Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.
PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model. We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes. Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered. Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.


Aggression in fragile X syndrome.
Individuals with fragile X syndrome (FXS), especially men, have long been described as presenting with significant behavioural challenges. Despite this known aspect of the phenotype, there has been little research exploring the prevalence, frequency, nature or consequences of aggressive behaviour in FXS. This study used survey methodology to gather caregiver reports on the types, frequency and severity of aggressive behaviour in 774 individuals with FXS. Based on caregiver report, nearly all (>90%) male and female individuals were reported to have engaged in some aggression over the previous 12 months, with a third of male cases and slightly fewer than 20% of female cases being described as engaging in moderate to severe aggression or being diagnosed or treated for aggression. Further, aggressive behaviours in male individuals were serious enough that 30% had caused injuries to caregivers and 22% had caused injuries to peers or friends. Sensory issues and hyperactivity were significant predictors of the frequency of aggressive acts, while sensory issues and anxiety were predictive of the severity of aggression. Traditional behaviour management techniques as well as medication was described as the most common and successful treatment options. Aggressive behaviours are a significant concern for a subsample of both male and female individuals with FXS. Given that sensory concerns were predictive of both the frequency and the severity of aggression suggests these behaviours may be a reactive means of escaping uncomfortable situations.


Gamma oscillations in the auditory cortex of awake rats.
Numerous reports of human electrophysiology have demonstrated gamma (30-150 Hz) frequency oscillations in the auditory cortex during listening. However, only a small number of studies in non-human animals have provided evidence for gamma oscillations during listening. In this report, multi-site recordings from primary auditory cortex (A1) were carried out using a 16-channel microelectrode array in awake rats as they passively listened to tones. We addressed two fundamental questions: (i) Is passive listening associated with an increase in gamma oscillation in A1? And, if so: (ii) Are A1 gamma oscillations during passive listening coherent within local networks and/or over long distances? All sites within A1 showed a short-latency burst of activity in the low-gamma (30-70 Hz) and high-gamma (90-150 Hz) bands in the local field potential (LFP). Additionally, 53% of sites within A1 also showed longer-latency bursts of gamma oscillation that occurred episodically for up to 350 ms after tone onset, but these varied both in latency and in occurrence across trials. There was significant coherence in the low-gamma band between spike activity and the LFP recorded with the same electrode. However, neither LFPs nor the spike activity between sites spaced at least 300 μm apart showed coherent activity in the gamma band. The experiments demonstrated that gamma oscillations are present, but not uniformly expressed, throughout A1 during passive listening and that there is strong local coherence in the spatiotemporal organization of gamma activity.


Comparison of executive and visuospatial memory function in Huntington's disease and dementia of Alzheimer type matched for degree of dementia.
Groups of patients with Hungington's disease and probable dementia of Alzheimer type (DAT) matched for level of dementia on the basis of mini mental state examination scores were compared in several tests of visual memory and tests sensitive to frontal lobe dysfunction. Whereas recall of patients with DAT tended to be worse on the Kendrick object learning test, the two groups were equivalent on tests of sensorimotor ability and delayed matching to sample performance. By contrast, the patients with Huntington's disease were significantly worse on tests of pattern and spatial recognition, simultaneous matching to sample, visuospatial paired associates, and on three tests sensitive to frontal lobe dysfunction--namely, the Tower of London test of planning, spatial working memory, and a visual discrimination learning and reversal paradigm. The impairments in these tests, however, did not always qualitatively resemble those seen in patients with frontal lobe damage and may be more characteristic of primary neostriatal deficit. In the visual discrimination paradigm the patients with Hungtington's disease were significantly worse than the patients with DAT at the simple reversal stage, where they displayed significant preservation to the previously rewarded alternative. The results are consistent with the hypothesis that patients with Huntington's disease exhibit deficits in tests sensitive to frontostriatal dysfunction and that this form of intellectual deterioration is qualitatively distinct from that seen in Alzheimer's disease.


Transgenerational effects of global environmental change: long-term CO(2) and nitrogen treatments influence offspring growth response to elevated CO(2).
Global environmental changes can have immediate impacts on plant growth, physiology, and phenology. Long-term effects that are only observable after one or more generations are also likely to occur. These transgenerational effects can result either from maternal environmental effects or from evolutionary responses to novel selection pressures and are important because they may alter the ultimate ecological impact of the environmental change. Here, we show that transgenerational effects of atmospheric carbon dioxide (CO(2)) and soil nitrogen (N) treatments influence the magnitude of plant growth responses to elevated CO(2) (eCO(2)). We collected seeds from Lupinus perennis, Poa pratensis, and Schizachyrium scoparium populations that had experienced five growing seasons of ambient CO(2) (aCO(2)) or eCO(2) treatments and ambient or increased N deposition and planted these seeds into aCO(2) or eCO(2) environments. We found that the offspring eCO(2) treatments stimulated immediate increases in L. perennis and P. pratensis growth and that the maternal CO(2) environment influenced the magnitude of this growth response for L. perennis: biomass responses of offspring from the eCO(2) maternal treatments were only 54% that of the offspring from the aCO(2) maternal treatments. Similar trends were observed for P. pratensis and S. scoparium. We detected some evidence that long-term N treatments also altered growth responses to eCO(2); offspring reared from seed from maternal N-addition treatments tended to show greater positive growth responses to eCO(2) than offspring from ambient N maternal treatments. However, the effects of long-term N treatments on offspring survival showed the opposite pattern. Combined, our results suggest that transgenerational effects of eCO(2) and N-addition may influence the growth stimulation effects of eCO(2), potentially altering the long-term impacts of eCO(2) on plant populations.


The reliability of drug use data collected in the classroom: what is the problem, why does it matter and how should it be approached?
Difficulties in collecting reliable data on drug use in the context of an exploratory trial of a drug prevention intervention have led to a consideration of the wider issues of the reliability of routinely collected data. A problem is identified, and although its magnitude cannot currently be described, its nature and possible significance are considered. In this methodological discussion, significant practical and ethical issues are explored, including some of the complexities inherent in conducting research on drug use in schools, along with the need to develop improved methods of study which address the specific challenges posed by the school environment. Implications for the development of effective drug prevention interventions in schools are also examined.


RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery.
Many ribosomally synthesized and posttranslationally modified peptide classes (RiPPs) are reliant on a domain called the RiPP recognition element (RRE). The RRE binds specifically to a precursor peptide and directs the posttranslational modification enzymes to their substrates. Given its prevalence across various types of RiPP biosynthetic gene clusters (BGCs), the RRE could theoretically be used as a bioinformatic handle to identify novel classes of RiPPs. In addition, due to the high affinity and specificity of most RRE-precursor peptide complexes, a thorough understanding of the RRE domain could be exploited for biotechnological applications. However, sequence divergence of RREs across RiPP classes has precluded automated identification based solely on sequence similarity. Here, we introduce RRE-Finder, a new tool for identifying RRE domains with high sensitivity. RRE-Finder can be used in precision mode to confidently identify RREs in a class-specific manner or in exploratory mode to assist in the discovery of novel RiPP classes. RRE-Finder operating in precision mode on the UniProtKB protein database retrieved ∼25,000 high-confidence RREs spanning all characterized RRE-dependent RiPP classes, as well as several yet-uncharacterized RiPP classes that require future experimental confirmation. Finally, RRE-Finder was used in precision mode to explore a possible evolutionary origin of the RRE domain. The results suggest RREs originated from a co-opted DNA-binding transcriptional regulator domain. Altogether, RRE-Finder provides a powerful new method to probe RiPP biosynthetic diversity and delivers a rich data set of RRE sequences that will provide a foundation for deeper biochemical studies into this intriguing and versatile protein domain.IMPORTANCE Bioinformatics-powered discovery of novel ribosomal natural products (RiPPs) has historically been hindered by the lack of a common genetic feature across RiPP classes. Herein, we introduce RRE-Finder, a method for identifying RRE domains, which are present in a majority of prokaryotic RiPP biosynthetic gene clusters (BGCs). RRE-Finder identifies RRE domains 3,000 times faster than current methods, which rely on time-consuming secondary structure prediction. Depending on user goals, RRE-Finder can operate in precision mode to accurately identify RREs present in known RiPP classes or in exploratory mode to assist with novel RiPP discovery. Employing RRE-Finder on the UniProtKB database revealed several high-confidence RREs in novel RiPP-like clusters, suggesting that many new RiPP classes remain to be discovered.


Characteristics of visual field progression in medically treated normal-tension glaucoma patients with unstable ocular perfusion pressure.
To investigate the characteristics of visual field (VF) progression in medically treated normal-tension glaucoma (NTG) patients (Koreans) with unstable ocular perfusion pressure (OPP). One hundred one eyes of 101 NTG patients followed up for more than 4 years (mean follow-up, 6.2 years ± 12.1 months) were included. Modified Anderson criteria (MC) and linear regression analysis (LA) of VF mean deviation (MD) within the central 10° and 10° to 24° area were assessed for determining VF progression in groups with lowest (LMF) and highest (HMF) 24-hour mean OPP [MOPP = 2/3;(mean arterial pressure - IOP)] fluctuation. Kaplan-Meier analyses were used to compare the elapsed time of confirmed VF progression in the two groups. Hazard ratios (HRs) for the association between clinical risk factors including 24-hour MOPP and central VF progression were obtained by using Cox proportional hazards models. Three of 33 eyes in the LMF progressed, whereas 12 of 34 eyes in the HMF progressed within the central 10° according to the MC; the between-group difference was significant (P = 0.010). By LA within the central 10°, two eyes from the LMF and nine from the HMF groups showed progression (P = 0.025). The HMF showed a greater cumulative probability of central VF progression than the LMF, by both LA and MC (Kaplan-Meier analysis, P = 0.003, 0.015, log-rank test). In multivariate analysis, only 24-hour MOPP fluctuation was significantly associated with central VF progression (P = 0.014). The 24-hour MOPP fluctuation was the most consistent prognostic factor among various IOP, blood pressure, and clinical factors for central VF glaucomatous progression in our series of NTG eyes.


Endocrine therapy in the years following a diagnosis of breast cancer: A proof of concept study using the primary care prescription database linked to cancer registration data.
National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied. Cancer registrations for women diagnosed with breast cancer during 1995-2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April-July 2015. Among 369 277 survivors of breast cancer diagnosed during 1995-2015, 37% were prescribed ET during April-July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors. The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research.


Reducing Crime and Violence: Experimental Evidence from Cognitive Behavioral Therapy in Liberia.
We show that a number of noncognitive skills and preferences, including patience and identity, are malleable in adults, and that investments in them reduce crime and violence. We recruited criminally engaged men and randomized one-half to eight weeks of cognitive behavioral therapy designed to foster self-regulation, patience, and a noncriminal identity and lifestyle. We also randomized $200 grants. Cash alone and therapy alone initially reduced crime and violence, but effects dissipated over time. When cash followed therapy, crime and violence decreased dramatically for at least a year. We hypothesize that cash reinforced therapy's impacts by prolonging learning-by-doing, lifestyle changes, and self-investment.


Community Composition of Nitrous Oxide Consuming Bacteria in the Oxygen Minimum Zone of the Eastern Tropical South Pacific.
The ozone-depleting and greenhouse gas, nitrous oxide (N2O), is mainly consumed by the microbially mediated anaerobic process, denitrification. N2O consumption is the last step in canonical denitrification, and is also the least O2 tolerant step. Community composition of total and active N2O consuming bacteria was analyzed based on total (DNA) and transcriptionally active (RNA) nitrous oxide reductase (nosZ) genes using a functional gene microarray. The total and active nosZ communities were dominated by a limited number of nosZ archetypes, affiliated with bacteria from marine, soil and marsh environments. In addition to nosZ genes related to those of known marine denitrifiers, atypical nosZ genes, related to those of soil bacteria that do not possess a complete denitrification pathway, were also detected, especially in surface waters. The community composition of the total nosZ assemblage was significantly different from the active assemblage. The community composition of the total nosZ assemblage was significantly different between coastal and off-shore stations. The low oxygen assemblages from both stations were similar to each other, while the higher oxygen assemblages were more variable. Community composition of the active nosZ assemblage was also significantly different between stations, and varied with N2O concentration but not O2. Notably, nosZ assemblages were not only present but also active in oxygenated seawater: the abundance of total and active nosZ bacteria from oxygenated surface water (indicated by nosZ gene copy number) was similar to or even larger than in anoxic waters, implying the potential for N2O consumption even in the oxygenated surface water.


First Report of the Anamorph of Glomerella acutata Causing Anthracnose on Avocado Fruits in Mexico.
Mexico is a major avocado (Persea americana) producer in the world. Glomerella cingulata (anamorph Colletotrichum gloeosporioides) has been reported as a causal agent of anthracnose on avocado fruits worldwide (3), while G. acutata (anamorph Colletotrichum acutatum) has been identified as the cause of this disease only in New Zealand (2) and Australia (4). This study was done with the objective to determine the Glomerella spp. involved as the causal agents of avocado anthracnose in Mexico. From 2003 to 2006, avocado fruits cv. Hass with anthracnose symptoms appearing as brown-black lesions on the pericarp and soft rot in the mesocarp were collected in 10 counties in Michoacan, the leading avocado-producing Mexican state. Glomerella spp. were isolated on potato dextrose agar (PDA) for molecular and morphological identification. A phylogenetic analysis was done by amplifying the internal transcribed spacer region of rDNA for 28 of the isolates. Primers ITS5/NL4 was used and successfully amplified bands of approximately 1,000 bp. Each sequence corresponding to Glomerella spp. was compared with sequences deposited in the GenBank database using BLAST. The results from molecular approach indicated 86% of the isolates used in this study were G. cingulata and 14% were G. acutata. Sequences of both species were deposited in GenBank under Accession Nos. EF221828, EF221829, and EF221830 for G. cingulata and EF175780, EF221831, and EF221832 for G. acutata. Colonies of G. acutata that developed on PDA medium were pale gray, occasionally the lower surface was olive green, and the center was covered with orange-to-salmon pink masses of conidia and perithecia. Conidia grown in the same media were straight, fusiform, 8.2 to 16.5 μm long, and 2.7 to 4.0 μm wide (4). Pathogenicity tests of G. acutata were carried out by inoculating six healthy cv. Hass fruits (1) at three evenly spaced locations on the fruit surface with a needle dipped in a conidial mass from a 3-day-old monoconidial culture of G. acutata. Fruits were then incubated in a moist chamber for 3 days. Anthracnose symptoms were observed on healthy fruits inoculated with G. acutata, while control fruits inoculated with sterile water did not develop symptoms. The fungi were reisolated successfully to confirm the pathogen's identity using morphological key. To our knowledge, this is the first report of G. acutata causing anthracnose on avocado fruits in Mexico. References: (1) R. Guetsky et al. Phytopathology 95:1341, 2005. (2) W. F. T. Hartill. N. Z. J. Crop Hortic. Sci. 19:297, 1991. (3) D. Prusky. Annu. Rev. Phytopathol. 34:413, 1996. (4) J. H. Simmonds. Qld. J. Agric. Anim. Sci. 22:437, 1965.


Adenovirus-mediated prothymosin α gene transfer inhibits the development of atherosclerosis in ApoE-deficient mice.
Prothymosin α (ProT) is involved in regulating expression of the oxidative stress-protective genes and it also exerts immunomodulatory activities. In this study, we investigated the therapeutic effects of ProT gene transfer on atherosclerosis in endothelial cells and in ApoE-deficient mice. Adenoviruses encoding mouse ProT (AdProT) were used for the management of atherosclerosis. In vitro, the effects of ProT on antioxidant gene expressions and the protection effect against oxidant-mediated injury in endothelial cells were examined. In vivo, AdProT were administered intraventricularly into the heart of ApoE(-/-) mice. Histopathological and immunohistochemical assessments of the aortic tissues were performed. Expressions of HO-1 and antioxidant genes in the aortic tissues were also determined. Our results demonstrated that ProT gene transfer increased antioxidant gene expressions, eNOS expression and NO release, as well as reduced the reactive oxygen species production in endothelial cells. Intraventricular administration of AdProT reduced the lesion formation, increased expressions of HO-1 and SOD genes, and reduced infiltrating macrophages in the aorta of ApoE(-/-) mice. This study suggests that ProT gene transfer may have the therapeutic potential for the management of atherosclerosis via inducing antioxidant gene expressions, eNOS expression and NO release, reducing ROS production and macrophage infiltration in endothelium.


New substrates and interactors of the mycobacterial Serine/Threonine protein kinase PknG identified by a tailored interactomic approach.
PknG from Mycobacterium tuberculosis is a multidomain Serine/Threonine protein kinase that regulates bacterial metabolism as well as the pathogen's ability to survive inside the host by still uncertain mechanisms. To uncover PknG interactome we developed an affinity purification-mass spectrometry strategy to stepwise recover PknG substrates and interactors; and to identify those involving PknG autophosphorylated docking sites. We report a confident list of 7 new putative substrates and 66 direct or indirect partners indicating that PknG regulates many physiological processes, such as nitrogen and energy metabolism, cell wall synthesis and protein translation. GarA and the 50S ribosomal protein L13, two previously reported substrates of PknG, were recovered in our interactome. Comparative proteome analyses of wild type and pknG null mutant M. tuberculosis strains provided evidence that two kinase interactors, the FHA-domain containing protein GarA and the enzyme glutamine synthetase, are indeed endogenous substrates of PknG, stressing the role of this kinase in the regulation of nitrogen metabolism. Interestingly, a second FHA protein was identified as a PknG substrate. Our results show that PknG phosphorylates specific residues in both glutamine synthetase and FhaA in vitro, and suggest that these proteins are phosphorylated by PknG in living mycobacteria.


Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.
Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.


Nitrogen availability alters macrofungal basidiomycete community structure in optimally fertilized loblolly pine forests.
• We investigated the effect of an optimal nutrition strategy designed to maximize loblolly pine (Pinus taeda) growth on the rank abundance structure and diversity of associated basidiomycete communities. • We conducted both small- and large-scale below-ground surveys 10 years after the initiation of optimal nutrition, and used TRFLP of selectively PCR-amplified nrDNA ITS to determine the distribution and abundance of macrofungal basidiomycete species in c. 200 soil samples collected from optimally fertilized and unfertilized treatments at the SETRES loblolly pine experimental site, North Carolina, USA. • Our results indicated an increased relative abundance of Tylopilus and Thelephora spp. on optimally fertilized stands. Our results also suggested improved mycelial growth of several species, possibly caused by increased connectivity in the forest floor as a result of increased plant growth. • In addition, our results suggest a trend towards reduced basidiomycete diversity, and that large-scale application of optimal nutrition may need to be sensitive to increased nitrate availability.


The impact of fire suppression tasks on firefighter hydration: a critical review with consideration of the utility of reported hydration measures.
Firefighting is a highly stressful occupation with unique physical challenges, apparel and environments that increase the potential for dehydration. Dehydration leaves the firefighter at risk of harm to their health, safety and performance. The purpose of this review was to critically analyse the current literature investigating the impact of fighting 'live' fires on firefighter hydration. A systematic search was performed of four electronic databases for relevant published studies investigating the impact of live fire suppression on firefighter hydration. Study eligibility was assessed using strict inclusion and exclusion criteria. The included studies were critically appraised using the Downs and Black protocol and graded according to the Kennelly grading system. Ten studies met the eligibility criteria for this review. The average score for methodological quality was 55 %, ranging from 50 % ('fair' quality) to 61 % ('good' quality) with a 'substantial agreement' between raters (k = .772). Wildfire suppression was considered in five studies and structural fire suppression in five studies. Results varied across the studies, reflecting variations in outcome measures, hydration protocols and interventions. Three studies reported significant indicators of dehydration resulting from structural fire suppression, while two studies found mixed results, with some measures indicating dehydration and other measures an unchanged hydration status. Three studies found non-significant changes in hydration resulting from wildfire firefighting and two studies found significant improvements in markers of hydration. Ad libitum fluid intake was a common factor across the studies finding no, or less severe, dehydration. The evidence confirms that structural and wildfire firefighting can cause dehydration. Ad libitum drinking may be sufficient to maintain hydration in many wildfire environments but possibly not during intense, longer duration, hot structural fire operations. Future high quality research better quantifying the effects of these influences on the degree of dehydration is required to inform policies and procedures that ensure firefighter health and safety.


Tarsus determination in Drosophila melanogaster.
Arista versus tarsus determination is well investigated in Drosophila, yet it remains unresolved whether Antennapedia (ANTP) cell autonomously or noncell autonomously determines tarsus identity and whether Sex combs reduced (SCR) is the HOX protein required for normal tarsus determination. Three observations rule out a cell autonomous role for ANTP in tarsus determination. (i) Clonal ectopic overexpression of ANTP did not repress the expression of the arista determining protein Homothorax (HTH) in early 3rd stadium antennal imaginal discs. (ii) Clonal ectopic expression of ANTP did not transform the arista to a tarsus. (iii) Ectopic overexpression of ANTP, Labial (LAB), Deformed (DFD), SCR, Ultrabithorax (UBX), Abdominal-A (ABD-A), or Abdominal-B (ABD-B), using the dppGAL4 driver, resulted in arista-to-tarsus transformations, and repressed HTH/Extradenticle (EXD) activity noncell autonomously in early 3rd stadium antennal imaginal discs. SCR may not be the HOX protein required for normal tarsus determination, because co-ectopic expression of Proboscipedia (PB) inhibited the arista-to-tarsus transformations induced by ectopic expression of DFD, SCR, ANTP, UBX, ABD-A, and ABD-B. The proposal that SCR is the HOX protein required for normal tarsus determination is dependent on SCR being the sole target of PB suppression, which is not the case. Therefore, the possibility exists that normal tarsus determination is HOX independent.


Biofield Physiology: A Framework for an Emerging Discipline.
Biofield physiology is proposed as an overarching descriptor for the electromagnetic, biophotonic, and other types of spatially-distributed fields that living systems generate and respond to as integral aspects of cellular, tissue, and whole organism self-regulation and organization. Medical physiology, cell biology, and biophysics provide the framework within which evidence for biofields, their proposed receptors, and functions is presented. As such, biofields can be viewed as affecting physiological regulatory systems in a manner that complements the more familiar molecular-based mechanisms. Examples of clinically relevant biofields are the electrical and magnetic fields generated by arrays of heart cells and neurons that are detected, respectively, as electrocardiograms (ECGs) or magnetocardiograms (MCGs) and electroencephalograms (EEGs) or magnetoencephalograms (MEGs). At a basic physiology level, electromagnetic activity of neural assemblies appears to modulate neuronal synchronization and circadian rhythmicity. Numerous nonneural electrical fields have been detected and analyzed, including those arising from patterns of resting membrane potentials that guide development and regeneration, and from slowly-varying transepithelial direct current fields that initiate cellular responses to tissue damage. Another biofield phenomenon is the coherent, ultraweak photon emissions (UPE), detected from cell cultures and from the body surface. A physiological role for biophotons is consistent with observations that fluctuations in UPE correlate with cerebral blood flow, cerebral energy metabolism, and EEG activity. Biofield receptors are reviewed in 3 categories: molecular-level receptors, charge flux sites, and endogenously generated electric or electromagnetic fields. In summary, sufficient evidence has accrued to consider biofield physiology as a viable scientific discipline. Directions for future research are proposed.


Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis.
Myasthenia gravis (MG) is an autoimmune disease in which 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), while autoantibodies to muscle-specific tyrosine kinase (MuSK) have been detected in half (5%) of the remaining 10%. Recently, the low-density lipoprotein receptor-related protein 4 (LRP4), identified as the agrin receptor, has been recognized as a third autoimmune target in a significant portion of the double sero-negative (dSN) myasthenic individuals, with variable frequency depending on different methods and origin countries of the tested population. There is also convincing experimental evidence that anti-LRP4 autoantibodies may cause MG. The aim of this study was to test the presence and diagnostic significance of anti-LRP4 autoantibodies in an Italian population of 101 myasthenic patients (55 dSN, 23 AChR positive and 23 MuSK positive), 45 healthy blood donors and 40 patients with other neurological diseases as controls. All sera were analyzed by a cell-based antigen assay employing LRP4-transfected HEK293T cells, along with a flow cytofluorimetric detection system. We found a 14.5% (8/55) frequency of positivity in the dSN-MG group and a 13% frequency of co-occurrence (3/23) in both AChR and MuSK positive patients; moreover, we report a younger female prevalence with a mild form of disease in LRP4-positive dSN-MG individuals. Our data confirm LRP4 as a new autoimmune target, supporting the value of including anti-LRP4 antibodies in further studies on Myasthenia gravis.


A sensitive x-ray phase contrast technique for rapid imaging using a single phase grid analyzer.
Phase contrast x-ray imaging (PCXI) is a promising imaging modality, capable of sensitively differentiating soft tissue structures at high spatial resolution. However, high sensitivity often comes at the cost of a long exposure time or multiple exposures per image, limiting the imaging speed and possibly increasing the radiation dose. Here, we demonstrate a PCXI method that uses a single short exposure to sensitively capture sample phase information, permitting high speed x-ray movies and live animal imaging. The method illuminates a checkerboard phase grid to produce a fine grid-like intensity reference pattern at the detector, then spatially maps sample-induced distortions of this pattern to recover differential phase images of the sample. The use of a phase grid is an improvement on our previous absorption grid work in two ways. There is minimal loss in x-ray flux, permitting faster imaging, and, a very fine pattern is produced for homogenous high spatial resolution. We describe how this pattern permits retrieval of five images from a single exposure; the sample phase gradient images in the horizontal and vertical directions, a projected phase depth image, an edge-enhanced image, and a type of scattering image. Finally, we describe how the reconstruction technique can achieve subpixel distortion retrieval and study the behavior of the technique in regard to analysis technique, Talbot distance, and exposure time.


A statistical analysis of the impact of advertising signs on road safety.
This research aims to investigate the impact of advertising signs on road safety. An exhaustive review of international literature was carried out on the effect of advertising signs on driver behaviour and safety. Moreover, a before-and-after statistical analysis with control groups was applied on several road sites with different characteristics in the Athens metropolitan area, in Greece, in order to investigate the correlation between the placement or removal of advertising signs and the related occurrence of road accidents. Road accident data for the 'before' and 'after' periods on the test sites and the control sites were extracted from the database of the Hellenic Statistical Authority, and the selected 'before' and 'after' periods vary from 2.5 to 6 years. The statistical analysis shows no statistical correlation between road accidents and advertising signs in none of the nine sites examined, as the confidence intervals of the estimated safety effects are non-significant at 95% confidence level. This can be explained by the fact that, in the examined road sites, drivers are overloaded with information (traffic signs, directions signs, labels of shops, pedestrians and other vehicles, etc.) so that the additional information load from advertising signs may not further distract them.


Identification of cerebral response to balloon distention of the bile duct.
To identify the brain loci that process human biliary sensation. In 6 patients (age range: 42-74 years; 4 men), who underwent percutaneous transhepatic biliary drainage (PTBD), the distal biliary tract was stimulated by repeatedly inflating the balloon of the PTBD catheter so that it reached volumes that produced a definite painless sensation. The functional magnetic resonance imaging (fMRI) of the cortical response to biliary sensation was examined. Biliary balloon stimulation elicited activation of the insular cortex, prefrontal cortex, and somatosensory cortex (P < 0.001). Biliary balloon stimulation evoked a cerebral cortical response detectable by fMRI.


Costing analysis and anthropological assessment of the vaccine supply chain system redesign in the Comé District (Benin).
At the end of 2013, a pilot experiment was carried out in Comé health zone (HZ) in an attempt to optimize the vaccine supply chain. Four commune vaccine storage facilities were replaced by one central HZ facility. This study evaluated the incremental financial needs for the establishment of the new system; compared the economic cost of the supply chain in the Comé HZ before and after the system redesign; and analyzed the changes induced by the pilot project in immunization logistics management. The purposive sampling method was used to draw a sample from 37 health facilities in the zone for costing evaluation. Data on inputs and prices were collected retrospectively for 2013 and 2014. The analysis used an ingredient-based approach. In addition, 44 semi-structured interviews with health workers for anthropological analysis were completed in 2014. The incremental financial costs amounted to US$55,148, including US$50,605 for upfront capital investment and US$4543 for ongoing recurrent costs. Annual economic cost per dose administered (including all vaccines distributed through the Expanded Program on Immunization (EPI)) in the Comé HZ increased from US$0.09 before system redesign to US$0.15 after implementation, mainly due to a high initial investment and the operational cost of HZ mobile warehouse. Interviews with health workers suggested that the redesigned system was associated with improvements in motivation and professional awareness due to training, supportive supervision, and improved work conditions. The system redesign involved a considerable investment at HZ level. Benefits were found in the reduction of transportation costs to health posts (HP) and commune health center (CHC) levels, and the strengthening of health workers professional skills at all levels in Comé. The redesigned system contributed to a decrease in funding needs at HP and CHC levels. The benefits of the investment need to be examined after the introduction of new vaccines and after a longer period.


Increased levels of RECQ5 shift DNA repair from canonical to alternative pathways.
RECQ5 (RECQL5) is one of several human helicases that dissociates RAD51-DNA filaments. The gene that encodes RECQ5 is frequently amplified in human tumors, but it is not known whether amplification correlates with increased gene expression, or how increased RECQ5 levels affect DNA repair at nicks and double-strand breaks. Here, we address these questions. We show that RECQ5 gene amplification correlates with increased gene expression in human tumors, by in silico analysis of over 9000 individual tumors representing 32 tumor types in the TCGA dataset. We demonstrate that, at double-strand breaks, increased RECQ5 levels inhibited canonical homology-directed repair (HDR) by double-stranded DNA donors, phenocopying the effect of BRCA deficiency. Conversely, at nicks, increased RECQ5 levels stimulated 'alternative' HDR by single-stranded DNA donors, which is normally suppressed by RAD51; this was accompanied by stimulation of mutagenic end-joining. Even modest changes (2-fold) in RECQ5 levels caused significant dysregulation of repair, especially HDR. These results suggest that in some tumors, RECQ5 gene amplification may have profound consequences for genomic instability.


Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis.
Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), and Joubert syndrome (JBTS) are a group of heterogeneous cystic kidney disorders with partially overlapping loci. Many of the proteins associated with these diseases interact and localize to cilia and/or basal bodies. One of these proteins is MKS1, which is disrupted in some MKS patients and contains a B9 motif of unknown function that is found in two other mammalian proteins, B9D2 and B9D1. Caenorhabditis elegans also has three B9 proteins: XBX-7 (MKS1), TZA-1 (B9D2), and TZA-2 (B9D1). Herein, we report that the C. elegans B9 proteins form a complex that localizes to the base of cilia. Mutations in the B9 genes do not overtly affect cilia formation unless they are in combination with a mutation in nph-1 or nph-4, the homologues of human genes (NPHP1 and NPHP4, respectively) that are mutated in some NPHP patients. Our data indicate that the B9 proteins function redundantly with the nephrocystins to regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons. Together, these data suggest that the human homologues of the novel B9 genes B9D2 and B9D1 will be strong candidate loci for pathologies in human MKS, NPHP, and JBTS.


RAD51 localization and activation following DNA damage.
The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability. In response to ionizing radiation and other DNA-damaging agents, the RAD51 protein, which is essential for homologous recombination, relocalizes within the nucleus to form distinct foci that can be visualized by microscopy and are thought to represent sites where repair reactions take place. The formation of RAD51 foci in response to DNA damage is dependent upon BRCA2 and a series of proteins known as the RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3), indicating that the components present within foci assemble in a carefully orchestrated and ordered manner. By contrast, RAD51 foci that form spontaneously as cells undergo DNA replication at S phase occur without the need for BRCA2 or the RAD51 paralogues. It is known that BRCA2 interacts directly with RAD51 through a series of degenerative motifs known as the BRC repeats. These interactions modulate the ability of RAD51 to bind DNA. Taken together, these observations indicate that BRCA2 plays a critical role in controlling the actions of RAD51 at both the microscopic (focus formation) and molecular (DNA binding) level.


Frequency stabilization of a semiconductor laser using an external phase modulator.
A Ti:LiNbO(3) waveguide phase modulator is used as an external frequency stabilizer to reduce the linewidth of an AlGaAs semiconductor laser. A ring interferometer is used as a frequency discriminator, and a wideband servo controller (dc to 30 MHz) is constructed in which feed-forward control of the external phase modulator is combined with feedback control of the injection current. A linewidth of 45 kHz is obtained.


Axial level-specific regulation of neuronal development: lessons from PITX2.
Transcriptional regulation of gene expression is vital for proper control of proliferation, migration, differentiation, and survival of developing neurons. Pitx2 encodes a homeodomain transcription factor that is highly expressed in the developing and adult mammalian brain. In humans, mutations in PITX2 result in Rieger syndrome, characterized by defects in the development of the eyes, umbilicus, and teeth and variable abnormalities in the brain, including hydrocephalus and cerebellar hypoplasia. Alternative splicing of Pitx2 in the mouse results in three isoforms, Pitx2a, Pitx2b, and Pitx2c, each of which is expressed symmetrically along the left-right axis of the brain throughout development. Here, we review recent evidence for axial and brain region-specific requirements for Pitx2 during neuronal migration and differentiation, highlighting known isoform contributions.


Comparative uptake of sparfloxacin and ciprofloxacin into human THP 1 monocytic cells.
The uptake of sparfloxacin (CAS 11542-93-9) by human monocytes was studied by comparison with ciprofloxacin (CAS 86393-32-0). The human monocytic THP 1 cells were incubated with the antibiotics for 2 h. Entry of antimicrobials into the cells was determined by means of a velocity gradient centrifugation technique and HPLC assay. Antibiotic uptake was expressed as the ratio of the intracellular to the extracellular drug concentration (IC/EC). Quinolones enter readily in monocytic cells but sparfloxacin is taken up more rapidly than ciprofloxacin. At steady-state the IC/EC ratio of sparfloxacin (9.07) is higher than IC/EC of ciprofloxacin (4.29). Characterization of quinolone uptake suggests that these drugs penetrate throughout the THP 1 membrane by passive diffusion. However, the results of the present study indicate that additional mechanisms may contribute to intracellular accumulation of ciprofloxacin and sparfloxacin. Gemfibrozil, an inhibitor of organic anion transport, increases the accumulation of ciprofloxacin but does not modify IC/EC of sparfloxacin. It can be concluded that human monocyte-like cells have functional organic anion transporters and that this way of secretion is quinolone selective.


Home-Time as a Surrogate Marker for Functional Outcome After Aneurysmal Subarachnoid Hemorrhage.
Background and Purpose—Commonly used tools to determine functional outcome after aneurysmal subarachnoid hemorrhage (aSAH) have limitations. Time spent at the patient's home has previously been proposed as a robust outcome measure after ischemic stroke. Here, we set out to validate home-time as an outcome measure after aSAH. Methods—We examined prospectively collected data from a nationwide multicenter registry of aSAH patients admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009–2015). We calculated mean home-time (defined as days spent at home for the first 90 days after aSAH) and 95% CIs for each category of modified Rankin Scale at discharge and 1-year follow-up, using linear regression models to analyze home-time differences per modified Rankin Scale category. Results—We had home-time data from 1076 of 1866 patients (57.7%), and multiple imputation was used to fill-in missing data from the remaining 790 patients. Increasing home-time was associated with improved modified Rankin Scale scores at time of hospital discharge (P<0.0001) and at 1-year follow-up (P<0.0001). Within each of the 8 participating hospitals, the relationship between home-time and modified Rankin Scale was maintained. Conclusions—Home-time for the first 90 days after aSAH offers a robust and easily ascertainable outcome measure, discriminating particularly well across better recovery levels at time of hospital discharge and at 1-year follow-up. This measure complies with the modern trend of patient-centered healthcare and research, representing an outcome that is particularly relevant to the patient.


Assessing acceptance in mindfulness with direct-worded items: The development and initial validation of the Athlete Mindfulness Questionnaire.
The purpose of the current study was to develop and validate a sport-specific mindfulness measure, the Athlete Mindfulness Questionnaire (AMQ), through 5 related studies using 4 separate samples of Chinese athletes. The AMQ is a 3-factor measure designed to assess mindfulness that reflects present-moment attention, awareness, and acceptance in a sport context. In Study 1, an initial pool of items was generated based on previous literature, existing mindfulness scales, as well as interviews with and feedback from the athletes, coaches, and mindfulness experts. Initial support for the 3-factor structure of the AMQ was established via exploratory factor analysis in Study 2, and cross-validated through confirmatory factor analysis in Studies 3 and 4. In Study 5, a modified 3-factor AMQ with direct-worded acceptance items was examined in a fourth independent sample. Convergent and concurrent validities of the acceptance subscale failed to be established in Studies 3 and 4 which may be due to the inattention and confusion of the athletes whilst interpreting the reverse-worded items. A modified 16-item AMQ in Study 5 displayed satisfactory model fit and acceptable internal consistencies. Most importantly, convergent and concurrent validities of the 16-item AMQ were supported. The 3 subscales showed significant positive associations with mindfulness, flow, well-being, and positive affect and significant negative associations with experiential avoidance, burnout, and negative affect. The AMQ is a psychometrically sound measure of mindfulness in a sport context. The importance of using direct-worded acceptance items is discussed.


Nursing documentation in patient records: experience of the use of the VIPS model.
The VIPS model for the documentation of nursing care in patient records was scientifically developed and published in 1991, with the aim of supporting the systematic documentation of nursing care and promoting individualized care. As the model seemed to be accepted and used in many parts of Sweden, a study was conducted in order to gather further information on the validity of the model, to describe the clinical and educational experience of its use and to refine it. Experience of the use of the model was gathered from a review of the scientific papers and other reports on it, from questionnaires addressed to nurses (n = 514), from comments by key informants, and from interviews with faculty members at all the nursing schools in the country. The findings showed that an intense process of change and development was occurring regarding nursing documentation. However, there were limitations in the use of the entire nursing process, especially in the specification of patient problems and the formulation of nursing diagnoses and nursing interventions. The keywords (Swedish spelling) of the VIPS model had good content validity in different areas of nursing care. The findings also indicated the need for further elaboration and revision of some of the keywords. A revised version of the VIPS model based on these findings is presented.


Epidemiology of human papillomavirus infection in men, cancers other than cervical and benign conditions.
Human papillomavirus (HPV) infection is commonly found in the genital tract of men and women with or without any clinical lesion. The association of HPV DNA with several different ano-genital cancers other than cervical has been reported for the vulva, vagina, anus and penis. HPV DNA has also been identified in head and neck cancers in the oral cavity, the oropharynx and the larynx in both sexes. In men, 80-85% of anal cancers and close to 50% of penile cancers are associated with HPV infection. In women, HPV DNA is prevalent in 36-40% vulvar cancer cases and close to 90% of vaginal cancers. There is limited data available on the natural history and HPV-related diseases in the genital tract in men, although studies are ongoing. Efficacy of HPV vaccines in the prevention of HPV infection and disease among men also remains unknown. Among HPV DNA positive ano-genital cancer cases, HPV-16 is the most frequently found followed distantly by HPV-18. In benign HPV-related diseases such as genital warts or recurrent respiratory papillomatosis HPV-6 and 11, the two most frequent non-oncogenic types, are the predominant types detected. Oncogenic types are rarely detected. In this article we summarize and review studies describing the natural history of HPV infections among men and its impact on HPV related disease in women. We summarize the evidence linking HPV in the epidemiology and etiology of cancers of the vulva, vagina, anus and oropharynx and present recent estimates of the burden of and HPV type distribution in genital warts and in cases of HPV infection of the airways.


A possible molecular basis of natriuresis during ischemic-reperfusion injury in the kidney.
Ischemic renal injury is associated with increased fractional excretion of sodium, suggesting a Na+ reabsorption deficiency in renal tubules. To determine whether alterations in expression of the major Na+ transporter genes might contribute to the natriuresis that follows ischemic acute renal failure, the expression of these genes was analyzed in renal cortex and medulla after ischemic-reperfusion injury. Rats were subjected to 30 min of renal pedicle clamping and then sacrificed at 12, 24, or 48 h after reperfusion. Serum creatinine increased significantly at 12 and 24 h, indicative of acute renal failure, but decreased substantially by 48 h. mRNA levels for the NHE-3 Na/H exchanger of the proximal tubule, the apical Na-K-2Cl cotransporter of the thick ascending limb of Henle, the Na-Cl cotransporter of the distal convoluted tubule, the epithelial Na+ channel of the collecting duct, and the basolateral Na(+)-K(+)-ATPase were measured by Northern hybridization. NHE-3 mRNA decreased by approximately 75% at 12 h and remained suppressed at 24 and 48 h after reperfusion. Na-K-2Cl cotransporter mRNA decreased by approximately 88% at 12 h and remained suppressed at 24 and 48 h. Na-Cl cotransporter mRNA remained unchanged at 12 h, decreased by approximately 60% at 24 h, and returned to almost control levels at 48 h. mRNA levels for sodium channels (beta subunit) remained unchanged. Na(+)-K(+)-ATPase mRNA in the medulla decreased by approximately 35 to 40% at 12 and 24 h and by 70% at 48 h, whereas in cortex it decreased by only < 15% at 12 or 48 h after reperfusion. These results suggest that sharp reductions in expression of the NHE-3 Na/H exchanger and the apical Na-K-2Cl cotransporter are major factors in the natriuresis/diuresis that is one of the hallmarks of ischemic acute renal failure. Lasting suppression of these transporters, despite improvement in renal function, could contribute to the deranged NaCl and water excretion that often leads to volume depletion during recovery from ischemic acute renal failure.


Improving the stability of algebraic curves for applications.
An algebraic curve is defined as the zero set of a polynomial in two variables. Algebraic curves are practical for modeling shapes much more complicated than conics or superquadrics. The main drawback in representing shapes by algebraic curves has been the lack of repeatability in fitting algebraic curves to data. Usually, arguments against using algebraic curves involve references to mathematicians Wilkinson (and Runge). The first goal of this article is to understand the stability issue of algebraic curve fitting. Then a fitting method based on ridge regression and restricting the representation to well behaved subsets of polynomials is proposed, and its properties are investigated. The fitting algorithm is of sufficient stability for very fast position-invariant shape recognition, position estimation, and shape tracking, based on invariants and new representations. Among appropriate applications are shape-based indexing into image databases.


Multiple target-specific molecular imaging agents detect liver cancer in a preclinical model.
Liver cancer is the fifth most common cause of cancer deaths worldwide. Noninvasive diagnosis is difficult and the disease heterogeneity reduces the accuracy of pathological assays. Improvement in diagnostic imaging of specific molecular disease markers has provided hope for accurate and early noninvasive detection of liver cancer. However, all current imaging technologies, including ultrasonography, computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging, are not specific targets for detection of liver cancer. The aim of this study was to test the feasibility of injecting a cocktail of specific molecular imaging agents to noninvasively image liver cancer. The target-specific cocktail contained agents for imaging the neovasculature (RGD peptide), matrix metalloproteinase (MMP), and glucose transport ((18)F-fluorodeoxyglucose [(18)F-FDG]). Imaging studies were performed in liver cancer cells and xenograft models. The distribution of MMP at the intracellular level was imaged by confocal microscopy. RGD, MMP, and (18)F-FDG were imaged on tumor-bearing mice using PET, CT, X-ray, and multi-wavelength optical imaging modalities. Image data demonstrated that each agent bound to a specific disease target component. The same liver cancer xenograft contained multiple disease markers. Those disease markers were heterogenetically distributed in the same tumor nodule. The molecular imaging agents had different distributions in the whole body and inside the tumor nodule. All target-specific agents yielded high tumor-to-background ratios after injection. In conclusion, target-specific molecular imaging agents can be used to study liver cancer in vitro and in vivo. Noninvasive multimodal/multi-target-specific molecular imaging agents could provide tools to simultaneously study multiple liver cancer components.


Detection of Helicobacter pylori gastritis by PCR: correlation with inflammation scores and immunohistochemical and CLOtest findings.
We developed a polymerase chain reaction (PCR) assay to detect Helicobacter pylori in gastric and/or gastroesophageal biopsy specimens of adults with dyspepsia, compared the method with immunohistochemical analysis and CLOtest (Ballard Medical Products, Draper, UT), and correlated the results of each test with the histologic features of infection. H pylori was identified in 36 (60%) of 60 patients irrespective of biopsy site and testing method. In the gastric biopsy specimens, PCR detected H pylori in 29 (52%) of 56 cases, including 11 (100%) of 11 immunohistochemically and/or CLOtest-positive cases. PCR-positive gastric biopsy specimens correlated with a higher average cumulative inflammatory score compared with PCR-negative specimens (P = .001). In gastroesophageal biopsy specimens, PCR detected H pylori in 15 (34%) of 44 cases, including 1 (20%) of 5 immunohistochemically positive specimens. PCR-positive gastroesophageal junction biopsy specimens did not correlate with a higher average cumulative inflammatory score. Overall, PCR detected an additional 23 cases negative by immunohistochemical analysis and/or CLOtest. This PCR assay identified a significant number of H pylori infections that would not be detected by immunohistochemical analysis and/or CLOtest.


Ethanol and water extract of purple sweet potato exhibits anti-atherosclerotic activity and inhibits protein glycation.
It is well known that extracts of purple sweet potato (PSP) have potent antioxidant activity. However, it has not been established whether extracts of PSP inhibit oxidation of low-density lipoprotein (LDL) or protein glycation. LDL oxidation and protein glycation are well-known risk factors for chronic metabolic diseases, such as atherosclerosis and diabetes mellitus. Chopped and sliced PSP and yellow sweet potato (YSP) were extracted individually at a concentration of 1 g of PSP tuber/mL using either ethanol or water for 6 hours. The PSP ethanol extract (100-fold diluted) showed stronger radical (2,2-diphenyl-1-picrylhydrazyl radical) scavenging activity than the water extract of PSP and the ethanol extract of YSP (up to a sixfold higher activity). The ethanol extract of PSP also exhibited the highest increase in ferric reducing ability among all extracts. Cupric ion-mediated LDL oxidation was strongly inhibited by the ethanol extract of PSP, with similar potency to vitamin C treatment (final concentration, 10 mM). The PSP extract strongly inhibited fructose-mediated protein glycation as determined by fluorescence spectroscopy. The PSP extract-treated apolipoprotein (apo) A-I showed a decreased multimerization pattern on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas glycated apoA-I showed the strongest multimeric band. PSP extract treatment also inhibited the uptake of oxidized LDL into human macrophage cells with suppression of malondialdehyde production in the cell culture medium. In conclusion, these results suggest that the extract of PSP can be used as a putative anti-atherosclerotic and antidiabetic agent with strong antioxidant functions. This is the first report to show the biological functions of PSP extract to treat hyperlipidemic and hyperglycemic disorders.


PECC--factor structure and findings in three longitudinal cohorts of patients with schizophrenia.
Symptom control by drug treatment is the most important task in routine clinical care of patients with schizophrenia. Structured assessment methods are needed in this task but not used much. The US-developed Positive and Negative Syndrome Scale (PANSS) is a standard tool for symptom assessment. The Psychosis Evaluation tool for Common use by Caregivers (PECC) was constructed in Europe some years ago, with the intent to overcome some of the PANSS drawbacks. To validate PECC on three longitudinal cohorts of schizophrenic patients representative of Swedish outpatients (n = 225, six assessments over 5 years), international forensic patients (n = 186) and matched non-forensic controls (n = 116), five assessments over 2 years for both. The factor structure of PECC appears to be highly robust. Norm values (in percentiles) were calculated on the materials. Such data provides for analyses of symptom profiles and improvement over time measured in absolute numbers. Forensic patients appear to have a much lower symptom load (except for cognitive symptoms) than the other groups. Forensic controls had much shorter inpatient times than any other group and never caught up with respect to symptom control, even after 2 years. These differences suggest that the scale is clinically valid. PECC has a more robust factor structure than PANSS and is simpler to use. Percentile norms have been constructed for outpatients with schizophrenia in general and forensic psychiatry. Percentile scores are accessed readily by the net. PECC is available in many languages. Its separate self-harm item may improve assessments of suicide risk among patients with schizophrenia.


Captopril reduces left ventricular enlargement induced by chronic volume overload.
The effect of captopril treatment on left ventricular (LV) function, mass, and volume during chronic volume overload induced by production of aortic insufficiency (AI) was studied. AI was caused by mechanical disruption of the aortic valve in 175- to 225-g male Sprague-Dawley rats. At 24 h after surgery, AI and sham-operated rats were divided into control and captopril treatment (2 g/l drinking water) groups. After 2 mo of treatment, hemodynamics were measured in open-chest rats, and the LV pressure-volume relation was determined ex vivo. Compared with sham-operated rats, in the untreated AI rats, aortic pulse pressure was increased nearly 100%, LV end-diastolic pressure was 10 +/- 1 vs 3 +/- 1 mmHg, and LV end-diastolic volume was 1.25 +/- 0.07 vs 0.36 +/- 0.03 ml. LV weight was increased 43% and the LV pressure-volume relation was shifted rightward by AI. LV systolic and diastolic wall stress were increased in rats with AI. Peak LV pressure during aortic occlusion was decreased in AI rats, however, peak wall stress during aortic occlusion was not different compared with sham-operated rats. Captopril treatment decreased aortic pulse pressure and LV systolic pressure. Both LV weight and LV end-diastolic volume measured from the ex vivo pressure-volume relation at LV end-diastolic pressure were increased by 33% in untreated AI rats compared with captopril-treated AI rats. Captopril treatment of AI rats shifted the LV pressure-volume to the left compared with untreated rats. LV pressure and wall stress during aortic occlusion were not changed in captopril-treated AI rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Whole genome sequencing Mycobacterium tuberculosis directly from sputum identifies more genetic diversity than sequencing from culture.
Repeated culture reduces within-sample Mycobacterium tuberculosis genetic diversity due to selection of clones suited to growth in culture and/or random loss of lineages, but it is not known to what extent omitting the culture step altogether alters genetic diversity. We compared M. tuberculosis whole genome sequences generated from 33 paired clinical samples using two methods. In one method DNA was extracted directly from sputum then enriched with custom-designed SureSelect (Agilent) oligonucleotide baits and in the other it was extracted from mycobacterial growth indicator tube (MGIT) culture. DNA directly sequenced from sputum showed significantly more within-sample diversity than that from MGIT culture (median 5.0 vs 4.5 heterozygous alleles per sample, p = 0.04). Resistance associated variants present as HAs occurred in four patients, and in two cases may provide a genotypic explanation for phenotypic resistance. Culture-free M. tuberculosis whole genome sequencing detects more within-sample diversity than a leading culture-based method and may allow detection of mycobacteria that are not actively replicating.


Use of the Radionics Image Fusiontrade mark and Stereoplantrade mark programs for target localization in functional neurosurgery.
We describe the use of Radionics Image Fusiontrade mark and Stereoplantrade mark in defining the target for thalamotomy and pallidotomy in functional surgery for parkinsonism and tremor. Using this to fuse and spatially correct magnetic resonance imaging (MRI) to computed tomography (CT) images our calculated targets were a mean of 0.6 +/- 1.5 mm from the end target determined physiologically by stimulation. This is significantly better than the values of 2.6 +/- 1.6 mm for thalamic targets and 7.1 +/- 3.7 mm for pallidal targets using CT alone. As a consequence, determination of the target and the lesion making are routinely performed in one pass of the electrode allowing for faster, more accurate and, we believe, safer functional procedures.


Prognostic factors for disease progression after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for recurrent or refractory Hodgkin's lymphoma.
Our purpose was to study the risk factors associated with disease progression after high-dose chemotherapy followed by autologous stem cell transplantation in patients with recurrent or refractory Hodgkin's lymphoma (HL). We analyzed the long-term outcome of 184 patients with recurrent or refractory HL who underwent autologous hematopoietic stem cell transplantation. At the time of transplantation, 82 patients were in first relapse or second remission, 46 patients were refractory to the primary induction chemotherapy, and 56 patients were beyond first relapse or second remission. In 64 patients, the disease had proved refractory to the chemotherapy regimen administered immediately prior to transplantation. The median follow-up of patients who were alive and free of disease at the time of this report was 8.9 years (range, 0.1-19.0 years). At 10 years, the overall and disease-free survival rates were 34% (95% CI 27-42) and 29% (95% CI 22-36) respectively. The major cause of treatment failure was disease relapse. Chemotherapy resistance prior to transplantation, advanced stage, and higher number of chemotherapy regimens administered prior to transplantation were adverse prognostic factors for disease progression. We conclude that autologous transplantation is an effective salvage treatment for recurrent HL.


BAK1 is not a target of the Pseudomonas syringae effector AvrPto.
Plant cell surface-localized receptor kinases such as FLS2, EFR, and CERK1 play a crucial role in detecting invading pathogenic bacteria. Upon stimulation by bacterium-derived ligands, FLS2 and EFR interact with BAK1, a receptor-like kinase, to activate immune responses. A number of Pseudomonas syringae effector proteins are known to block immune responses mediated by these receptors. Previous reports suggested that both FLS2 and BAK1 could be targeted by the P. syringae effector AvrPto to inhibit plant defenses. Here, we provide new evidence further supporting that FLS2 but not BAK1 is targeted by AvrPto in plants. The AvrPto-FLS2 interaction prevented the phosphorylation of BIK1, a downstream component of the FLS2 pathway.


Pufendorf on Passions and Sociability.
Samuel Pufendorf is known for his normative natural law philosophy, and particularly for his theory of sociability. This article concentrates on a topic that has received very little attention - his theory of the motivating character of passions in social life. It will demonstrate that individually and politically governed passions play a central role in Pufendorf's description of the structure of human societies. I argue that for Pufendorf the norms of sociability are effective in social life because social interaction, guided by political governance, enables people to moderate their antisocial passions and habituate themselves to sociable passions.


The grouping benefit in extinction: overcoming the temporal order bias.
Grouping between contra- and ipsilesional stimuli can alleviate the lateralised bias in spatial extinction (Gilchrist, Humphreys, & Riddoch, 1996; Ward, Goodrich, & Driver, 1994). In the current study we demonstrate for the first time that perceptual grouping can also modulate the spatio/temporal biases in temporal order judgements affecting the temporal as well as the spatial coding of stimuli. Perceived temporal order was assessed by presenting two coloured letter stimuli in either hemi-field temporally segregated by a range of onset-intervals. Items were either identical (grouping condition) or differed in both shape and colour (non-grouping condition). Observers were required to indicate which item appeared second. Patients with visual extinction had a bias against the contralesional item appearing first, but this was modulated by perceptual grouping. When both items were identical in shape and colour the temporal bias against reporting the contralesional item was reduced. The results suggest that grouping can alter the coding of temporal relations between stimuli.


Effect of CPoint, EndoSequence BC, and Gutta-percha Points on Viability and Gene Expression of Periodontal Ligament Fibroblasts.
This study aimed to investigate the cytotoxic and biomodulatory potential of conventional gutta-percha (CGP) points, gutta-percha points containing bioceramics (BC), and CPoint polymer (CP) points on periodontal ligament (PDL) cells in vitro. PDL fibroblasts were cultured and stimulated with extracts of CGP, BC, and CP in serial dilutions to evaluate cell viability using MTT assay. Next, the 1:5 dilution was used to stimulate the cells for 72 h to assess the gene expression of type I collagen (COL-1) and cement protein 1 (CEMP-1), by reverse transcription followed by quantitative PCR. Data were statistically analyzed using one-way analysis of variance (ANOVA) (P<0.05). Pure extracts of CGP and CP were found to be cytotoxic for PDL (P<0.01). Once diluted to 1:5, only CP showed cytotoxicity. BC did not affect cell viability in any extract sample. No extract significantly altered the gene expression of COL-1. For CEMP-1, a significant increase in gene expression was observed only for CGP (P<0.05). CP was found to be more cytotoxic than CGP, while BC demonstrated no cytotoxicity. The tested cones did not affect COL-1 gene expression, while CGP upregulated CEMP-1. Our results suggest that obturation point components may affect the biological responses of PDL fibroblasts.


Autoantibodies to agrin in myasthenia gravis patients.
To determine if patients with myasthenia gravis (MG) have antibodies to agrin, a proteoglycan released by motor neurons and is critical for neuromuscular junction (NMJ) formation, we collected serum samples from 93 patients with MG with known status of antibodies to acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related 4 (LRP4) and samples from control subjects (healthy individuals and individuals with other diseases). Sera were assayed for antibodies to agrin. We found antibodies to agrin in 7 serum samples of MG patients. None of the 25 healthy controls and none of the 55 control neurological patients had agrin antibodies. Two of the four triple negative MG patients (i.e., no detectable AChR, MuSK or LRP4 antibodies, AChR-/MuSK-/LRP4-) had antibodies against agrin. In addition, agrin antibodies were detected in 5 out of 83 AChR+/MuSK-/LRP4- patients but were not found in the 6 patients with MuSK antibodies (AChR-/MuSK+/LRP4-). Sera from MG patients with agrin antibodies were able to recognize recombinant agrin in conditioned media and in transfected HEK293 cells. These sera also inhibited the agrin-induced MuSK phosphorylation and AChR clustering in muscle cells. Together, these observations indicate that agrin is another autoantigen in patients with MG and agrin autoantibodies may be pathogenic through inhibition of agrin/LRP4/MuSK signaling at the NMJ.


Prevention of Late Onset Sepsis and Central-line Associated Blood Stream Infection in Preterm Infants.
Late onset sepsis (LOS) and central-line associated blood stream infection (CLA-BSI) contribute toward the mortality and morbidity in prematurely born infants. The aim of this study is to investigate the effects of hospital-wide and unit-based interventions on LOS and CLA-BSI in infants born at <32 weeks gestation. Intensive care, high dependency days and catheter days were obtained from the unit database and blood culture results from a microbiology laboratory database. Poisson regression was used to evaluate the effects of interventions on LOS and CLA-BSI. Quarterly rates of LOS reduced from 26.1 to 2.9 per 1000 intensive care, high dependency days and CLA-BSI from 31.6 to 4.3 per 1000 catheter days between 2007 and 2012. Appointment of a hospital specialist vascular device nurse, a change in the mode of administration of vancomycin, standardization of the hospital skin and hub disinfection policy and the introduction of a venous infusion phlebitis scoring system were associated with a reduction of LOS to 55% (95% confidence interval: 40-74%) and CLA-BSI 45% (95% confidence interval: 33-61%) of pre-intervention levels. The standardization of the neonatal unit policy for skin disinfection and a move to a new building were associated with reductions of LOS to 64% (47-87%) and 54% (34-88%), respectively, and aseptic no touch technique for infusion access with CLA-BSI to 53% (37-75%) of pre-intervention levels. A multifaceted approach involving changes in antimicrobial and skin disinfection policy, training for aseptic no touch technique and surveillance resulted in sustained reduction in LOS and CLA-BSI rates.


Tumor-Infiltrating T Cells From Clear Cell Renal Cell Carcinoma Patients Recognize Neoepitopes Derived From Point and Frameshift Mutations.
Mutation-derived neoantigens are important targets for T cell-mediated reactivity toward tumors and, due to their unique tumor expression, an attractive target for immunotherapy. Neoepitope-specific T cells have been detected across a number of solid cancers with high mutational burden tumors, but neoepitopes have been mostly selected from single nucleotide variations (SNVs), and little focus has been given to neoepitopes derived from in-frame and frameshift indels, which might be equally important and potentially highly immunogenic. Clear cell renal cell carcinomas (ccRCCs) are medium-range mutational burden tumors with a high pan-cancer proportion of frameshift mutations. In this study, the mutational landscape of tumors from six RCC patients was analyzed by whole-exome sequencing (WES) of DNA from tumor fragments (TFs), autologous tumor cell lines (TCLs), and tumor-infiltrating lymphocytes (TILs, germline reference). Neopeptides were predicted using MuPeXI, and patient-specific peptide-MHC (pMHC) libraries were created for all neopeptides with a rank score < 2 for binding to the patient's HLAs. T cell recognition toward neoepitopes in TILs was evaluated using the high-throughput technology of DNA barcode-labeled pMHC multimers. The patient-specific libraries consisted of, on average, 258 putative neopeptides (range, 103-397, n = 6). In four patients, WES was performed on two different sources (TF and TCL), whereas in two patients, WES was performed only on TF. Most of the peptides were predicted from both sources. However, a fraction was predicted from one source only. Among the total predicted neopeptides, 16% were derived from frameshift indels. T cell recognition of 52 neoepitopes was detected across all patients (range, 4-18, n = 6) and spanning two to five HLA restrictions per patient. On average, 21% of the recognized neoepitopes were derived from frameshift indels (range, 0-43%, n = 6). Thus, frameshift indels are equally represented in the pool of immunogenic neoepitopes as SNV-derived neoepitopes. This suggests the importance of a broad neopeptide prediction strategy covering multiple sources of tumor material, and including different genetic alterations. This study, for the first time, describes the T cell recognition of frameshift-derived neoepitopes in RCC and determines their immunogenic profile.


Cytochemical characterization of microvillar and perimicrovillar membranes in the posterior midgut epithelium of Rhodnius prolixus.
Perimicrovillar membranes (PMM) are structures present on the surface of midgut epithelial cells of the hematophagous insect, Rhodnius prolixus. They cover the microvilli and are especially evident 10 days after blood meal, providing the compartmentalization of the enzymatic processes in the intestinal microenvironment. Using an enzyme cytochemical approach, Mg2+-ATPase and ouabain-sensitive Na+K+-ATPase activities were observed in the plasma (or microvillar) membrane (MM) of midgut cells and in the PMM. In contrast, alkaline phosphatase was only detected in MM. Using cationized ferritin and colloidal iron hydroxide particles, anionic sites were found only on the luminal surface of the PMM. Using fluorescein isothiocyanate (FITC)-labeled lectins, residues of alpha-d-galactose, mannose, N-acetyl-neuraminic acid, N-acetyl-d-galactosamine and N-acetyl-galactosamine-alpha-1,3-galactose were detected on the apical surface of posterior midgut epithelial cells. On the other hand, using FITC-labeled neoglycoproteins (NGP) it was possible to detect the presence of carbohydrate binding molecules (CBM) recognizing N-acetyl-d-galactosamine, alpha-d-mannose, alpha-l-fucose and alpha-d-glucose in the posterior midgut epithelium. The use of digitonin showed the presence of sterols in the MM and PMM. These results have led the authors to suggest that for some components the PMM resembles the MM lining the midgut cells of R. prolixus, composing a system which covers the microvilli and stretches to the luminal space.


Detection and quantification of maternal-effect gene transcripts in mouse second polar bodies: potential markers of embryo developmental competence.
To test the hypothesis that quantification of messenger RNAs originating from the second polar body (PB(2)) provides a noninvasive tool for assessing embryo quality. Prospective study. Hospital-based academic research laboratory. CD1 female mice. Metaphase II oocytes obtained from 7- to 8-week-old mice after pregnant mare's serum gonadotropin and hCG priming. After in vitro fertilization, the PB(2) was biopsied from zygote, followed by reverse transcription. Real-time polymerase chain reaction was performed to quantify gene expression levels in single PB(2). The sibling zygotes were continuously cultured to blastocyst stage. Embryo developmental competence and six maternal-effect gene (Dnmt1, Mater, Nobox, Npm2, Tcl1, and Zar1) transcripts in the PB(2). Second polar body messenger RNA was detected in all candidate genes. Transcripts that were present in greater abundance in the zygote were more likely to be detected in quantitative polymerase chain reaction replicates from single PB(2). Four candidate genes (Dnmt1, Nobox, Npm2, and Tcl1) expression levels in PB(2) between two groups (two-cell embryo vs. blastocyts) approached statistical significance. Second polar bodies may contain a representative transcript profile to that of the zygote after fertilization. Differences in gene expression in PB(2) may be potential biomarkers of embryo quality.


Cinnamon effects on metabolic syndrome: a review based on its mechanisms.
Nowadays, cardiovascular diseases (CVDs) are the major risk factors of death globally. One of the most undeniable reasons of CVDs is metabolic syndrome (MetS). MetS is defined as a complex of diseases including insulin resistance, hyperglycemia, obesity, high blood pressure and dyslipidemia. The use of complementary medicine such as traditional herbal species can be effective in treatment of MetS's complications. Cinnamomum verum (family Lauraceae) is a medicinal global plant which has been used daily by people all over the world. Positive effects of cinnamon in reducing blood pressure, plasma glucose, obesity and ameliorating dyslipidemia which represented in traditional medicine introduced it as probable decreasing MetS's complications agent. The aim of this review was to investigate the mechanisms of C. verum in reducing the MetS's complications and CVDs risk factors. Various databases such as PubMed, Science Direct, Scopus, Web of Science, Google Scholar and Persian Websites such as www.sid.ir with keywords search of cinnamon, cinnamomum, cinnamaldehyde, atherogenic, hypertension, hyperglycemia, insulin resistance, obesity and dyslipidemia have been included in this search. Clinical data and mechanisms of action of C. verum and its active ingredients that have been shown in this review indicated that cinnamon has protective effects against MetS's aspects in various ways. The use of this plant can be effective in reducing MetS's complications and its morbidity and mortality.


Spatio-temporal analysis of pneumonia and influenza hospitalizations in Ontario, Canada.
Pneumonia and influenza represent a significant public health and health care system burden that is expected to increase with the aging of developed nations' populations. The burden of these illnesses is far from uniform however, with recent studies showing that they are both highly spatially and temporally variable. We have combined spatial and time-series analysis techniques to examine pneumonia and influenza hospitalizations in the province of Ontario, Canada, to determine how temporal patterns vary over space, and how spatial patterns of hospitalizations vary over time. Knowledge of these patterns can provide clues to disease aetiology and inform the effective management of health care system resources. Spatial analysis revealed significant clusters of high hospitalization rates in northern and rural counties (Moran's I = 0.186; P <0.05), while county level time series analysis demonstrated significant upward trends in rates in almost a quarter of the counties (P <0.05), and significant seasonality in all but one county (Fisher-Kappa and Barlett Kolmogorov Smirnov tests significant at the level P <0.01). Areas of weak seasonality were typically seen in rural areas with high rates of hospitalizations. The highest levels of spatial clustering of pneumonia and influenza hospitalizations were found to occur in months when rates were lowest. The findings provide evidence of spatio-temporal interaction over the study period, with marked spatial variability in temporal patterns, and temporal variability in spatial patterns. Results point to the need for the effective allocation of services and resources based on regional and seasonal demands, and more regionally focused prevention strategies. This research represents an important step towards understanding the dynamic nature of these illnesses, and sets the stage for the application of spatio-temporal modelling techniques to explain them.


The Diversity of Strawberry latent ringspot virus in New Zealand.
Strawberry latent ringspot virus (SLRSV) is widespread in many countries, especially in Europe. The virus was thought to be uncommon in New Zealand, having only been recorded in Prunus spp. However, this study revealed that SLRSV infects a much wider range of hosts. From 1999 to 2009, SLRSV was isolated from anemone (Anemone × hybrida), blackberry (Rubus spp.), impatiens (Impatiens walleriana), pepino (Solanum muricatum), and tibouchina (Tibouchina sp.) in the North Island of New Zealand. These SLRSV isolates were identified using electron microscopy, mechanical inoculation, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction techniques. This is thought to be the first report of anemone, impatiens, pepino, and tibouchina as hosts of SLRSV. Phylogenetic analysis and host range suggest that the five newly identified New Zealand isolates belong to two distinct strains: blackberry and impatiens isolates represent one strain and the other three isolates, plus the flowering cherry isolate reported previously in New Zealand, represent another strain. Both these strains are distinct from isolates reported elsewhere in the world. The strain infecting blackberry and impatiens is especially different and produced an unusual reaction in mechanical inoculation tests on herbaceous indicators. It is postulated that SLRSV may have gone undetected on its wider host range in New Zealand due to the latent infection in some hosts. The relationship of SLRSV isolates between New Zealand and overseas and the transmission modes of this virus are also discussed.


Development of Merkel Cell Carcinoma in a Patient Receiving Rituximab.
Merkel cell carcinoma (MCC) is a rare, rapidly growing, and aggressive dermatological neoplasm. It is commonly reported in Caucasian ethnicities, and almost 50% of the patients have a concomitant malignancy and are on immunosuppressive chemotherapy. Here, we present a 79-year-old woman with a history of relapsed Stage II, grade III follicular lymphoma, receiving maintenance rituximab infusions. She presented with a raised erythematous papule on her left cheek. An excisional biopsy of the lesion confirmed a diagnosis of Merkel cell carcinoma. After which, she underwent a wider excision with 1-2 cm margins. PET scan did not reveal any FDG-avid uptake lesions that would be concerning for metastatic disease. However, she underwent a sentinel lymph node biopsy which was also negative. Thus, the diagnosis was finalized as Stage I (T1 N0 M0) MCC. There are only two reported cases in literature about the significant progression of Merkel cell carcinoma in patients who coincidentally were receiving rituximab as a part of treatment for another disease. This raises questions for future investigation and research on whether there is a direct association between rituximab use specifically and the rapid growth of MCC.


Lung hyperinflation and flow limitation in chronic airway obstruction.
We reasoned that if flow limitation plays an important role in lung hyperinflation, then bronchodilatation should be associated with a decrease of functional residual capacity (FRC) only in subjects breathing under conditions of flow limitation. This hypothesis was tested in 33 subjects with chronic airway narrowing due to asthma or chronic obstructive pulmonary disease (COPD). Flow limitation during tidal breathing was inferred from the impingement of the tidal flow-volume loop on the flow recorded during submaximally forced expiratory manoeuvres initiated from end-tidal inspiration. At baseline, flow limitation during tidal breathing was present in seven asthmatic (Group 1) and eight COPD subjects (Group 2), but absent in 11 asthmatic (Group 3) and seven COPD subjects (Group 4). FRC (mean+/-SEM) was similar in the four groups (range 117+/-7 to 134+/-6% of predicted). Inhalation of salbutamol (200 microg) caused significant increments of the forced expiratory volume in one second (FEVI) (range 6+/-1 to 21+/-8% of baseline) and forced expiratory flows at 30% of baseline forced vital capacity (V'30) (range 58+/-13 to 235+/-93% of baseline) in all groups. In groups with flow limitation during tidal breathing at baseline the FRC measured by plethysmography decreased significantly (12+/-2% in Group 1, and 9+/-2% in Group 2), and the inspiratory capacity (IC) measured by spirometry increased significantly (17+/-3% in Group 1 and 7+/-3% in Group 2). This was associated with flow limitation disappearing at the volume of baseline end-tidal expiration. In Groups 3 and 4 neither FRC nor IC changed significantly. The breathing pattern was not modified in any group after salbutamol. These findings suggest that flow limitation may contribute to generation of lung hyperinflation both in asthma and chronic obstructive pulmonary disease. We speculate that the increment of functional residual capacity could be triggered by dynamic airway compression downstream from the flow-limiting segment.


[Clinical aspects and outcome of meningococcal disease due to Neisseria meningitidis of serogroup W135 in 5 children].
Meningococcal disease due to Neisseria meningitidis of serogroup W135 (N. meningitidis W135) is increasing in France. Clinical and outcome data concerning these infections in children are scarce. We report five cases of children hospitalized between June 2000 and December 2002 for N. meningitidis W135 infection. Extra-meningeal septic and/or non-septic complications were frequent and a prolonged post meningococcal inflammatory syndrome was reported. In N. meningitidis W135 infections a careful clinical evaluation of potential extra-meningeal complications and a long term follow up of children are needed.


Search for neutral minimal supersymmetric standard model Higgs bosons decaying to tau pairs in pp collisions at √s=7 TeV.
A search for neutral minimal supersymmetric standard model (MSSM) Higgs bosons in pp collisions at the LHC at a center-of-mass energy of 7 TeV is presented. The results are based on a data sample corresponding to an integrated luminosity of 36 pb(-1) recorded by the CMS experiment. The search uses decays of the Higgs bosons to tau pairs. No excess is observed in the tau-pair invariant-mass spectrum. The resulting upper limits on the Higgs boson production cross section times branching fraction to tau pairs, as a function of the pseudoscalar Higgs boson mass, yield stringent new bounds in the MSSM parameter space.


Antiquated tests within the clinical pathology laboratory.
To provide evidence supporting the discontinuation of laboratory tests that do not have clinical utility today. We selected 10 representative tests considered antiquated by most experts in the clinical laboratory medicine field: creatine kinase-MB, myoglobin, serum folate and red blood cell folate, amylase, lecithin/sphingomyelin ratio, qualitative serum human chorionic gonadotropin, prostatic acid phosphatase, bleeding time, and erythrocyte sedimentation rate. Published literature was reviewed to provide evidence of the poor performance and/or limited clinical utility of these tests. When available, subscriptions to the Proficiency Testing Program of the College of American Pathologists were tracked from 1993 to 2008 as supporting evidence. Finally, when appropriate, alternative testing was suggested. The data show clearly that there is a national trend toward reduction or elimination of these 10 tests. Together with their clinical colleagues, clinical laboratorians should review their menu of tests and consider removing tests that do not provide clinical benefit. In most cases, alternative tests are already in clinical use.


Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.


Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.
This study illustrates that Plekhm1 is an essential protein for bone resorption, as loss-of-function mutations were found to underlie the osteopetrotic phenotype of the incisors absent rat as well as an intermediate type of human osteopetrosis. Electron and confocal microscopic analysis demonstrated that monocytes from a patient homozygous for the mutation differentiated into osteoclasts normally, but when cultured on dentine discs, the osteoclasts failed to form ruffled borders and showed little evidence of bone resorption. The presence of both RUN and pleckstrin homology domains suggests that Plekhm1 may be linked to small GTPase signaling. We found that Plekhm1 colocalized with Rab7 to late endosomal/lysosomal vesicles in HEK293 and osteoclast-like cells, an effect that was dependent on the prenylation of Rab7. In conclusion, we believe PLEKHM1 to be a novel gene implicated in the development of osteopetrosis, with a putative critical function in vesicular transport in the osteoclast.


One stage placement of permanent implant compared to two stage tissue expander reconstruction.
With the advent of the skin sparing mastectomy, immediate breast reconstruction with placement of the definitive prosthesis at the time of mastectomy is possible. The question remains: does single-stage prosthetic reconstruction result in greater numbers of complications or rates of re-operation, compared to two-stage tissue expander reconstruction? A retrospective cohort study of a single centre?s experience with these techniques was carried out. From 2004 to 2012, 54 cases of immediate breast reconstruction with implant were identified, and 108 cases of immediate breast reconstruction using a tissue expander were identified. Gathered preoperative data included tumour, prior exposure to radiation, preoperative chemotherapy, smoking, and comorbidities. Complication rates, as well as the rate of secondary operations, were examined. There were no significant increased risks in the rate of post-operative complications (p = .910, odds ratio = 0.9) nor in the rate of re-operation (p = 0.421, odds ratio = 1.4) associated with the insertion of a definitive prosthesis at the time of skin sparing mastectomy. However, previously radiated breasts experienced a 100% rate of wound complications in our subset of 9 breasts that underwent one stage breast reconstruction with immediate final prosthesis placement. Our study suggests that patients with early stage disease can undergo single stage breast reconstruction without increased risk of complications nor need for secondary operations. While the mean time to completion of the reconstructive process is shortened by 5 months with the single stage technique, implant based breast reconstruction requires careful counseling and patient selection in radiated patients.