein. The dopaminergic and serotoninergic brain systems have been identified as key neurotransmitter systems involved in economic behavior. Both are known to be prone to significant changes during the adult lifespan. Similarly, economic behavior undergoes significant age-related changes over the course of the adult lifespan. Here we propose a triadic relationship between (a) economic decision making, (b) dopaminergic and serotonergic neuromodulation, and (c) aging. In this review, we describe the different relationships around this triad in detail and summarize current evidence that supports them. Based on the reviewed evidence, we propose new research agendas that take the entire triad into account.


Evolution of reproductive mode variation and host associations in a sexual-asexual complex of aphid parasitoids.
The Lysiphlebus fabarum group is a taxonomically poorly resolved complex of aphid parasitoids, presently split into three described species that comprise sexual (arrhenotokous) and asexual (thelytokous) lineages of unknown relationship. Specifically, it is unclear how asexuals evolved from sexuals in this system, to what extent reproductive modes are still connected by genetic exchange, how much the complex is structured by geography or by host-associated differentiation, and whether species designations are valid. Using a combination of population genetic and phylogenetic approaches, we addressed these issues in a comprehensive sample of parasitoid wasps from across Europe. Asexual reproduction predominated in parasitoids of the L. fabarum group, with asexual populations exhibiting high genotypic diversity. Sexual populations were only common in southern France; elsewhere sexual reproduction was restricted to specific aphid hosts. Although reproductive modes were aggregated on the mitochondrial genealogy and significantly differentiated at nuclear microsatellite loci, there was clear evidence for genetic exchange, especially on hosts attacked by sexual and asexual parasitoids. The microsatellite data further revealed that parasitoids collected from certain host aphids were significantly differentiated, yet the mitochondrial sequence variation across the entire L. fabarum group did not exceed 1.32% and exhibited a very shallow topology. Morphological characters used for delineation of described species were found to be phylogenetically non-conservative. Our results suggest that the sexual-asexual L. fabarum group represents a young complex of lineages with incomplete isolation between reproductive modes. We propose three mechanisms of genetic exchange that may jointly explain the high genotypic diversity observed in asexual parasitoids: (i) the formation of new asexual lineages via 'contagious parthenogenesis', (ii) introgression from sexual lineages through matings between sexual males and thelytokous females, and (iii) 'cryptic sex' within asexuals, mediated by rare males that thelytokous lines are known to produce spontaneously. The partially strong differentiation among wasps collected from different aphids suggests that host specialization can evolve readily in these parasitoids. Finally, we conclude that in the light of our data, the current taxonomic division of the L. fabarum group into three species cannot be upheld.


Membrane-coating granules and the intercellular cementing substance (membrane-coating material) in the epidermis in different regions of the equine hoof.
This study aimed to carry out a comprehensive morphological examination of the structure and ultrastructure of the membrane-coating granules (MCG) and membrane-coating material (MCM) common to all hoof segments as well as segment-specific features in the MCG and MCM regarding their synthesis, structure and biochemical composition. Tissue samples from the hooves of the left front and right hind limb of 20 adult riding horses were used. Samples were preserved and embedded for histological routine methods as well as for histochemical techniques and tracer techniques for light and electron microscopy. The MCM shows a segment-specific structure, biochemical composition and function, which were demonstrated for the different parts of the hoof. The MCM and its properties are related to the segment-specific horn quality. Besides intercellular structural factors the MCM is of major importance for the structural integrity and the biomechanical properties of the hoof horn. The physiological structure and composition of MCM provides explanation for the existence of clinically well-known sites of predilection for hoof disorders such as the White Line Disease. Alterations of the MCM play a role in dysfunction and diseases of the hoof epidermis; they are particularly involved in the pathogenesis of infectious diseases of the hoof.


Divergent regulation of the evolutionarily closely related promoters of the Saccharomyces cerevisiae STA2 and MUC1 genes.
The 5' upstream regions of the Saccharomyces cerevisiae glucoamylase-encoding genes STA1 to -3 and of the MUC1 (or FLO11) gene, which is critical for pseudohyphal development, invasive growth, and flocculation, are almost identical, and the genes are coregulated to a large extent. Besides representing the largest yeast promoters identified to date, these regions are of particular interest from both a functional and an evolutionary point of view. Transcription of the genes indeed seems to be dependent on numerous transcription factors which integrate the information of a complex network of signaling pathways, while the very limited sequence differences between them should allow the study of promoter evolution on a molecular level. To investigate the transcriptional regulation, we compared the transcription levels conferred by the STA2 and MUC1 promoters under various growth conditions. Our data show that transcription of both genes responded similarly to most environmental signals but also indicated significant divergence in some aspects. We identified distinct areas within the promoters that show specific responses to the activating effect of Flo8p, Msn1p (or Mss10p, Fup1p, or Phd2p), and Mss11p as well as to carbon catabolite repression. We also identified the STA10 repressive effect as the absence of Flo8p, a transcriptional activator of flocculation genes in S. cerevisiae.


Sigje, a member of the small inducible gene family that includes platelet factor 4 and melanoma growth stimulatory activity, is on mouse chromosome 11.
Stiles and coworkers originally identified a gene they termed JE that is transcriptionally activated in mouse fibroblasts early after treatment with platelet derived growth factor or serum. This gene, now named Sigje, can encode a 148-amino acid secreted, basic polypeptide that belongs to the small inducible gene (SIG) family whose members include, for example, platelet factor 4, melanoma growth stimulatory activity (Mgsa), and interferon inducible protein 10. SIG family members share a conserved array of cysteine and proline residues and a similar predicted secondary structure, and may have evolved from a common ancestral gene. Several members of the SIG family have been assigned to the proximal long arm of human chromosome 4, to a region that has genetic homoeology with a portion of mouse Chromosome 5. We report here that mouse Sigje, in contrast to Mgsa, is on Chromosome 11. Sigje restriction fragment length polymorphisms in Mus spretus DNA were identified with the enzymes TaqI, MspI, BclI, and XbaI, and will be useful in mapping by meiotic recombination.


In vivo probe of central cholinergic systems.
Age-related cognitive impairments and dementia of Alzheimer type have been linked to alterations in the cholinergic system. In the present study, evoked potentials and neuropsychological testing were obtained in healthy subjects during neuropharmacological manipulations including: scopolamine (anticholinergic), scopolamine plus physostigmine (anticholinesterase), scopolamine plus methylphenidate (adrenergic), and placebo. Scopolamine prolonged P3 latency and reduced spectral power of long latency evoked potentials without significantly altering earlier components. Physostigmine partially reversed these effects, but methylphenidate did not. Motor speed was slowed by scopolamine, but not by scopolamine plus methylphenidate. Cholinergic systems appear to be involved in generation or modulation of the P3 potential, possibly secondary to the cholinergic role in selective attention. Similar techniques may be useful as in vivo probes of central cholinergic function and thus as research and diagnostic aids in aging and disease.


Staphylococcal enterotoxin D functions as a human B cell superantigen by rescuing VH4-expressing B cells from apoptosis.
Staphylococcal enterotoxins are potent superantigens, in that they activate T cells bearing specific V beta-chain gene segments. In this study, we analyzed the capacity of staphylococcal enterotoxin D (SED) to function as a B cell superantigen. SED induced T cell-dependent polyclonal proliferation and differentiation of B cells. In the absence of T cells, SED induced survival of B cells uniquely expressing VH4 containing IgM. The mechanism of survival of VH4-expressing B cells appeared to relate to the countering of apoptosis initiated by the engagement of HLA-DR by SED. Analysis of the VH4 gene products expressed by SED-stimulated B cells revealed the usage of six of the known functional VH4 genes with a variety of different CDR3 regions, employing different DH and JH gene segments. Moreover, the sequence analysis identified a possible site for SED binding of VH4 that includes the solvent-exposed surfaces of 3' CDR2/FR3 and/or FR1. Thus, SED appears to function as a unique B cell superantigen by inducing survival of VH4-expressing B cells.


Composition of riparian litter input regulates organic matter decomposition: Implications for headwater stream functioning in a managed forest landscape.
Although the importance of stream condition for leaf litter decomposition has been extensively studied, little is known about how processing rates change in response to altered riparian vegetation community composition. We investigated patterns of plant litter input and decomposition across 20 boreal headwater streams that varied in proportions of riparian deciduous and coniferous trees. We measured a suite of in-stream physical and chemical characteristics, as well as the amount and type of litter inputs from riparian vegetation, and related these to decomposition rates of native (alder, birch, and spruce) and introduced (lodgepole pine) litter species incubated in coarse- and fine-mesh bags. Total litter inputs ranged more than fivefold among sites and increased with the proportion of deciduous vegetation in the riparian zone. In line with differences in initial litter quality, mean decomposition rate was highest for alder, followed by birch, spruce, and lodgepole pine (12, 55, and 68% lower rates, respectively). Further, these rates were greater in coarse-mesh bags that allow colonization by macroinvertebrates. Variance in decomposition rate among sites for different species was best explained by different sets of environmental conditions, but litter-input composition (i.e., quality) was overall highly important. On average, native litter decomposed faster in sites with higher-quality litter input and (with the exception of spruce) higher concentrations of dissolved nutrients and open canopies. By contrast, lodgepole pine decomposed more rapidly in sites receiving lower-quality litter inputs. Birch litter decomposition rate in coarse-mesh bags was best predicted by the same environmental variables as in fine-mesh bags, with additional positive influences of macroinvertebrate species richness. Hence, to facilitate energy turnover in boreal headwaters, forest management with focus on conifer production should aim at increasing the presence of native deciduous trees along streams, as they promote conditions that favor higher decomposition rates of terrestrial plant litter.


Preventing α-synuclein aggregation: the role of the small heat-shock molecular chaperone proteins.
Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. The failure of proteostasis can result in the accumulation of non-native proteins leading to their aggregation and deposition in cells and in tissues. The amyloid fibrillar aggregation of the protein α-synuclein into Lewy bodies and Lewy neuritis is associated with neurodegenerative diseases classified as α-synucleinopathies, which include Parkinson's disease and dementia with Lewy bodies. The small heat-shock proteins (sHsps) are molecular chaperones that are one of the cell's first lines of defence against protein aggregation. They act to stabilise partially folded protein intermediates, in an ATP-independent manner, to maintain cellular proteostasis under stress conditions. Thus, the sHsps appear ideally suited to protect against α-synuclein aggregation, yet these fail to do so in the context of the α-synucleinopathies. This review discusses how sHsps interact with α-synuclein to prevent its aggregation and, in doing so, highlights the multi-faceted nature of the mechanisms used by sHsps to prevent the fibrillar aggregation of proteins. It also examines what factors may contribute to α-synuclein escaping the sHsp chaperones in the context of the α-synucleinopathies.


Food Sources of Shortfall Nutrients among Latin Americans: Results from the Latin American Study of Health and Nutrition (ELANS).
Increased consumption of energy-dense, nutrient-poor foods can lead to inadequate intakes of shortfall nutrients, including vitamin A, D, C, and E, dietary folate, calcium, iron, magnesium, potassium, and fiber. The objective was to examine the prevalence of inadequate intake of shortfall nutrients and identify food sources of shortfall nutrients in eight Latin American countries. Data from ELANS, a multi-country, population-based study of 9218 adolescents and adults were used. Dietary intake was collected through two 24 h Recalls from participants living in urban areas of Argentina, Brazil, Chile, Colombia, Ecuador, Peru, and Venezuela. Foods and beverages were classified using the adapted version of the NHANES "What We Eat in America" system. Nutrients inadequacy was estimated using the Institute of Medicine recommendations and descriptive statistics were calculated. Prevalence of inadequacy was above 50% for most of the nutrients, which the exception of vitamin C with a prevalence of inadequacy of 39%. Milk, cheese, seafoods, breads, and fruit juices/drinks were among the top 5 sources for each of the 10 shortfall nutrients examined. Many food categories were top contributors to more than one dietary component examined. Understanding the nutrient intake and food sources can help inform dietary guidance and intervention approaches.


Clopidogrel use and hospital quality in medically managed patients with non-ST-segment-elevation myocardial infarction.
Clopidogrel prescription is a class I guideline recommendation for medically managed patients with non-ST-segment-elevation myocardial infarction (NSTEMI). However, clopidogrel has historically been underused in this population. We evaluated contemporary rates of its use and evaluated associated factors, with a particular focus on hospital quality of myocardial infarction (MI) care. We examined clopidogrel prescription rates among 23 186 patients with NSTEMI discharged from 382 US hospitals between October 2009 and March 2011. Associations between clopidogrel prescription and various patient and hospital factors, including hospital quality of MI care, were determined with regression modeling. Of the sample, 54.9% of eligible patients with NSTEMI received clopidogrel prescription at hospital discharge. Variation in rate by hospital was large, ranging from 22% to 97%. A variety of patient and hospital factors were associated with clopidogrel prescription. Hospital quality of MI care demonstrated modest association with clopidogrel prescription (odds ratio, 0.68; 95% CI, 0.54-0.85) between the lowest and highest hospital quality quartile) and accounted for 5.7% of the variation in prescription rates. Clopidogrel prescription is significantly underused in the medically managed NSTEMI population and demonstrates wide variability by hospital. Although hospital quality of MI care is associated with its use, the findings suggest that it only has a modest effect. Therefore, efforts to improve clopidogrel use likely will require measures beyond improving the overall hospital quality of MI care.


Dynamics of Tissue-Induced Alignment of Fibrous Extracellular Matrix.
Aligned fibers of extracellular matrix (ECM) affect the direction, efficiency, and persistence of migrating cells. To uncover the mechanisms by which multicellular tissues align their surrounding ECM before migration, we used an engineered three-dimensional culture model to investigate the dynamics of ECM alignment around tissues of defined geometry. Analysis of ECM alignment over time revealed that tissues rapidly reorganize their surrounding matrix, with a characteristic time that depends on the type of cell and the initial tissue geometry. We found that matrix metalloproteinase activity is not required for matrix alignment before cell migration. Instead, alignment is driven by Rho-mediated cytoskeletal contractility and accelerated by propagation of tension through intercellular adhesions. Our data suggest that multicellular tissues align their surrounding matrix by pulling collectively to exert strain, which is primarily a physical process. Consistently, the pattern of matrix alignment depends on tissue geometry and the resulting distribution of mechanical strain, with asymmetric tissues generating a higher degree of matrix alignment along their longest axes. The rapid ability of multicellular tissues to physically remodel their matrix enables their constituent cells to migrate efficiently along aligned fibers and to quickly change their direction according to other microenvironmental cues, which is important for both normal and disease processes.


Longterm follow-up in European respiratory health studies - patterns and implications.
Selection bias is a systematic error in epidemiologic studies that may seriously distort true measures of associations between exposure and disease. Observational studies are highly susceptible to selection bias, and researchers should therefore always examine to what extent selection bias may be present in their material and what characterizes the bias in their material. In the present study we examined long-term participation and consequences of loss to follow-up in the studies Respiratory Health in Northern Europe (RHINE), Italian centers of European Community Respiratory Health Survey (I-ECRHS), and the Italian Study on Asthma in Young Adults (ISAYA). Logistic regression identified predictors for follow-up participation. Baseline prevalence of 9 respiratory symptoms (asthma attack, asthma medication, combined variable with asthma attack and/or asthma medication, wheeze, rhinitis, wheeze with dyspnea, wheeze without cold, waking with chest tightness, waking with dyspnea) and 9 exposure-outcome associations (predictors sex, age and smoking; outcomes wheeze, asthma and rhinitis) were compared between all baseline participants and long-term participants. Bias was measured as ratios of relative frequencies and ratios of odds ratios (ROR). Follow-up response rates after 10 years were 75% in RHINE, 64% in I-ECRHS and 53% in ISAYA. After 20 years of follow-up, response was 53% in RHINE and 49% in I-ECRHS. Female sex predicted long-term participation (in RHINE OR (95% CI) 1.30(1.22, 1.38); in I-ECRHS 1.29 (1.11, 1.50); and in ISAYA 1.42 (1.25, 1.61)), as did increasing age. Baseline prevalence of respiratory symptoms were lower among long-term participants (relative deviations compared to total baseline population 0-15% (RHINE), 0-48% (I-ECRHS), 3-20% (ISAYA)), except rhinitis which had a slightly higher prevalence. Most exposure-outcome associations did not differ between long-term participants and all baseline participants, except lower OR for rhinitis among ISAYA long-term participating smokers (relative deviation 17% (smokers) and 44% (10-20 pack years)). We found comparable patterns of long-term participation and loss to follow-up in RHINE, I-ECRHS and ISAYA. Baseline prevalence estimates for long-term participants were slightly lower than for the total baseline population, while exposure-outcome associations were mainly unchanged by loss to follow-up.


Mycobacteriophage L5 integrase-mediated site-specific integration in vitro.
Mycobacteriophage L5, a temperate phage of the mycobacteria, forms stable lysogens in Mycobacterium smegmatis via site-specific integration of the phage genome. Recombination occurs within specific phage and bacterial attachment sites and is catalyzed by the phage-encoded integrase protein in vivo. We describe here the overexpression and purification of L5 integrase and its ability to mediate integrative recombination in vitro. We find that L5 integrase-mediated recombination is greatly stimulated by extracts of M. smegmatis but not by Escherichia coli extracts, purified E. coli integration host factor, or purified HU, indicating the presence of a novel mycobacterial integration host factor.


Displaced Distal Radius Fracture Treatment: A Survey of POSNA Membership.
Distal radius fractures (DRFs) are the most common pediatric orthopaedic fracture, of which 20% are displaced injuries. Displaced metaphyseal DRFs are often treated with sedated or anesthetized reduction. The necessity of reduction treatment of displaced fractures to achieve good clinical outcomes is unclear. The purpose of this investigation was to determine the treatment preferences for DRFs among pediatric orthopaedic surgeons and to determine whether they were uncertain enough in their decisions to randomize treatment. Twenty-eight DRF scenarios in children aged 3 to 10 years were constructed in an electronic survey to represent a spectrum of age, angulation in sagittal and coronal planes, and displacement. The survey was disseminated to the full membership of the Pediatric Orthopaedic Society of North America (POSNA). Respondents could select either a treatment of (a) attempt anatomic reduction with sedation or (b) nonsedated immobilization. Respondents also denoted whether they would be willing to randomize the treatment of each injury scenario. Patient, fracture, and surgeon characteristics were analyzed to develop predictors of treatment recommendations and willingness to randomize treatment. A total of 319 surgeons responded (23% of POSNA membership). Respondents were a characteristic representation of POSNA membership (well distributed by years in practice, 78% academic, 91% whose work is >80% pediatrics, and 84% work with residents). Predictors of sedated reduction were complete displacement [odds ratio (OR), 9.23; 95% confidence interval (CI), 2.27-37.51; P=0.002] and coronal angulation (per 1-degree increase, OR, 1.09; 95% CI, 1.02-1.17; P=0.016), Willingness to randomize was inversely related to larger coronal plane angulation (per 1-degree increase, OR, 0.96; 95% CI, 0.93-0.99; P=0.01). A majority of surgeons were willing to randomize 7 of the 8 scenarios involving complete displacement and shortening, and >64% of surgeons were willing to randomize 5 of these 8 scenarios. POSNA members recommend sedated reduction of DRFs primarily based on existence of complete displacement. Although most completely displaced DRFs would undergo reduction, most surgeons would be willing to randomize the treatment of these injuries. This suggests that most POSNA members do not know whether their recommended treatment for displaced DRFs is necessary or correct. This survey establishes the groundwork for a randomized, prospective trial comparing nonsedated immobilization with sedated/anesthetized reduction in the treatment of displaced pediatric DRFs. Level II-survey study.


Phylogeny and taxonomy of powdery mildew on Viburnum species.
The phylogeny and taxonomy of powdery mildew on Viburnum species is evaluated and discussed. Morphological and phylogenetic analyses revealed two new species and demonstrated that Erysiphe hedwigii and E. viburni should be reduced to synonymy and are referred to herein as E. viburni. The two new species, E. viburniphila and E. pseudoviburni, previously hidden under E. viburni (including E. hedwigii), is described on the basis of European, North American, and East Asian powdery mildew collections on Viburnum edule, V. tinus, V. odoratissimum var. awabuki, and V. sieboldii. The sexual morph of E. viburniphila is similar to that of E. viburni; however, morphological differences exist in their asexual morphs. Analyses of sequences from the internal transcribed spacer (ITS) and 28S genomic regions of Erysiphe species obtained on Viburnum species (and other closely allied Eryisphe species) throughout the world reveled that E. viburniphila and E. pseudoviburni are in two different monophyletic groups that are separate from all other Erysiphe species. Erysiphe hedwigii and E. viburni on Viburnum species have often been recognized as separate species based on morphological differences in the size of their chasmothecia and the number of chasmothecial appendages. Taxonomic conclusions based on these morphological distinctions within these species are unreliable (these characters are rather variable and often have overlapping ranges). The present phylogenetic analyses suggest that E. hedwigii has to be reduced to synonymy with E. viburni. To fix the application of the species names E. hedwigii and E. viburni, epitypes have been designated for these taxa with ex-epitype sequences. Additionally, the Asian species E. miranda is phylogenetically confirmed as a species of its own, described in detail and discussed.


Physical Functioning Trends among US Women and Men Age 45-64 by Education Level.
Functional limitations and disability declined in the US during the 1980s and 1990s, but reports of early 21st century trends are mixed. Whether educational inequalities in functioning increased or decreased is also poorly understood. Given the importance of disability for productivity, independent living, and health care costs, these trends are critical to US social and health policies. We examine recent trends in functional limitations and disability among women and men aged 45-64. Using 2000-2015 National Health Interview Surveys data on over 155,000 respondents, semiparametric and logistic regression models visualize and test functioning trends by education. Among women and men with at least a college degree, there was no change in disability and mild increase in limitations over time. All other education levels experienced significant increases in functioning problems ranging from 18% higher odds of functional limitations in 2015 compared to 2000 among men with some college to about 80% increase in the odds of disability among women and men with less than high school education. The similar trends for both genders suggest common underlying causes, possibly including the worsening economic well-being of middle- and working-class families. The pervasive growth of functioning problems is a cause for concern that necessitates further scholarly investigation.


Optimizing Patient Management and Adherence for Children Receiving Growth Hormone.
Poor adherence with growth hormone (GH) therapy has been associated with worse clinical outcomes, which in children relates specifically to their linear growth and loss of quality of life. The "360° GH in Europe" meeting, held in Lisbon, Portugal, in June 2016 and funded by Merck KGaA (Germany), examined many aspects of GH diseases. The three sessions, entitled "Short Stature Diagnosis and Referral," "Optimizing Patient Management," and "Managing Transition," each benefited from three guest speaker presentations, followed by an open discussion and are reported as a manuscript, authored by the speakers. Reported here is a summary of the proceedings of the second session, which reviewed the determinants of GH therapy response, factors affecting GH therapy adherence and the development of innovative technologies to improve GH treatment in children. Response to GH therapy varies widely, particularly in regard to the underlying diagnosis, although there is little consensus on the definition of a poor response. If the growth response is seen to be less than expected, the possible reasons should be discussed with patients and their parents, including compliance with the therapy regimen. Understanding and addressing the multiple factors that influence adherence, in order to optimize GH therapy, requires a multi-disciplinary approach. Because therapy continues over many years, various healthcare professionals will be involved at different periods of the patient's journey. The role of the injection device for GH therapy, frequent monitoring of response, and patient support are all important for maintaining adherence. New injection devices are incorporating electronic technologies for automated monitoring and recording of clinically relevant information on injections. Study results are indicating that such devices can at least maintain GH adherence; however, acceptance of novel devices needs to be assessed and there remains an on-going need for innovations.


Microscale diffusion properties of the cartilage pericellular matrix measured using 3D scanning microphotolysis.
Chondrocytes, the cells in articular cartilage, are enclosed within a pericellular matrix (PCM) whose composition and structure differ from those of the extracellular matrix (ECM). Since the PCM surrounds each cell, molecules that interact with the chondrocyte must pass through the pericellular environment. A quantitative understanding of the diffusional properties of the PCM may help in elucidating the regulatory role of the PCM in controlling transport to and from the chondrocyte. The diffusivities of fluorescently labeled 70 kDa and 500 kDa dextrans were quantified within the PCM of porcine articular cartilage using a newly developed mathematical model of scanning microphotolysis (SCAMP). SCAMP is a rapid line photobleaching method that accounts for out-of-plane bleaching attributable to high magnification. Data were analyzed by a best-fit comparison to simulations generated using a discretization of the diffusion-reaction equation in conjunction with the microscope-specific three-dimensional excitation and detection profiles. The diffusivity of the larger molecule (500 kDa dextran) was significantly lower than that of the smaller molecule (70 kDa dextran), and values were consistent with those reported previously using standard techniques. Furthermore, for both dextran sizes, the diffusion coefficient was significantly lower in the PCM than in the ECM; however, this difference was not detected in early-stage arthritic tissue. We have successfully modified the SCAMP technique to measure diffusion coefficients within the small volume of the PCM using confocal laser scanning microscopy. Our results support the hypothesis that diffusivity within the PCM of healthy articular cartilage is lower than that within the ECM, presumably due to differences in proteoglycan content.


St. Jude Cancer Education for Children Program: The Impact of a Teacher-Led Intervention on Student Knowledge Gains.
In 2006, St. Jude Children's Research Hospital (Memphis, Tennessee) began developing a school-based outreach program known as the St. Jude Cancer Education for Children Program (SJCECP). The aim of this program is to teach Memphis-area children about cells, cancer, and healthy habits that can prevent the development of cancer in adulthood. Initial plans for delivery of the program was for St. Jude staff to present the program at local schools. This plan for disseminating instruction was not feasible due to the limited availability of St. Jude staff. As a next step, during the 2012-2014 academic years, we conducted a study entitled SJCECP2, utilizing the SJCECP curriculum, with the objective of evaluating the impact of the educational intervention on knowledge acquisition and retention among fourth-grade students participating in a modified, teacher-led version of the program. Eighteen teachers and 426 students from 10 local schools in the greater Memphis area participated in the program evaluation. This study used a single-group, pre-test/post-test design to determine the impact of the SJCECP intervention on changes in knowledge scores among fourth-grade students. Testing was on cells, cancer, and healthy living. The mean scores increased from 6.45 to 8.12, 5.99 to 7.65, and 5.92 to 7.96 on cell, cancer, and health behaviors units, respectively (all p values <.001). Preliminary evidence suggests that the SJCECP2 intervention is a useful tool for teachers to improve student knowledge of knowledge of cells, cancer, and healthy living concepts at the fourth-grade level.


An assessment of health risks associated with arsenic exposure via consumption of homegrown vegetables near contaminated glassworks sites.
The health risk posed by arsenic in vegetables grown in private gardens near 22 contaminated glassworks sites was investigated in this study. Firstly, vegetable (lettuce and potato) and soil samples were collected and arsenic concentrations measured to characterize the arsenic uptake in the selected crops. Secondly, a probabilistic exposure assessment was conducted to estimate the average daily intake (ADIveg), which was then evaluated against toxicological reference values by the calculation of hazard quotients (HQs) and cancer risks (CRs). The results show that elevated arsenic concentrations in residential garden soils are mirrored by elevated concentrations in vegetables, and that consumption of these vegetables alone may result in an unacceptable cancer risk; the calculated reasonable maximum exposure, for example, corresponded to a cancer incidence 20 times higher than the stated tolerance limit. However, the characterization of risk depends to a great extent on which toxicological reference value is used for comparison, as well as how the exposure is determined. Based on the assumptions made in the present study, the threshold levels for chronic non-carcinogenic or acute effects were not exceeded, but the cancer risks indicated highlight the need for further exposure studies, as dietary intake involves more than just homegrown vegetables and total exposure is a function of more than just one exposure pathway. In addition, glassworks sites--and contaminated sites in general--contain multiple contaminants, affecting the final and total risk.


Suboccipital lateral injection of intrathecal chemotherapy in a patient with mantle cell lymphoma.
Even today patients who suffer from mantle cell lymphoma have a poor prognosis, especially when the CNS is involved. To confirm the diagnosis of meningeosis lymphomatosa, asservation of the liquor cerebrospinalis is necessary. During this procedure, intrathecal chemotherapy may be given if there is clinical evidence of meningeosis. If lumbar puncture cannot be performed, a lateral suboccipital puncture may be an alternative approach. We report the case of a 65-year-old patient who suffered from mantle cell lymphoma stage IV. The patient presented with symptoms of progressive paraparesis of both legs and incontinence, with tumor mass intradural from the 12th thoracic vertebra to the level of S1. During irradiation, the patient developed symptoms of diffuse meningiosis lymphomatosa. The conventional lumbar puncture was impossible, because of tumor present in the thoracico-lumbar junction. A suboccipital puncture was performed for both collecting cerebrospinal fluid and application of chemotherapy (cytosine arabinoside/dexamethasone). This lead to remarkable improvement of the patient's clinical symptoms. The suboccipital cervical puncture was performed without complications. A variation of the intrathecal approach is described, which may serve as alternative when conventional lumbar puncture is not possible.


Brain angiotensin converting enzyme-2 in central cardiovascular regulation.
The brain renin-angiotensin system (RAS) plays an important role in the regulation of autonomic and neuroendocrine functions, and maintains cardiovascular homeostasis. Ang-II is the major effector molecule of RAS and exerts most of its physiological functions, including blood pressure (BP) regulation, via activation of AT1 receptors. Dysregulation of brain RAS in the central nervous system results in increased Ang-II synthesis that leads to sympathetic outflow and hypertension. Brain angiotensin (Ang) converting enzyme-2 (ACE2) was discovered two decades ago as an RAS component, exhibiting a counter-regulatory role and opposing the adverse cardiovascular effects produced by Ang-II. Studies using synthetic compounds that can sustain the elevation of ACE2 activity or genetically overexpressed ACE2 in specific brain regions found various beneficial effects on cardiovascular function. More recently, ACE2 has been shown to play critical roles in neuro-inflammation, gut dysbiosis and the regulation of stress and anxiety-like behaviors. In the present review, we aim to highlight the anatomical locations and functional implication of brain ACE2 related to its BP regulation via modulation of the sympathetic nervous system and discuss the recent developments and future directions in the ACE2-mediated central cardiovascular regulation.


Wuchereria bancrofti and Cytology: A Retrospective Analysis of 110 Cases from an Endemic Area.
Wuchereriasis is a significant cause of chronic morbidity. It can affect any organ/tissue in the body. Fine-needle aspiration cytology (FNAC) is an easy method for its detection. A comprehensive analysis of the various facets involved has not been discussed in detail in any publication. A twenty-six year (February 1994 to January 2020) retrospective audit of all patients who were cytologically diagnosed with wuchereriasis was performed. Data regarding age, sex, organ/tissue involved, and presence of co-existing disease were noted. Hematoxylin and eosin (H and E) and May-Grünwald-Giemsa (MGG) stained slides were screened for microfilaria, adult worm, larval forms, microfilaria ghosts, epithelioid cell granuloma, and eosinophils. Audit yielded 19,323 cases of which 110 had wuchereriasis giving an incidence of 0.57%. The 11-30 year age group accounted for 41.8% cases. Male: female ratio was 1.04:1. Duration of disease at presentation ranged from 3 days to 24 years. Lymph node was the commonest site involved (40%), followed by soft tissue (23.6%) and female breast (14.5%). Highest parasitic load was encountered in female breast aspirates. Microfilaria bancrofti was seen in 105 (95.4%) cases. In the five cases where microfilaria bancrofti was not encountered, diagnosis was established by the presence of adult gravid female worm (2 cases), coiled larvae (2 cases), and both adult gravid female worm and coiled larvae (1 case). Microfilaria ghosts were seen in 18.2% cases. Coexisting benign and malignant diseases were encountered in 17.3% and 13.6% cases, respectively. FNAC provides a simple and inexpensive means of detecting wuchereriasis and is preferred over histopathology. All stages of development of this nematode in human beings are identified in cytology. Microfilaria ghost is a useful clue in screening. The presence of granuloma and eosinophilic infiltrate indicates tissue reaction only. Patients with asymptomatic microfilaraemia should be reported in cytology as they merit treatment.


1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age.
1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteoporotic fractures. 1,25D/VDR signaling exerts feedback control of Ca/PO4 via regulation of FGF23, klotho, and CYP24A1 to prevent age-related, ectopic calcification, fibrosis, and associated pathologies. Vitamin D also elicits xenobiotic detoxification, oxidative stress reduction, neuroprotective functions, antimicrobial defense, immunoregulation, anti-inflammatory/anticancer actions, and cardiovascular benefits. Many of the healthspan advantages conferred by 1,25D are promulgated by its induction of klotho, a renal hormone that is an anti-aging enzyme/coreceptor that protects against skin atrophy, osteopenia, hyperphosphatemia, endothelial dysfunction, cognitive defects, neurodegenerative disorders, and impaired hearing. In addition to the high-affinity 1,25D hormone, low-affinity nutritional VDR ligands including curcumin, polyunsaturated fatty acids, and anthocyanidins initiate VDR signaling, whereas the longevity principles resveratrol and SIRT1 potentiate VDR signaling. 1,25D exerts actions against neural excitotoxicity and induces serotonin mood elevation to support cognitive function and prosocial behavior. Together, 1,25D and klotho maintain the molecular signaling systems that promote growth (p21), development (Wnt), antioxidation (Nrf2/FOXO), and homeostasis (FGF23) in tissues crucial for normal physiology, while simultaneously guarding against malignancy and degeneration. Therefore, liganded-VDR modulates the expression of a "fountain of youth" array of genes, with the klotho target emerging as a major player in the facilitation of health span by delaying the chronic diseases of aging.


Lactobacillus reuteri 6475 Increases Bone Density in Intact Females Only under an Inflammatory Setting.
We previously demonstrated that short-term oral administration of the probiotic Lactobacillus reuteri 6475 enhanced bone density in male but not female mice. We also established that L. reuteri 6475 enhanced bone health and prevented bone loss in estrogen-deficient female mice. In this study, we tested whether a mild inflammatory state and/or a long-term treatment with the probiotic was required to promote a positive bone effect in estrogen-sufficient female mice. A mild inflammatory state was induced in female mice by dorsal surgical incision (DSI). Following DSI animals were orally supplemented with L. reuteri or vehicle control for a period of 8 weeks. Gene expression was measured in the intestine and bone marrow by qPCR. Distal femoral bone density and architecture was analyzed by micro-CT. We report that 8 weeks after DSI there is a significant increase in the weight of spleen, thymus and visceral (retroperitoneal) fat pads. Expression of intestinal cytokines and tight junction proteins are also altered 8 weeks post-DSI. Interestingly, L. reuteri treatment was found to display both intestinal region- and inflammation-dependent effects. Unexpectedly we identified that 1) L. reuteri treatment increased bone density in females but only in those that underwent DSI and 2) DSI benefited cortical bone parameters. In the bone marrow, dorsal surgery induced CD4+ T cell numbers, a response that was unaffected by L. reuteri treatment, whereas expression of RANKL, OPG and IL-10 were significantly affected by L. reuteri treatment. Our data reveals a previously unappreciated effect of a mild surgical procedure causing a long-lasting effect on inflammatory gene expression in the gut and the bone. Additionally, we demonstrate that in intact female mice, the beneficial effect of L. reuteri on bone requires an elevated inflammatory status.


Improved analyzer multilayers for aluminium and boron detection with x-ray fluorescence.
We have developed improved analyzer multilayers for the detection of aluminium (Al) and boron (B) on silicon (Si) wafers with wavelength-dispersive x-ray fluorescence spectrometers. For the detection of Al on Si wafers we show that WSi(2)/Si and Ta/Si multilayers provide detection limits that are 42% and 60% better, respectively, than with currently used W/Si multilayers. For the detection of B on Si wafers we show that La/B(4)C multilayers improve the detection limit by approximately 28% compared with a conventionally used Mo/B(4)C multilayer.


Clinical and microbiologic characteristics of invasive Streptococcus pyogenes infections in north and south India.
The lack of epidemiologic data on invasive Streptococcus pyogenes infections in many developing countries is concerning, as S. pyogenes infections are commonly endemic in these areas. Here we present the results of the first prospective surveillance study of invasive Streptococcus pyogenes infections in India. Fifty-four patients with invasive S. pyogenes infections were prospectively enrolled at two study sites, one in the north and one in the south of India. Sterile-site isolates were collected, and clinical information was documented using a standardized questionnaire. Available acute-phase sera were tested for their ability to inhibit superantigens produced by the patient's own isolate using a cell-based neutralizing assay. The most common clinical presentations were bacteremia without focus (30%), pneumonia (28%), and cellulitis (17%). Only two cases of streptococcal toxic shock syndrome and no cases of necrotizing fasciitis were identified. Characterization of the isolates revealed great heterogeneity, with 32 different emm subtypes and 29 different superantigen gene profiles being represented among the 49 sterile-site isolates. Analyses of acute-phase sera showed that only 20% of the cases in the north cohort had superantigen-neutralizing activity in their sera, whereas 50% of the cases from the south site had neutralizing activity. The results demonstrate that there are important differences in both clinical presentation and strain characteristics between invasive S. pyogenes infections in India and invasive S. pyogenes infections in Western countries. The findings underscore the importance of epidemiologic studies on streptococcal infections in India and have direct implications for current vaccine developments.


OSTEOTOMIES OF THE CORACOID PROCESS: AN ANATOMICAL STUDY.
Relate the main tendinous and ligamentous structures attached in the coracoid process, correlating it to several levels of osteotomy and describing the involved structures. Thirty shoulders were dissected. The coracoid process with mainly inserted anatomic structures was dissected, and five levels of osteotomy (1.0; 1.5; 2.0; 2.5; 3.0 cm) were made from the apex of the process and the mainly involved structures were recorded. In osteotomies of 1.0 cm, in 100% of the cases only the conjoint tendon (CT). In osteotomies of 1.5 cm there were 63.33% of cases involved with the CT and the Pectoralis minor (PMi), in 20% of cases only the CT, and in 16.66% the CT, PMi, and the coracohumeral ligament (CUL). In osteotomies of 2.0 cm, in 80% of the shoulders, the osteotomies embraced the CT, PMi and the CUL, and in 20% only the CT and the PMi were involved. In the osteotomies of 2.5cm there was involvement of the CT, PMi and CUL in 100% of cases. In the osteotomies of 3.0cm, six cases (20%) have presented an injury on the trapezoid ligament, and in 100% of these osteotomies, the osteotomized distal fragment had embraced the CT, PMi, CUL. The knowledge of anatomic structures inserted and involved in the osteotomies cuts of the coracoid process is very importan to lead with osteotomies performed in the treatment techniques of the coracoid process. Osteotomies of 3.0 cm can injure the trapezoid ligament.


Air-drop blood supply in the French Army.
Haemorrhagic shock remains the leading cause of preventable death in overseas and austere settings. Transfusion of blood components is critical in the management of this kind of injury. For French naval and ground military units, this supply often takes too long considering the short shelf-life of red blood cell concentrates (RBCs) and the limited duration of transport in cooling containers (five to six days). Air-drop supply could be an alternative to overcome these difficulties on the condition that air-drop does not cause damage to blood units. After a period of study and technical development of packaging, four air-drops at medium and high altitudes were performed with an aircraft of the French Air Force. After this, one air-drop was carried out at medium altitude with 10 RBCs and 10 French lyophilised plasma (FLYP). A second air-drop was performed with a soldier carrying one FLYP unit at 12 000 feet. For these air-drops real blood products were used, and quality control testing and temperature monitoring were performed. The temperatures inside the containers were within the normal ranges. Visual inspection indicated that transfusion packaging and dumped products did not undergo deterioration. The quality control data on RBCs and FLYP, including haemostasis, suggested no difference before and after air-drop. The operational implementation of the air-drop of blood products seems to be one of the solutions for the supply of blood products in military austere settings or far forward on battlefield, allowing safe and early transfusion.


Determination of polydimethylsiloxane-seawater distribution coefficients for polychlorinated biphenyls and chlorinated pesticides by solid-phase microextraction and gas chromatography-mass spectrometry.
Applications of solid-phase microextraction (SPME) in the measurement of very hydrophobic organic compounds (VHOCs) are limited, partly due to the difficulty of calibrating SPME fibers for VHOCs. This study used a static SPME strategy with a large sample volume (1.6 L) and a five-point calibration procedure to determine the distribution coefficients for a large suite of polychlorinated biphenyls (PCBs) and chlorinated pesticides between a polydimethylsiloxane (PDMS) phase (100 microm thickness) coated on a glass fiber and seawater. An extraction time of 12 days was deemed adequate for equilibrium calibration from kinetic experiments. Two groups of randomly selected fibers divided into three batches (up to nine fibers in each batch) were processed separately with two gas chromatography-mass spectrometry (GC-MS) systems. Matrix effects arising from losses of the analytes to glass container walls and stirring bars were corrected. Relative standard deviations within the same batch were generally smaller than those for the entire group. Furthermore, KfVf (Kf and Vf are the distribution coefficient of an analyte between the polymer-coated fiber and aqueous phase and the fiber volume, respectively) values determined with two GC-MS systems were statistically different. These results indicate the calibrated KfVf values were less affected by the random selection of SPME fibers than by other experimental conditions, and therefore average KfVf values may be used for the same type of commercially available SPME fibers. The relative accuracy of our calibration method was similar to that of a previous study [P. Mayer. W.H.J. Vaes, J.L.M. Hermens, Anal. Chem. 72 (2000) 459] employing different coating thickness and calibration procedure. The present study also obtained a bell-shaped relationship between log Kf and log Kow (octanol-water partition coefficient) for PCB congeners with the maximum log Kf corresponding to log Kow approximately 6.5. This bell-shaped relationship was attributed mainly to steric effects arising from the interplay between the PDMS thickness and molecular sizes of the target analytes.


Gender and transcriptional regulation of NO synthase and ET-1 in porcine aortic endothelial cells.
Experiments were designed to determine whether normal fluctuations in sex steroid hormones alter gene transcription for endothelial nitric oxide synthase (NOS) and preproendothelin-1 (prepro-ET-1). Aortic endothelial cells were removed from adult, gonadally intact male and female or ovariectomized Yorkshire pigs. Endothelial cells were prepared for Northern blot analysis, Western blot analysis or enzyme activity. Nitric oxide products (NOx) and endothelin-1 (ET-1) in plasma were measured by chemiluminescence and radioimmunoassay, respectively. Northern blot analysis identified single bands corresponding to endothelial NOS and prepro-ET-1. Quantification of the blots showed an increase in expression of mRNA for both endothelial NOS and prepro-ET-1 in ovariectomized pigs compared with gonadally intact male and female pigs. There were no differences in amount of endothelial NOS protein identified by Western blot analysis among groups. On the contrary, plasma concentrations of NOx were significantly decreased in ovariectomized pigs, and there were no differences either in the concentrations of ET-1 in the plasma or extracts from the coronary arteries. These results suggest that expression of endothelial NOS and prepro-ET-1 may be regulated at transcriptional level by ovarian hormones. In addition, the ovarian hormones may regulate production of these endothelium-derived factors at the posttranscriptional level.


Registration of 3D fetal brain US and MRI.
We propose a novel method for registration of 3D fetal brain ultrasound and a reconstructed magnetic resonance fetal brain volumes. The reconstructed MR volume is first segmented using a probabilistic atlas and an ultrasound-like image volume is simulated from the segmentation of the MR image. This ultrasound-like image volume is then affinely aligned with real ultrasound volumes of 27 fetal brains using a robust block-matching approach which can deal with intensity artefacts and missing features in ultrasound images. We show that this approach results in good overlap of four small structures. The average of the co-aligned US images shows good correlation with anatomy of the fetal brain as seen in the MR reconstruction.


Interaction of the European genotype porcine reproductive and respiratory syndrome virus (PRRSV) with sialoadhesin (CD169/Siglec-1) inhibits alveolar macrophage phagocytosis.
Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus that shows a restricted in vivo tropism for subsets of porcine macrophages, with alveolar macrophages being major target cells. The virus is associated with respiratory problems in pigs of all ages and is commonly isolated on farms with porcine respiratory disease complex (PRDC). Due to virus-induced macrophage death early in infection, PRRSV hampers the innate defence against pathogens in the lungs. In addition, the virus might also directly affect the antimicrobial functions of macrophages. This study examined whether interaction of European genotype PRRSV with primary alveolar macrophages (PAM) affects their phagocytic capacity. Inoculation of macrophages with both subtype I PRRSV (LV) and subtype III PRRSV (Lena) showed that the virus inhibits PAM phagocytosis. Similar results were obtained using inactivated PRRSV (LV), showing that initial interaction of the virion with the cell is sufficient to reduce phagocytosis, and that no productive infection is required. When macrophages were incubated with sialoadhesin- (Sn) or CD163-specific antibodies, two entry mediators of the virus, only Sn-specific antibodies downregulated the phagocytic capacity of PAM, indicating that interaction with Sn, but not CD163, mediates the inhibitory effect of PRRSV on phagocytosis. In conclusion, this study shows that European genotype PRRSV inhibits PAM phagocytosis in vitro, through the interaction with its internalization receptor Sn. If similar events occur in vivo, this interaction may be important in the development of PRDC, as often seen in the field.


Crystal structure of the catalytic alpha subunit of E. coli replicative DNA polymerase III.
Bacterial replicative DNA polymerases such as Polymerase III (Pol III) share no sequence similarity with other polymerases. The crystal structure, determined at 2.3 A resolution, of a large fragment of Pol III (residues 1-917), reveals a unique chain fold with localized similarity in the catalytic domain to DNA polymerase beta and related nucleotidyltransferases. The structure of Pol III is strikingly different from those of members of the canonical DNA polymerase families, which include eukaryotic replicative polymerases, suggesting that the DNA replication machinery in bacteria arose independently. A structural element near the active site in Pol III that is not present in nucleotidyltransferases but which resembles an element at the active sites of some canonical DNA polymerases suggests that, at a more distant level, all DNA polymerases may share a common ancestor. The structure also suggests a model for interaction of Pol III with the sliding clamp and DNA.


Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.
Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.


The regulation of ketogenesis.
Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC 188.8.131.52). The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC 220.127.116.11) such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process.


Swapping structural determinants of ribonucleases: an energetic analysis of the hinge peptide 16-22.
Bovine seminal ribonuclease (BS-RNase) is a homodimeric enzyme strictly homologous to the pancreatic ribonuclease (RNase A). Native BS-RNase is an equilibrium mixture of two distinct dimers differing in the interchange of the N-terminal segments and in their biological properties. The loop 16-22 plays a fundamental role on the relative stability of the two isomers. Both the primary and tertiary structures of the RNase A differ substantially from those of the seminal ribonuclease in the loop region 16-22. To analyze the possible stable conformations of this loop in both enzymes, structure predictions have been attempted, according to a procedure described by Palmer and Scheraga [Palmer, K. A. & Scheraga, H. A. (1992) J. Comput. Chem. 13, 329-350]. Results compare well with experimental x-ray structures and clarify the structural determinants that are responsible for the swapping of the N-terminal domains and for the peculiar properties of BS-RNase. Minimal modifications of RNase A sequence needed to form a stable swapped dimer are also predicted.


[A proposed guideline for economic evaluation of health technologies].
Over the last few years, economic evaluation of health technologies has become a major tool used by European health policy decision-makers to create strategies for prioritizing the allocation of health resources and the approval of new technologies. Spain was a pioneer in proposing the standardization of methodology applicable to economic evaluation studies. However, because health policy decision-makers refused to support the initiative, the methodology was never put into practice. In the medium term, evidence of the economic value of new health technologies financed by the national health system will probably be increasingly required. At that time, stakeholders and decision-makers will have to agree upon a clear and concise set of rules on the technical and methodological issues that must be followed by economic evaluations of health technologies. Consequently, we have provided guidelines and recommendations for producing first-rate economic evaluations. The recommendations appear under seventeen headings or sections. In each case, the recommended requirements to be satisfied by an economic evaluation of health technologies are provided and each recommendation is followed by a commentary, providing a justification and comparing and contrasting the proposal with other available alternatives.


A Universal Theoretical Framework in Material Characterization for Tailored Porous Surface Design.
The distinct interaction of adsorbate-adsorbent pair is attributed to the characteristics of heterogeneous surface and structure of porous materials. In material science, the porous structure is modified in response to certain applications. Backed by the chemical recipes, such conventional approach rely on the material characterization techniques to verify the resultant porous structure and its interaction with the adsorbate molecules. Such a practice is best assisted by a theoretical approach that can pre-define the required heterogeneous structure of porous surfaces and its role in selective adsorbate-adsorbent interaction, to facilitate material scientists for the synthesis of only those energy sites which can enhance or tailor its responses for a certain application or target. It has been reported here that the understanding of porous structure in terms of energy sites and their distribution, which controls the adsorbate-adsorbent interaction, is the key for porous surface engineering. Understanding of such porous surface characteristics empower the scientists to alter kinetics and thermodynamics of material according to the 'sweet spots' of an application. Therefore, a theoretical framework, to express the energy sites and their distribution over the porous heterogeneous surface, is demonstrated here as a prerequisite criterion for porous material development and characterization.


[Variability of antibiotic treatment in paediatric acute pharyngotonsillitis in Asturias, Spain].
Introduction. Acute pharyngotonsillitis accounts for a large portion of antibiotic prescriptions in pediatric offces. Our aim was to analyze the antimicrobial prescription habits for acute pharyngotonsillitis in children from hospital emergency departments and primary care pediatric clinics in Asturias (Spain). Methods. Multicenter descriptive study evaluating pediatric patients with a diagnosis of acute pharyngotonsillitis in 5 hospital emergency departments and 80 pediatric primary care clinics. Appropriateness of prescription was established by comparing with reference standards. Results. Five hundred sixty-three children with acute pharyngotonsillitis [49.7% in primary care CI 95% 45.6-53.8%)] were included along 30 nonconsecutive days. Antibiotics were prescribed in 75.5% of cases (95% CI 71.9-79.0%) [78.3% in children under 3 years of age (95% CI 71.8-84.8%)]. Amoxicillin was the antibiotic most frequently prescribed [39.1% (95% CI 34.4-43.7%)]. Signifcant differences in the frequency or antibiotic prescription were found between primary care and hospital emergency departments (70% vs. 80.9%, p= 0.003). The treatment prescribed was considered frst choice in 43.3% (95% CI 38.6-48.0%) and inappropriate in 56.0% (95% CI 51.3-60.7%). Conclusions. Although in most cases pediatric acute pharyngotonsillitis is viral in origin, three out of four are treated with antibiotics. Treatment was inappropriate in more than half of the cases in our study.


Increased stability of nitroxide radicals in ionic liquids: more than a viscosity effect.
Radical stability has been subject to continuous research due to its importance in polymerization as well as in all-organic batteries. Recently, the SOMO-HOMO conversion was identified as the main factor in controlling the stability of distonic radicals, for which the negative charge resides on the same molecule. Based on this finding, the idea of ionic liquids stabilizing radicals was hypothesized in this study. A series of ionic liquids were tested in EPR measurements of the 3-carboxy-2,2,5,5-tetramethyl-pyrroline-1-oxyl. Unusually high rotational diffusion constants (τR), 4 times larger compared to conventional media such as dichloromethane (DCM), were recorded at room temperature. This finding could only be explained by a strong interaction existing between the radical and ionic liquid ions, which was confirmed with quantum chemical calculations, with interaction energies falling between -17.1 kJ mol-1 for tetramethylphosphonium tetrafluoroborate and -85.6 kJ mol-1 for 1,3-dimethylimidazolium triflate. Elevated temperature measurements performed at 80 °C reduced the viscosity of the ionic liquids to that of DCM, while the τR values remained relatively high, thus further confirming that the rotational hindrance occurred due to radical-ionic liquid interactions. The calculated interaction energies between the radical and ionic liquids ions were also found to correlate well with experimental rotational diffusion constants, thus offering us a valuable tool in tailoring ionic liquids for enhanced stability of nitroxide radicals. The findings of this study showcase the ability of ionic liquids to reduce reactivity of nitroxides without the need for any chemical modification of the radical.


Changes in selective information processing with three psychological treatments for bulimia nervosa.
Data from a treatment trial were used to test whether interference with colour-naming eating, shape and weight related words on the Stroop colour-naming task changed with treatment. Interference decreased with treatment and there was no difference between three treatments in the size of this effect. These findings suggest that interference with colour-naming words related to eating, shape and weight in subjects with bulimia nervosa may be a useful objective measure of patients' concerns about these issues.


Variations in total ozone column and biologically effective solar UV exposure doses in Bologna, Italy during the period 2005-2010.
Variations in total ozone column and sun exposures able to cause erythema and damage the DNA molecules were observed by the narrow-band filter radiometer UV-RAD in Bologna, Italy from 2005 to 2010. The ozone columns determined from the UV-RAD measurements were found to be close to those provided by the satellite Ozone Monitoring Instrument (OMI) showing an average discrepancy of 1% with standard deviation of ± 6%. Analysis of the data highlights a well-marked annual cycle of the ozone column variations while the oscillations with periods of 8, 18 and 34 months present much smaller amplitudes. The influence of the frequency of solar irradiance measurements on the accuracy of the evaluated daily exposure dose has been studied and it was found that time intervals no longer than 5-10 min between the measurements of erythema and DNA damage effective UV irradiances provide a satisfactory assessment of the corresponding daily exposures. The latter do not present significant year-to-year variations for the period under study, while their annual distributions show slight changes likely due to the specific cloud cover and ozone column variability for different years. The annual erythemal exposure dose for 2007-2010 varied between 603.7 and 638.1 kJ m(-2), while the corresponding sun exposure affecting DNA changed from 6.38 to 7.91 kJ m(-2).


High-Performance Integrated Virtual Environment (HIVE) Tools and Applications for Big Data Analysis.
The High-performance Integrated Virtual Environment (HIVE) is a high-throughput cloud-based infrastructure developed for the storage and analysis of genomic and associated biological data. HIVE consists of a web-accessible interface for authorized users to deposit, retrieve, share, annotate, compute and visualize Next-generation Sequencing (NGS) data in a scalable and highly efficient fashion. The platform contains a distributed storage library and a distributed computational powerhouse linked seamlessly. Resources available through the interface include algorithms, tools and applications developed exclusively for the HIVE platform, as well as commonly used external tools adapted to operate within the parallel architecture of the system. HIVE is composed of a flexible infrastructure, which allows for simple implementation of new algorithms and tools. Currently, available HIVE tools include sequence alignment and nucleotide variation profiling tools, metagenomic analyzers, phylogenetic tree-building tools using NGS data, clone discovery algorithms, and recombination analysis algorithms. In addition to tools, HIVE also provides knowledgebases that can be used in conjunction with the tools for NGS sequence and metadata analysis.


Emerging role of topotecan in front-line treatment of carcinoma of the ovary.
The conventional front-line chemotherapy strategy for advanced epithelial ovarian carcinoma has become adjuvant administration of platinum (carboplatin and cisplatin), either alone or, most often, in combination with a taxane. However, a number of active agents have been identified in phase II/III trials of second-line and salvage ovarian cancer patients that may augment this front-line strategy. One agent, topotecan, has antitumor activity comparable with paclitaxel in patients with recurrent ovarian cancer and is an established treatment in second-line or salvage settings. Additionally, its mechanism of action is different from paclitaxel and is nonoverlapping. These properties, coupled with the in vitro synergy observed in tumor models among topotecan, paclitaxel, and platinum, have provided the rationale for investigators to examine topotecan in front-line ovarian cancer therapy. A number of strategies for incorporating topotecan into front-line therapy are under active investigation, including the replacement of paclitaxel with topotecan, a triplet regimen with cisplatin or carboplatin and paclitaxel, a consolidation regimen consisting of several courses of a platinum agent and paclitaxel followed by several courses of topotecan, and a sequential doublet regimen in which patients receive platinum in every course as part of a doublet with alternating or sequential topotecan and paclitaxel. Preliminary data from ongoing clinical trials of these new regimens show favorable response rates and generally manageable toxicity profiles. This review summarizes the preliminary clinical findings associated with the four strategies and outlines ongoing and future randomized studies of topotecan in front-line ovarian cancer.


S-1 monotherapy as a neoadjuvant treatment for locally advanced gastric cancer.
S-1, a novel oral fluoropyrimidine, is an effective therapeutic agent for gastric cancer. Herein, we report a case with locally advanced gastric cancer that achieved a curative resection after S-1 monotherapy as neoadjuvant treatment. A 68-year-old man was diagnosed with gastric cancer and massive lymphadenopathy involving the perigastric, celiac axis and splenic hilum. His clinical stage was cT3N2H0P0M0. Considering his relatively poor performance (ECOG 2, severe weight loss) and advanced age, we started the patient on S-1 monotherapy at a dose of 35 mg/m2 bid for 4 consecutive weeks followed by a 2-week rest. Follow-up study after 4 treatment cycles revealed disappearance of the lymphadenopathy of the perigastric and celiac axis with diminished extension of the stomach mass. The patient had a partial response (PR) with a 72% tumor reduction, according to the Response Evaluation Criteria in Solid Tumors (RECIST). His performance status was improved to an ECOG 1 and he gained 7 kg. A curative (R0) resection was achieved with a radical total gastrectomy and D2 dissection. The pathological stage was pT3N2M0, stage IIIB. In conclusion, S-1 neoadjuvant chemotherapy aided in the treatment of gastric cancer in this patient.


Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis.
The links between the cell cycle machinery and the cytoskeletal proteins controlling cytokinesis are poorly understood. The small guanine nucleotide triphosphate (GTP)-binding protein RhoA stimulates type II myosin contractility and formin-dependent assembly of the cytokinetic actin contractile ring. We found that budding yeast Polo-like kinase Cdc5 controls the targeting and activation of Rho1 (RhoA) at the division site via Rho1 guanine nucleotide exchange factors. This role of Cdc5 (Polo-like kinase) in regulating Rho1 is likely to be relevant to cytokinesis and asymmetric cell division in other organisms.