Transforming growth factor alpha expression helps to distinguish keratoacanthomas from squamous cell carcinomas.
Keratoacanthomas may be difficult to distinguish histologically from squamous cell carcinomas. We studied 20 keratocanthomas and 22 squamous cell carcinomas immunohistochemically using an antibody directed against transforming growth factor alpha to determine if the pattern of transforming growth factor alpha expression would provide a useful method of differentiating these tumors. Ninety percent of the keratoacanthomas demonstrated a diffuse pattern within tumor lobules in which all but the most peripheral rim of cells were stained. A similar localization of transforming growth factor alpha was not identified in squamous cell carcinomas. In addition, 40% of the squamous cell carcinomas but none of the keratoacanthomas showed focal transforming growth factor alpha immunostaining. Our results suggest that transforming growth factor alpha expression may be a marker of epithelial differentiation and may help distinguish between these two tumors.


Imagery in the aftermath of viewing a traumatic film: using cognitive tasks to modulate the development of involuntary memory.
Involuntary autobiographical memories that spring unbidden into conscious awareness form part of everyday experience. In psychopathology, involuntary memories can be associated with significant distress. However, the cognitive mechanisms associated with the development of involuntary memories require further investigation and understanding. Since involuntary autobiographical memories are image-based, we tested predictions that visuospatial (but not other) established cognitive tasks could disrupt their consolidation when completed post-encoding. In Experiment 1, participants watched a stressful film then immediately completed a visuospatial task (complex pattern tapping), a control-task (verbal task) or no-task. Involuntary memories of the film were recorded for 1-week. In Experiment 2, the cognitive tasks were administered 30-min post-film. Compared to both control and no-task conditions, completing a visuospatial task post-film reduced the frequency of later involuntary memories (Expts 1 and 2) but did not affect voluntary memory performance on a recognition task (Expt 2). Voluntary memory was assessed using a verbal recognition task and a broader range of memory tasks could be used. The relative difficulty of the cognitive tasks used was not directly established. An established visuospatial task after encoding of a stressful experience selectively interferes with sensory-perceptual information processing and may therefore prevent the development of involuntary autobiographical memories.


Antidepressants and psychostimulants in pediatric populations: is there an association with mania?
This article reviews the literature that examines whether exposure to psychostimulants or antidepressants precipitates or exacerbates manic symptoms, or decreases the age at onset of mania in pediatric populations. A PubMed search using relevant key words identified studies targeting five distinct clinical groups: (i) youth without a diagnosis of bipolar disorder (BD) at the time of exposure to psychostimulants; (ii) youth with a diagnosis of BD at the time of exposure to psychostimulants; (iii) youth without a diagnosis of BD at the time of exposure to antidepressants; (iv) youth with a diagnosis of BD at the time of exposure to antidepressants; and (v) youth who develop BD after exposure to these medications. In patients with attention-deficit hyperactivity disorder (ADHD), the risk for mania was found to be relatively low with the use of psychostimulants. For patients with BD and ADHD, effective mood stabilization is important prior to adding a stimulant. For children with depression and/or anxiety, the risk of antidepressant-induced mania (AIM) was generally low (<2%), but the risk of general 'activation' secondary to a selective serotonin reuptake inhibitor (SSRI) may be greater (2-10%). However, rates of AIM in specialty clinics appear to be much higher. SSRIs may be particularly problematic in specific populations, such as those with some symptoms of mania or a family history of BD, but the precise risk is unknown. There is no clear evidence that stimulants or SSRIs accelerate the natural course of BD development in overall samples, but in individual cases prescribers should proceed cautiously when using these agents in youth already at risk for developing BD, such as those with ADHD and mood dysregulation, a history of prior AIM, a history of psychosis, or a family history of BD.


Jitter reduction by intracavity active phase modulation in a mode-locked semiconductor laser.
We experimentally verify the theory of Haus et al. [IEEE J. Quantum Electron. 40, 41 (2004)] on the effects of timing jitter using intracavity phase modulation on the pulse train of a mode-locked laser. The theory is based on the solution of the Heisenberg-Langevin equation in the presence of dispersion and intracavity phase modulation. Using active intracavity phase modulation, we have reduced the timing jitter on a 10.24 GHz mode-locked diode laser by 50% from 304 to 150 fs integrated from 1 Hz to the Nyquist frequency of 5.12 GHz.


Anxiety sensitivity and rumination: Transdiagnostic factors involved in the relation between subjective social status and anxiety and depressive symptoms and disorders among economically disadvantaged Latinos in primary care.
Latinos face striking physical and mental health disparities. One factor associated with such disparities is subjective social status, reflecting subjective ratings of social standing. Yet there is presently a lack of empirical information about the mechanisms underlying relations between subjective social status and anxiety and depressive symptoms and disorders among Latinos in community medical services that serve as focal catchment areas for assessment and intervention programming. The present investigation examined the unique explanatory roles of 2 transdiagnostic factors, rumination and anxiety sensitivity, in the relation between subjective social status and depressive, suicidal, social anxiety, and anxious arousal symptoms as well as anxiety/depressive disorders, among Latinos seeking health services at a primary health care facility. Participants included 253 Latino adults with annual incomes of less than $30,000 (M age = 39.1, SD = 11.1). Results indicated that rumination and anxiety sensitivity each significantly (independently) mediated associations between subjective social status and all dependent variables except suicidal symptoms. For suicidal symptoms, only rumination was a mediator. The present findings suggest that rumination and anxiety sensitivity may represent mechanisms for associations between subjective social status and anxiety and depressive symptoms and disorders among economically disadvantaged Latinos in primary care settings. (PsycINFO Database Record


Shifting distributions of adult Atlantic sturgeon amidst post-industrialization and future impacts in the Delaware River: a maximum entropy approach.
Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) experienced severe declines due to habitat destruction and overfishing beginning in the late 19(th) century. Subsequent to the boom and bust period of exploitation, there has been minimal fishing pressure and improving habitats. However, lack of recovery led to the 2012 listing of Atlantic sturgeon under the Endangered Species Act. Although habitats may be improving, the availability of high quality spawning habitat, essential for the survival and development of eggs and larvae may still be a limiting factor in the recovery of Atlantic sturgeon. To estimate adult Atlantic sturgeon spatial distributions during riverine occupancy in the Delaware River, we utilized a maximum entropy (MaxEnt) approach along with passive biotelemetry during the likely spawning season. We found that substrate composition and distance from the salt front significantly influenced the locations of adult Atlantic sturgeon in the Delaware River. To broaden the scope of this study we projected our model onto four scenarios depicting varying locations of the salt front in the Delaware River: the contemporary location of the salt front during the likely spawning season, the location of the salt front during the historic fishery in the late 19(th) century, an estimated shift in the salt front by the year 2100 due to climate change, and an extreme drought scenario, similar to that which occurred in the 1960's. The movement of the salt front upstream as a result of dredging and climate change likely eliminated historic spawning habitats and currently threatens areas where Atlantic sturgeon spawning may be taking place. Identifying where suitable spawning substrate and water chemistry intersect with the likely occurrence of adult Atlantic sturgeon in the Delaware River highlights essential spawning habitats, enhancing recovery prospects for this imperiled species.


How homologous recombination maintains telomere integrity.
Telomeres protect the ends of linear chromosomes against loss of genetic information and inappropriate processing as damaged DNA and are therefore crucial to the maintenance of chromosome integrity. In addition to providing a pathway for genome-wide DNA repair, homologous recombination (HR) plays a key role in telomere replication and capping. Consistent with this, the genomic instability characteristic of HR-deficient cells and tumours is driven in part by telomere dysfunction. Here, we discuss the mechanisms by which HR modulates the response to intrinsic cellular challenges that arise during telomere replication, as well as its impact on the assembly of telomere protective structures. How normal and tumour cells differ in their ability to maintain telomeres is deeply relevant to the search for treatments that would selectively eliminate cells whose capacity for HR-mediated repair has been compromised.


α6β1 and α7β1 integrins are required in Schwann cells to sort axons.
During development, Schwann cells extend lamellipodia-like processes to segregate large- and small-caliber axons during the process of radial sorting. Radial sorting is a prerequisite for myelination and is arrested in human neuropathies because of laminin deficiency. Experiments in mice using targeted mutagenesis have confirmed that laminins 211, 411, and receptors containing the β1 integrin subunit are required for radial sorting; however, which of the 11 α integrins that can pair with β1 forms the functional receptor is unknown. Here we conditionally deleted all the α subunits that form predominant laminin-binding β1 integrins in Schwann cells and show that only α6β1 and α7β1 integrins are required and that α7β1 compensates for the absence of α6β1 during development. The absence of either α7β1 or α6β1 integrin impairs the ability of Schwann cells to spread and to bind laminin 211 or 411, potentially explaining the failure to extend cytoplasmic processes around axons to sort them. However, double α6/α7 integrin mutants show only a subset of the abnormalities found in mutants lacking all β1 integrins, and a milder phenotype. Double-mutant Schwann cells can properly activate all the major signaling pathways associated with radial sorting and show normal Schwann cell proliferation and survival. Thus, α6β1 and α7β1 are the laminin-binding integrins required for axonal sorting, but other Schwann cell β1 integrins, possibly those that do not bind laminins, may also contribute to radial sorting during peripheral nerve development.


Positive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks.
Proteins within a molecular network are expected to be subject to different selective pressures depending on their relative hierarchical positions. However, it is not obvious what genes within a network should be more likely to evolve under positive selection. On one hand, only mutations at genes with a relatively high degree of control over adaptive phenotypes (such as those encoding highly connected proteins) are expected to be "seen" by natural selection. On the other hand, a high degree of pleiotropy at these genes is expected to hinder adaptation. Previous analyses of the human protein-protein interaction network have shown that genes under long-term, recurrent positive selection (as inferred from interspecific comparisons) tend to act at the periphery of the network. It is unknown, however, whether these trends apply to other organisms. Here, we show that long-term positive selection has preferentially targeted the periphery of the yeast interactome. Conversely, in flies, genes under positive selection encode significantly more connected and central proteins. These observations are not due to covariation of genes' adaptability and centrality with confounding factors. Therefore, the distribution of proteins encoded by genes under recurrent positive selection across protein-protein interaction networks varies from one species to another.


An objective evaluation of an injured vessel wall using fluorescein sodium before microvascular anastomosis in an experimental rat model.
The aim of this study was to establish an objective evaluation method for intraoperative detection of damaged vascular endothelium in avulsion injuries. Twenty male Fischer rats were randomly assigned to control or experimental groups ( N = 10, each). Crush-avulsion injury was performed on right femoral arteries. Resection of damaged segments was performed according to operative microscopic findings in the control group; fluorescein sodium was applied to the artery lumen before resection in the experimental group to help visualize the damaged endothelium. Microvascular repair was performed in five rats in each group. In the other animals, the whole length of the femoral arteries was resected to assess the actual extent of injury histologically. At the end of the follow-up period, patency of microvascular anastomoses was examined and the lengths of the resected segments were compared with the actual length of the injured segment measured histologically. The difference between these two measurements was statistically significant in the control group ( P < 0.05) but not in the experimental group ( P > 0.05). Anastomosis patency was significantly higher in the experimental group ( P < 0.0001). In conclusion, fluorescein sodium may help to accurately determine the length of the injured vascular segment in avulsion injuries.


Falls-Related EvEnts in the first year after StrokE in Ireland: Results of the multi-centre prospective FREESE cohort study.
Falls are common post-stroke adverse events. This study aimed to describe the first-year falls incidence, circumstances and consequences among persons discharged home after stroke in Ireland, and to examine the association between potential risk factors and recurrent falls. Patients with acute stroke and planned home-discharge were recruited consecutively from five hospitals. Variables recorded pre-discharge included: age, stroke severity, co-morbidities, fall history, prescribed medications, hemi-neglect, cognition and functional independence (Barthel index). Falls were recorded with monthly diaries, and 6 and 12-month interviews. The association of pre-discharge factors with recurrent falls (>1 fall) was examined using univariable logistic regression. A total of 128 participants (mean age = 68.6, SD = 13.3) were recruited; 110 completed the 12-month follow-up. The first-year falls incidence was 44.5% (95% CI = 35.1-53.6) with 25.6% falling repeatedly (95% CI = 18.5-34.4). Fallers experienced 1-18 falls (median = 2) and five reported fractures; 47% of fallers experienced at least one fall outdoors. Only 10% of recurrent fallers had bone health medication prescribed at discharge. Lower Barthel index scores (<75/100, RR = 4.38, 1.64-11.72) and psychotropic medication prescription (RR = 2.10, 1.13-3.91) were associated with recurrent falls. This study presents prospectively collected information about falls circumstances. It was not powered for multivariable analysis of risk factors. One-quarter of stroke survivors discharged to the community fall repeatedly and mostly indoors in the first year. Specific attention may be required for individuals with poor functional independence or those on psychotropic medication. Future falls-management research in this population should explore falls in younger individuals, outdoor as well as indoor falls and post-stroke bone health status.


[Drug poisoning].
A review is made of acute poisoning by opiates and its treatment in the emergency services, bearing in mind the progressive decline in the number of cases presented with the arrival of new forms of their administration, as well as the presence of new addictive drugs that have resulted in a shift in consumption habits. Reference is also made to the way in which the different types of existing substances originated, with the aim of achieving a better understanding of their use and in order to administer the most suitable treatment when poisoning occurs. Cocaine poisoning is discussed, with reference to its clinical picture, diagnosis and treatment. The consumption of illegal drugs in our country has undergone a notable change in recent years, with heroin being relegated and the incorporation of cocaine, amphetamine derivatives such as "ecstasy" (MDMA), "liquid ecstasy" (GHB) and, to a lesser extent, ketamine. A review is made of cannabis and its derivates, from the history of its consumption and the preparations employed to the effects produced in the different bodily systems. A brief explanation is also given of its metabolites and its principal mechanisms of action. Finally, we comment on the effects of LSD and hallucinogenic mushrooms.


TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels.
The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as a type 2 diabetes locus from genome-wide linkage studies and subsequent association analysis. We investigated the role of two common variants in TCF7L2 in a large case-control study recruited from the Tayside region of Scotland, UK. We genotyped 6,516 participants for rs12255372 and rs7903146 and analysed the role in type 2 diabetes susceptibility using binary logistic regression. Age, sex and obesity status were examined as covariates. The distribution of the genotypes within different treatment groups of cases was examined. Both variants were associated with type 2 diabetes (p < 10(-13)). The variants were present at very similar frequencies and were in strong linkage disequilibrium (R(2) = 0.88, D' = 0.89). A gene dosage effect of the rare allele of both variants was observed, the heterozygote CT group of rs7903146 having an odds ratio of 1.36 (95% CI 1.2-1.5, p=1.54 x 10(-7)) for type 2 diabetes and the TT homozygote having a greater risk (OR = 2.03, 95% CI 1.7-2.5, p=1.40 x 10(-12)). An interaction with sex was observed, the males displaying a higher degree of genotype-associated risk compared with the females (p = 0.023). The T allele was associated with increased HbA(1c) levels in both cases and controls, and with decreased BMI and waist circumference in case but not controls. The T allele was overrepresented in individuals requiring insulin treatment and underrepresented in the patients being managed by diet alone (p = 0.006). We have confirmed TCF7L2 to be a diabetes locus in a large case-control study in Tayside, UK. Our data suggest that variants of TCF7L2 may be associated with increased disease severity and therapeutic failure.


Assessing the potential for restoration of surface permeability for permeable pavements through maintenance.
Permeable pavements (PPs) have been in use as stormwater management systems in Canada and the United States for over 20 years. After years of exposure to sediment and debris build-up, surface clogging reduces the infiltration of stormwater and inhibits the hydraulic and environmental functions of the pavement. Removal of surface material has been shown to restore infiltration but the majority of studies have been limited to small-scale testing. This paper presents the results of small- and full-sized equipment testing aimed at restoring surface permeability, including the first testing of regenerative-air and vacuum-sweeping streetsweepers in Ontario. Maintenance achieved partial restoration of PP surface permeability. Post-treatment surface infiltration rates displayed large spatial variability, highlighting that localized conditions throughout the pavement have a confounding influence on the overall effectiveness of maintenance. The impact of maintenance may be improved by establishing regular cleaning intervals and developing instructional guidelines for pavement owners and equipment operators.


An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers.
Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations.


In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936).
The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 microgram/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, < or = 0.5 microgram/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.


Automated Detection of Cerebral Aneurysms on TOF-MRA Using a Deep Learning Approach: An External Validation Study.
Cerebral aneurysms yield the risk of rupture, severe disability and death. Thus, early detection of cerebral aneurysms is crucial to ensure timely treatment, if necessary. AI-based software tools are expected to enhance radiologists' performance in detecting pathologies like cerebral aneurysms in the future. Our aim was to evaluate the diagnostic performance of an artificial intelligence-based software designed to detect intracranial aneurysms on TOF-MRA. One hundred ninety-one MR imaging data sets were analyzed using the software mdbrain for the presence of intracranial aneurysms on TOF-MRA obtained using two 3T MR imaging scanners or a 1.5T MR imaging scanner according to our clinical standard protocol. The results were compared with the reading of an experienced radiologist as a criterion standard to measure the sensitivity, specificity, positive and negative predictive values, and accuracy of the software. Additionally, detection rates depending on size, morphology, and location of the aneurysms were evaluated. Fifty-four aneurysms were detected by the expert reader. The overall sensitivity of the software for the detection of cerebral aneurysms was 72.6%, the specificity was 87.2%, and the accuracy was 82.6%. The positive predictive value was 67.9%, and the negative predictive value was 88.5%. We observed a sensitivity of 100% for saccular aneurysms of >5 mm without signs of thrombosis and low detection rates for fusiform or thrombosed aneurysms of 33.3% and 16.7%, respectively. Of 8 aneurysms that were not included in the initial written reports but were detected by the expert reader, retrospectively, 4 were detected by the software. Our data suggest that the software can assist radiologists in reporting TOF-MRA. The software was highly reliable in detecting saccular aneurysms, while for fusiform or thrombosed aneurysms, further improvements are needed. Further studies are necessary to investigate the impact of the software on detection rates, interrater reliability, and reading times.


Predicting pre-Columbian anthropogenic soils in Amazonia.
The extent and intensity of pre-Columbian impacts on lowland Amazonia have remained uncertain and controversial. Various indicators can be used to gauge the impact of pre-Columbian societies, but the formation of nutrient-enriched terra preta soils has been widely accepted as an indication of long-term settlement and site fidelity. Using known and newly discovered terra preta sites and maximum entropy algorithms (Maxent), we determined the influence of regional environmental conditions on the likelihood that terra pretas would have been formed at any given location in lowland Amazonia. Terra pretas were most frequently found in central and eastern Amazonia along the lower courses of the major Amazonian rivers. Terrain, hydrologic and soil characteristics were more important predictors of terra preta distributions than climatic conditions. Our modelling efforts indicated that terra pretas are likely to be found throughout ca 154 063 km(2) or 3.2% of the forest. We also predict that terra preta formation was limited in most of western Amazonia. Model results suggested that the distribution of terra preta was highly predictable based on environmental parameters. We provided targets for future archaeological surveys under the vast forest canopy and also highlighted how few of the long-term forest inventory sites in Amazonia are able to capture the effects of historical disturbance.


Serological evidence of subclinical transmission of the 2009 pandemic H1N1 influenza virus outside of Mexico.
Relying on surveillance of clinical cases limits the ability to understand the full impact and severity of an epidemic, especially when subclinical cases are more likely to be present in the early stages. Little is known of the infection and transmissibility of the 2009 H1N1 pandemic influenza (pH1N1) virus outside of Mexico prior to clinical cases being reported, and of the knowledge pertaining to immunity and incidence of infection during April-June, which is essential for understanding the nature of viral transmissibility as well as for planning surveillance and intervention of future pandemics. Starting in the fall of 2008, 306 persons from households with schoolchildren in central Taiwan were followed sequentially and serum samples were taken in three sampling periods for haemagglutination inhibition (HI) assay. Age-specific incidence rates were calculated based on seroconversion of antibodies to the pH1N1 virus with an HI titre of 1:40 or more during two periods: April-June and September-October in 2009. The earliest time period with HI titer greater than 40, as well as a four-fold increase of the neutralization titer, was during April 26-May 3. The incidence rates during the pre-epidemic phase (April-June) and the first wave (July-October) of the pandemic were 14.1% and 29.7%, respectively. The transmissibility of the pH1N1 virus during the early phase of the epidemic, as measured by the effective reproductive number R(0), was 1.16 (95% confidence interval (CI): 0.98-1.34). Approximately one in every ten persons was infected with the 2009 pH1N1 virus during the pre-epidemic phase in April-June. The lack of age-pattern in seropositivity is unexpected, perhaps highlighting the importance of children as asymptomatic transmitters of influenza in households. Although without virological confirmation, our data raise the question of whether there was substantial pH1N1 transmission in Taiwan before June, when clinical cases were first detected by the surveillance network.


Acromegaloid facial appearance: case report and literature review.
Pseudoacromegaly is characterized by an acromegalic appearance without any abnormality of growth hormone function. It may be caused by several congenital and acquired conditions. One such condition is the acromegaloid facial appearance (AFA) syndrome. This condition has been described in approximately eight cases/families. It encompasses a spectrum of acromegaloid physical findings, normal growth hormone (GH) and insulin-like growth factor one (IGF-1) levels, and variable mode of inheritance. The most common physical findings are coarse facies, bulbous nose, and thickened lips. We present a case and a review of the literature on this illness. The patient is a 57-year-old woman who was referred to the endocrinology division for evaluation of suspected acromegaly. She had an acromegaloid appearance since birth as well as a terminal hypertrichosis. Her endocrine laboratory evaluation and chromosomal analyses were normal. AFA needs to be considered when evaluating any patient with pseudoacromegaly. Additional cases/families need to be identified in order to better understand the clinical spectrum, clinical implications, and mode of inheritance of AFA.


Binding specificities of the GYF domains from two Saccharomyces cerevisiae paralogs.
We have used multivariate statistics and z-scales to represent peptide sequences in a PLS-QSAR model of previously studied binding affinities [Kofler,M., Motzny,K. and Freund,C. (2005b) Mol. Cell. Proteomics, 4, 1797-1811.] of two GYF domains to an array of immobilized synthetic peptides. As a result, we established structural determinants of the binding specificities of the two proteins. Our model was used to define new sets of yeast proteins potentially interacting with Syh1 (YPL105C) and Smy2 (YBR172C). These sets were subsequently examined for co-occurrence of Gene Ontology terms, leading to suggest a group of likely interacting proteins with a common function in mRNA catabolism. Finally, subcellular localization of a GFP-fused Syh1 and Smy2 reinforced the possibility that these proteins reside in cytoplasmic sites of mRNA degradation, thereby providing experimental confirmation to the predictions from the model.


Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity.
The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject by using a PCR-based technique. No significant finding was observed in the overall sample as well as in the pindolol group, while TPH*A/A was associated with a slower response to fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect was independent from the previously reported influence of 5-HTTLPR polymorphism. If confirmed, these results may shed further light on the genetically determined component of the response to pharmacological treatments, thus helping the clinician to individualize each patient's therapy according to their genetic pattern.


Emotional expression and physical health: revising traumatic memories or fostering self-regulation?
Health benefits derived from personal trauma disclosure are well established. This study examined whether disclosing emotions generated by imaginative immersion in a novel traumatic event would similarly enhance health and adjustment. College women, preselected for trauma presence, were randomly assigned to write about real traumas, imaginary traumas, or trivial events. Yoked real-trauma and imaginary-trauma participants wrote about real-trauma participants' experiences. Imaginary-trauma participants were significantly less depressed than real-trauma participants at immediate posttest, but they were similarly angry, fearful, and happy. Compared with control group participants, both trauma groups made significantly fewer illness visits at 1-month follow-up; however, real-trauma participants reported more fatigue and avoidance than did the other groups. Imaginary-trauma group effects could reflect catharsis, emotional regulation, or construction of resilient possible selves.


Investigational approach to adenoviral conjunctivitis: comparison of three diagnostic tests using a Bayesian latent class model.
Highly contagious adenoviral conjunctivitis represents 15-70% of all conjunctivitis worldwide. Human adenovirus (hAdV) serotypes 3,4,7,8,19 and 37 contributes to 89% of all adenoviral conjunctivitis. Accurate and rapid diagnosis of adenoviral infections at serotype level could prevent misdiagnosis, spread of disease, unnecessary antibiotic use and increased treatment costs. Sixty-two suspected viral conjunctivitis cases were recruited from November2013-January2015. Swabs collected from inferior palpebral conjunctiva and processed for viral culture (Hep2 cell line), immunofluorescence assay (IFA) and polymerase chain reaction (PCR) (targeting hexon gene). Serotype 3,4,7,8,19 and 37 identification was carried out with an optimized multiplex-PCR (based on hypervariable region of hexon gene) and confirmed by sequence analysis. Bayesian Latent Class Model (LCM) analysis was used to compare sensitivity and specificity of three tests. Adenovirus was detected in 54.8% (34/62) of cases by combination of all three methods. Culture was positive in 23/34 cases (67.6%). PCR and IFA detected adenovirus in 24 (70.5%) and 21 (61.7%) cases respectively. LCM analysis revealed, sensitivity and specificity of PCR, Culture and IFA was 77.8% and 92.4%; 72.2% and 90.8%; 67.6% and 92.9% respectively. Serotyping by multiplex-PCR showed, two cases each were hAdV3 and hAdV4, 18 hAdV8 and two remained unidentified. Results of Multiplex-PCR and sequence analysis showed 100% concordance Conclusion: LCM analysis revealed, PCR is the most appropriate method for identification. Multiplex-PCR is a simple and rapid method (serotypes identification within two days); owing its short turnaround time and accuracy, it can be used as a diagnostic tool for surveillance of adenoviral keratoconjunctivitis.


Adipose energy stores, physical work, and the metabolic syndrome: lessons from hummingbirds.
Hummingbirds and other nectar-feeding, migratory birds possess unusual adaptive traits that offer important lessons concerning obesity, diabetes and the metabolic syndrome. Hummingbirds consume a high sugar diet and have fasting glucose levels that would be severely hyperglycemic in humans, yet these nectar-fed birds recover most glucose that is filtered into the urine. Hummingbirds accumulate over 40% body fat shortly before migrations in the spring and autumn. Despite hyperglycemia and seasonally elevated body fat, the birds are not known to become diabetic in the sense of developing polyuria (glucosuria), polydipsia and polyphagia. The tiny (3-4 g) Ruby-throated hummingbird has among the highest mass-specific metabolic rates known, and loses most of its stored fat in 20 h by flying up to 600 miles across the Gulf of Mexico. During the breeding season, it becomes lean and maintains an extremely accurate energy balance. In addition, hummingbirds can quickly enter torpor and reduce resting metabolic rates by 10-fold. Thus, hummingbirds are wonderful examples of the adaptive nature of fat tissue, and may offer lessons concerning prevention of metabolic syndrome in humans.


Congenital ocular blindness in children, 1945 to 1984.
A total of 676 children born in British Columbia with congenital ocular blindness during the years 1945 through 1984 were studied. The birth prevalence rate of congenital blindness has decreased from eight per 10,000 live births in the late 1940s to three per 10,000 live births. Retinopathy of prematurity was replaced by genetic ocular disorders as the leading cause of congenital blindness, although the former is reemerging. The rate of congenital rubella infection also declined. There has been a significant increase in the rate of births with optic nerve lesions during the past 15 years, while the rate of births with lesions of the lens fell, reflecting the decline in the rate of maternal rubella infection. There are fewer children with congenital ocular legal blindness who have no light perception today, and they also have fewer associated handicaps.


Domain-engineered pyroelectric radiometer.
We built a large-area domain-engineered pyroelectric radiometer with high spatial and spectral response uniformity that is an excellent primary transfer standard for measurements in the near- and the mid-infrared wavelength regions. The domain engineering consisted of inverting the spontaneous polarization over a 10-mm-diameter area in the center of a uniformly poled, 15.5 mm x 15.5 mm square, 0.25-mm-thick LiNbO(3) plate. Gold black was used as the optical absorber on the detector surface, and an aperture was added to define the optically sensitive detector area. Our results indicate that we significantly reduced the acoustic sensitivity without loss of optical sensitivity. The detector noise equivalent power was not exceptionally low but was nearly constant for different acoustic backgrounds. In addition, the detector's spatial-response uniformity variation was less than 0.1% across the 7.5-mm-diameter aperture, and reflectance measurements indicated that the gold-black coating was spectrally uniform within 2%, from 800 to 1800 nm. Other detailed evaluations of the detector include detector responsivity as a function of temperature, electrical frequency response, angular response, and field of view.


Mechanistic Insights into Homogeneous Electrocatalytic and Photocatalytic Hydrogen Evolution Catalyzed by High-Spin Ni(II) Complexes with S2N2-Type Tetradentate Ligands.
We report homogeneous electrocatalytic and photocatalytic H2 evolution using two Ni(II) complexes with S2N2-type tetradentate ligands bearing two different sizes of chelate rings as catalysts. A Ni(II) complex with a five-membered SC2S-Ni chelate ring (1) exhibited higher activity than that with a six-membered SC3S-Ni chelate ring (2) in both electrocatalytic and photocatalytic H2 evolution despite both complexes showing the same reduction potentials. A stepwise reduction of the Ni center from Ni(II) to Ni(0) was observed in the electrochemical measurements; the first reduction is a pure electron transfer reaction to form a Ni(I) complex as confirmed by electron spin resonance measurements, and the second is a 1e-/1H+ proton-coupled electron transfer reaction to afford a putative Ni(II)-hydrido (NiII-H) species. We also clarified that Ni(II) complexes can act as homogeneous catalysts in the electrocatalytic H2 evolution, in which complex 1 exhibited higher reactivity than that of 2. In the photocatalytic system using [Ru(bpy)3]2+ as a photosensitizer and sodium ascorbate as a reductant, complex 1 with the five-membered chelate ring also showed higher catalytic activity than that of 2 with the six-membered chelate ring, although the rates of photoinduced electron-transfer processes were comparable. The Ni-H bond cleavage in the putative NiII-H intermediate should be involved in the rate-limiting step as evidenced by kinetic isotope effects observed in both photocatalytic and electrocatalytic H2 evolution. Kinetic analysis and density functional theory calculations indicated that the difference in H2 evolution activity between the two complexes was derived from that of activation barriers of the reactions between the NiII-H intermediates and proton, which is consistent with the fact that increase of proton concentration accelerates the H2 evolution.


The influence of carbon sources on the expression of the recA gene and genotoxicity detection by an Acinetobacter bioreporter.
Bacterial whole-cell bioreporters are practical and reliable analytical tools to assess the toxicity and bioavailability of environmental contaminants, yet evidence has shown that their performance could be affected by different carbon sources. This paper evaluated the influence of carbon sources on the recA gene (ACIAD1385) in a DNA damage-inducible recA::luxCDABE Acinetobacter bioreporter and optimized the induction conditions for its practical application in environmental monitoring. Different carbon sources, including LB, potassium acetate (MMA), sodium citrate (MMC), sodium pyruvate (MMP), and sodium succinate (MMS), significantly influenced (p < 0.05) the bioluminescence intensity of the genotoxicity bioreporter. A reverse transcription quantitative PCR (RT-qPCR) showed the different expression levels of the DNA damage-inducible gene recA (p < 0.05), suggesting that carbon sources influenced the DNA damage response in the Acinetobacter bioreporter at the transcriptional level. Additionally, proteomic analysis identified 122 proteins that were differentially expressed after exposure to mitomycin C in defined media and LB, and 5 of them were related to the DNA damage response, indicating the effects of carbon sources on the DNA damage response in Acinetobacter at the translational level. The repression effect caused by the rich medium, LB, was possibly related to the mechanism of carbon catabolite repression. Our results suggest that the practical application of Acinetobacter bioreporters to the genotoxicity assessment of polycyclic aromatic hydrocarbon (PAH)-contaminated soils could be significantly improved by using a standard medium of defined composition, as this could increase their sensitivity.


Postexercise Fructose-Maltodextrin Ingestion Enhances Subsequent Endurance Capacity.
Restoring skeletal muscle and hepatic glycogen content during short-term (<6 h) recovery from prolonged exercise is pertinent for athletes seeking to maximize performance in repeated exercise bouts. Previous research suggests that coingestion of fructose-glucose carbohydrate sources augments hepatic and has equivalent effects on skeletal muscle glycogen storage during short-term recovery from prolonged exercise compared with isocaloric glucose ingestion. The aim of the present investigation was to determine whether this has a discernible effect on subsequent exercise capacity. Eight trained endurance runners and triathletes performed two experimental trials in a single-blind, randomized, and counterbalanced crossover design. Trials involved treadmill running to exhaustion at 70% V˙O2max, a 4-h recovery with 90 g·h of glucose-maltodextrin (GLU + MAL) or fructose-maltodextrin (FRU + MAL) ingestion (1:1.5 ratio), and a second bout of treadmill running to exhaustion at 70% V˙O2max. Exercise capacity in bout 2 was significantly greater with FRU + MAL (81.4 ± 22.3 vs 61.4 ± 9.6 min, P = 0.02), a large magnitude effect (effect size = 1.84 ± 1.12, 32.4% ± 19.9%). Total carbohydrate oxidation rates were not significantly different during bout 1 or 2 between trials, although total carbohydrate oxidized in bout 2 was significantly greater with FRU + MAL (223 ± 66 vs 157 ± 26 g, P = 0.02). Ingested carbohydrate oxidation rates were greater during bout 2 with FRU + MAL (P = 0.001). Plasma glucose and nonesterified fatty acid concentrations were not significantly different between trials. Plasma lactate concentrations were significantly greater during recovery before bout 2 with FRU + MAL (P = 0.001). Self-reported nausea and stomach fullness during bout 2 were marginally in favor of FRU + MAL. Short-term recovery of endurance capacity was significantly enhanced with FRU + MAL versus GLU + MAL ingestion during recovery.


Targeting Non-coding RNA in Vascular Biology and Disease.
Only recently have we begun to appreciate the importance and complexity of the non-coding genome, owing in some part to truly significant advances in genomic technology such as RNA sequencing and genome-wide profiling studies. Previously thought to be non-functional transcriptional "noise," non-coding RNAs (ncRNAs) are now known to play important roles in many diverse biological pathways, not least in vascular disease. While microRNAs (miRNA) are known to regulate protein-coding gene expression principally through mRNA degradation, long non-coding RNAs (lncRNAs) can activate and repress genes by a variety of mechanisms at both transcriptional and translational levels. These versatile molecules, with complex secondary structures, may interact with chromatin, proteins, and other RNA to form complexes with an array of functional consequences. A body of emerging evidence indicates that both classes of ncRNAs regulate multiple physiological and pathological processes in vascular physiology and disease. While dozens of miRNAs are now implicated and described in relative mechanistic depth, relatively fewer lncRNAs are well described. However, notable examples include ANRIL, SMILR, and SENCR in vascular smooth muscle cells; MALAT1 and GATA-6S in endothelial cells; and mitochondrial lncRNA LIPCAR as a powerful biomarker. Due to such ubiquitous involvement in pathology and well-known biogenesis and functional genetics, novel miRNA-based therapies and delivery methods are now in development, including some early stage clinical trials. Although lncRNAs may hold similar potential, much more needs to be understood about their relatively complex molecular behaviours before realistic translation into novel therapies. Here, we review the current understanding of the mechanism and function of ncRNA, focusing on miRNAs and lncRNAs in vascular disease and atherosclerosis. We discuss existing therapies and current delivery methods, emphasising the importance of miRNAs and lncRNAs as effectors and biomarkers in vascular pathology.


Brainstem branches from olivocochlear axons in cats and rodents.
Horseradish peroxidase was used to label axons of olivocochlear (OC) neurons by intracellular injections in cats and extracellular injections in rodents. These axons arise from cell bodies in the superior olivary complex and project to the cochlea. En route to the cochlea, the thick axons (greater than 0.7 micron diam.) of medial olivocochlear (MOC) neurons formed collaterals that terminated in the ventral cochlear nucleus, the interstitial nucleus of the vestibular nerve (in cats), and the inferior vestibular nucleus (in rodents). The thin axons (less than 0.7 micron diam.), presumed to arise from lateral olivocochlear (LOC) neurons, did not branch near the CN. Within the CN, the MOC collaterals tended to ramify in and near regions with high densities of granule cells, regions also associated with the terminals of type II afferent axons (Brown et al.: J. Comp. Neurol. 278:581-590, '88). These results suggest that those fibers associated peripherally with outer hair cells (MOC efferents and type II afferents) are associated centrally with regions containing granule cells, whereas those fibers associated with inner hair cells peripherally (LOC efferents and type I afferents) are not.


Speciated arsenic in air: measurement methodology and risk assessment considerations.
Accurate measurement of arsenic (As) in air is critical to providing a more robust understanding of arsenic exposures and associated human health risks. Although there is extensive information available on total arsenic in air, less is known on the relative contribution of each arsenic species. To address this data gap, the authors conducted an in-depth review of available information on speciated arsenic in air. The evaluation included the type of species measured and the relative abundance, as well as an analysis of the limitations of current analytical methods. Despite inherent differences in the procedures, most techniques effectively separated arsenic species in the air samples. Common analytical techniques such as inductively coupled plasma mass spectrometry (ICP-MS) and/or hydride generation (HG)- or quartz furnace (GF)-atomic absorption spectrometry (AAS) were used for arsenic measurement in the extracts, and provided some of the most sensitive detection limits. The current analysis demonstrated that, despite limited comparability among studies due to differences in seasonal factors, study duration, sample collection methods, and analytical methods, research conducted to date is adequate to show that arsenic in air is mainly in the inorganic form. Reported average concentrations of As(III) and As(V) ranged up to 7.4 and 10.4 ng/m3, respectively, with As(V) being more prevalent than As(III) in most studies. Concentrations of the organic methylated arsenic compounds are negligible (in the pg/m3 range). However because of the variability in study methods and measurement methodology, the authors were unable to determine the variation in arsenic composition as a function of source or particulate matter (PM) fraction. In this work, the authors include the implications of arsenic speciation in air on potential exposure and risks. The authors conclude that it is important to synchronize sample collection, preparation, and analytical techniques in order to generate data more useful for arsenic inhalation risk assessment, and a more robust documentation of quality assurance/quality control (QA/QC) protocols is necessary to ensure accuracy, precision, representativeness, and comparability.


Determinants of hypertension in West Africa: contribution of anthropometric and dietary factors to urban-rural and socioeconomic gradients.
The determinants of hypertension in West Africa have not been well defined. The authors sampled 598 participants aged 45 years or more from a recent population-based survey in southwest Nigeria (190 rural men and women, 205 urban poor men and women, and 203 retired railway workmen). The estimated mean age was 61 (10) years. Mean pressures were low relative to westernized societies: systolic blood pressure = 124 (24) mmHg, diastolic blood pressure = 72 (13) mmHg. Both men and women were remarkably lean: body mass index = 21.3 (3.6) and 23.0 (5.2) kg/m2, respectively. Hypertension prevalence increased across the gradient from rural farmers to urban poor to railway workers: 14, 25, and 29 percent, respectively, had a blood pressure of 140/90 mmHg or greater, and 3, 11, and 14 percent, respectively, had a blood pressure of 160/95 mmHg or greater (p for trend < 0.01 for both cutpoints). On the basis of a 24-hour urine sample, daily electrolyte excretion was 110 (57) mEq of sodium and 46 (24) mEq of potassium. Mean sodium:potassium ratio was 2.6 (1.0) and was higher among the urban residents (p < 0.01) and correlated with systolic and diastolic pressures (r = 0.16-0.18, p < 0.01). These findings provide quantitative estimates of the impact of known hypertension risk factors in West Africa and demonstrate the basis for increased prevalence with urbanization and associated economic and dietary change. These results also provide support for recommendations for prevention in West Africa and provide a benchmark against which to compare populations in the African diaspora.


Investigation of rabies virus glycoprotein carboxyl terminus as an in vitro predictive tool of neurovirulence. A 3R approach.
In the field of live viral vaccines production, there is an unmet need for in vitro tests complying a 3R approach (Refine, Replace and Reduce the use of animal experimentation) to replace the post-licensing safety tests currently assayed in animals. Here, we performed a pilot study evaluating whether virulence of rabies virus, RABV, can be forecast by an in vitro test of neurite outgrowth. The rationale to use neurite outgrowth as a read-out for this test is based on the salient property of the cytoplasmic domain of the G-protein (Cyto-G) of virulent RABV strains - not of attenuated RABV strains - to stimulate neurite outgrowth in vitro. We observed that neurite elongation triggered by the Cyto-Gs encoded by different RABV field isolates correlate with the distinct virulence scores obtained in a mouse model of experimental rabies. Our results cast the idea that it could be feasible to predict RABV virulence by testing the in vitro property of a RABV strain to promote neurite outgrowth without the use of animal experimentation.


Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.


Treatment of Catatonia With Ultrabrief Right Unilateral Electroconvulsive Therapy: A Case Series.
Catatonia is a syndrome heterogeneous with regard to presentation and etiology. Electroconvulsive therapy (ECT) remains the first-line treatment for catatonia. Literature review reveals only a few published case reports on the use of right unilateral (RUL) ECT in catatonia, 1 case report on ultrabrief RUL ECT, and an absence of evidence on the relative effectiveness and tolerability of RUL versus bilateral ECT in treating catatonia. In contrast, there are multiple reports in the literature of robustly dosed bilateral ECT, often administered on consecutive days. Reasons for choosing this intervention over the better-tolerated RUL treatment include assumptions about its relative speed and/or breadth of efficacy. Here we present a case series of 13 catatonic patients treated in an academic center over the course of the last 3 years. Our experience suggests that ultrabrief RUL ECT can rapidly and effectively treat catatonia from diverse etiologies.


MCMC-ODPR: primer design optimization using Markov Chain Monte Carlo sampling.
Next generation sequencing technologies often require numerous primer designs that require good target coverage that can be financially costly. We aimed to develop a system that would implement primer reuse to design degenerate primers that could be designed around SNPs, thus find the fewest necessary primers and the lowest cost whilst maintaining an acceptable coverage and provide a cost effective solution. We have implemented Metropolis-Hastings Markov Chain Monte Carlo for optimizing primer reuse. We call it the Markov Chain Monte Carlo Optimized Degenerate Primer Reuse (MCMC-ODPR) algorithm. After repeating the program 1020 times to assess the variance, an average of 17.14% fewer primers were found to be necessary using MCMC-ODPR for an equivalent coverage without implementing primer reuse. The algorithm was able to reuse primers up to five times. We compared MCMC-ODPR with single sequence primer design programs Primer3 and Primer-BLAST and achieved a lower primer cost per amplicon base covered of 0.21 and 0.19 and 0.18 primer nucleotides on three separate gene sequences, respectively. With multiple sequences, MCMC-ODPR achieved a lower cost per base covered of 0.19 than programs BatchPrimer3 and PAMPS, which achieved 0.25 and 0.64 primer nucleotides, respectively. MCMC-ODPR is a useful tool for designing primers at various melting temperatures at good target coverage. By combining degeneracy with optimal primer reuse the user may increase coverage of sequences amplified by the designed primers at significantly lower costs. Our analyses showed that overall MCMC-ODPR outperformed the other primer-design programs in our study in terms of cost per covered base.


Aqueous oxidation of sulfonamide antibiotics: aromatic nucleophilic substitution of an aniline radical cation.
Sulfonamide antibiotics are an important class of organic micropollutants in the aquatic environment. For several, sulfur dioxide extrusion products have been previously reported upon photochemical or dark oxidation. Using quantum chemical modeling calculations and transient absorption spectroscopy, it is shown that single-electron oxidation from sulfadiazine produces the corresponding aniline radical cation. Density functional theory calculations indicate that this intermediate can exist in four protonation states. One species exhibits a low barrier for an intramolecular nucleophilic attack at the para position of the oxidized aniline ring, in which a pyrimidine nitrogen acts as a nucleophile. This attack can lead to a rearranged structure, which exhibits the same connectivity as the SO2 -extruded oxidation product that was previously observed in the aquatic environment and characterized by NMR spectroscopy. We report a detailed reaction mechanism for this intramolecular aromatic nucleophilic substitution, and we discuss the possibility of this reaction pathway for other sulfonamide drugs.


Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy.
Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.


Selection of reference genes for gene expression studies in human neutrophils by real-time PCR.
Reference genes, which are often referred to housekeeping genes, are frequently used to normalize mRNA levels between different samples. However the expression level of these genes may vary among tissues or cells, and may change under certain circumstances. Thus the selection of reference gene(s) is critical for gene expression studies. For this purpose, 10 commonly used housekeeping genes were investigated in isolated human neutrophils. Initial screening of the expression pattern demonstrated that 3 of the 10 genes were expressed at very low levels in neutrophils and were excluded from further analysis. The range of expression stability of the other 7 genes was (from most stable to least stable): GNB2L1 (Guanine nucleotide binding protein, beta polypeptide 2-like 1), HPRT1 (Hypoxanthine phosphoribosyl transferase 1), RPL32 (ribosomal protein L32), ACTB (beta-actin), B2M (beta-2-microglobulin), GAPD (glyceraldehyde-3-phosphate dehydrogenase) and TBP (TATA-binding protein). Relative expression levels of the genes (from high to low) were: B2M, ACTB, GAPD, RPL32, GNB2L1, TBP, and HPRT1. Our data suggest that GNB2L1, HPRT1, RPL32, ACTB, and B2M may be suitable reference genes in gene expression studies of neutrophils.


Abnormalities of cerebral perfusion in multiple sclerosis.
Measuring perfusion provides a potential indication of metabolic activity in brain tissue. Studies in multiple sclerosis (MS) have identified areas of decreased perfusion in grey matter (GM) and white matter (WM), but the pattern in clinical subgroups is unclear. This study investigated perfusion changes in differing MS clinical subgroups on or off beta-interferon therapy using a non-invasive MRI technique (continuous arterial spin labelling) to investigate whether different clinical MS subtypes displayed perfusion changes and whether this could give a further insight into the pathological mechanisms involved. Sixty patients (21 relapsing remitting, 14 secondary progressive, 12 primary progressive, 13 benign) and 34 healthy controls were compared. Statistical parametric mapping (SPM '99) was used to investigate regional variations in perfusion in both GM and WM. Global WM perfusion was derived by segmenting WM from images using T(1) relaxation times. Regions of lower perfusion in predominantly GM were observed in the primary and secondary progressive cohorts, particularly in the thalamus. Increased WM perfusion was seen in relapsing remitting and secondary progressive cohorts. Low GM perfusion could reflect decreased metabolism secondary to neuronal and axonal loss or dysfunction with a predilection for progressive forms of MS. Increased WM perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation. Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and cognitive impairment.


Caught between two Allee effects: trade-off between reproduction and predation risk.
Reproductive activities are often associated with conspicuous morphology or behaviour that could be exploited by predators. Individuals can therefore face a trade-off between reproduction and predation risk. Here we use simple models to explore population-dynamical consequences of such a trade-off for populations subject to a mate-finding Allee effect and an Allee effect due to predation. We present our results in the light of populations that belong to endangered species or pests and study their viability and resilience. We distinguish several qualitative scenarios characterized by the shape and strength of the trade-off and, in particular, identify conditions for which the populations survive or go extinct. Reproduction can be so costly that the population always goes extinct. In other cases, the population goes extinct only over a certain range of low, intermediate or high levels of reproductive activities. Moreover, we show that predator removal (e.g. in an attempt to save an endangered prey species) has the least effect on populations with low cost of reproduction in terms of predation and, conversely, predator addition (e.g. to eradicate a pest) is most effective for populations with high predation cost of reproduction. Our results indicate that a detailed knowledge of the trade-off can be crucial in applications: for some trade-off shapes, only intermediate levels of reproductive activities might guarantee population survival, while they can lead to extinction for others. We therefore suggest that the fate of populations subject to the two antagonistic Allee effects should be evaluated on a case-by-case basis. Although the literature offers no quantitative data on possible trade-off shapes in any taxa, indirect evidence suggests that the trade-off and both Allee effects can occur simultaneously, e.g. in the golden egg bug Phyllomorpha laciniata.


Allergic rhinitis.
Allergic rhinitis (AR) is caused by immunoglobulin E (IgE)-mediated reactions to inhaled allergens and is one of the most common chronic conditions globally. AR often co-occurs with asthma and conjunctivitis and is a global health problem causing major burden and disability worldwide. Risk factors include inhalant and occupational allergens, as well as genetic factors. AR impairs quality of life, affects social life, school and work, and is associated with substantial economic costs. The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative classified AR into intermittent or persistent and mild or moderate/severe. The diagnosis is based on the clinical history and, if needed in patients with uncontrolled rhinitis despite medications or with long-lasting symptoms, on skin tests or the presence of serum-specific IgE antibodies to allergens. The most frequently used pharmacological treatments include oral, intranasal or ocular H1-antihistamines, intranasal corticosteroids or a fixed combination of intranasal H1-antihistamines and corticosteroids. Allergen immunotherapy prescribed by a specialist using high-quality extracts in stratified patients is effective in patients with persistent symptoms. Real-world data obtained by mobile technology offer new insights into AR phenotypes and management. The outlook for AR includes a better understanding of novel multimorbid phenotypes, health technology assessment and patient-centred shared decision-making.


When stress and development go hand in hand: main hormonal controls of adventitious rooting in cuttings.
Adventitious rooting (AR) is a multifactorial response leading to new roots at the base of stem cuttings, and the establishment of a complete and autonomous plant. AR has two main phases: (a) induction, with a requirement for higher auxin concentration; (b) formation, inhibited by high auxin and in which anatomical changes take place. The first stages of this process in severed organs necessarily include wounding and water stress responses which may trigger hormonal changes that contribute to reprogram target cells that are competent to respond to rooting stimuli. At severance, the roles of jasmonate and abscisic acid are critical for wound response and perhaps sink strength establishment, although their negative roles on the cell cycle may inhibit root induction. Strigolactones may also inhibit AR. A reduced concentration of cytokinins in cuttings results from the separation of the root system, whose tips are a relevant source of these root induction inhibitors. The combined increased accumulation of basipetally transported auxins from the shoot apex at the cutting base is often sufficient for AR in easy-to-root species. The role of peroxidases and phenolic compounds in auxin catabolism may be critical at these early stages right after wounding. The events leading to AR strongly depend on mother plant nutritional status, both in terms of minerals and carbohydrates, as well as on sink establishment at cutting bases. Auxins play a central role in AR. Auxin transporters control auxin canalization to target cells. There, auxins act primarily through selective proteolysis and cell wall loosening, via their receptor proteins TIR1 (transport inhibitor response 1) and ABP1 (Auxin-Binding Protein 1). A complex microRNA circuitry is involved in the control of auxin response factors essential for gene expression in AR. After root establishment, new hormonal controls take place, with auxins being required at lower concentrations for root meristem maintenance and cytokinins needed for root tissue differentiation.


Zinc lozenges may shorten the duration of colds: a systematic review.
A number of controlled trials have examined the effect of zinc lozenges on the common cold but the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain part of the variation in the results. The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebocontrolled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and the high zinc dose trials. Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). This study shows strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses. The effects of zinc lozenges should be further studied to determine the optimal lozenge compositions and treatment strategies.


Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin.
To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin. Adults (n = 455) with HbA(1c) 7.5-11% on stable insulin therapy (30-150 U/day ± metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks. Patients were to maintain stable insulin doses but these could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or substantially increased insulin use were rescued with a flexible insulin regimen and remained in the study. Metformin doses were kept stable. The primary efficacy endpoint was change in HbA(1c) from baseline to week 24 (or rescue). Patients treated with saxagliptin versus placebo had significantly greater reductions in adjusted mean HbA(1c) (difference: -0.41%, p < 0.0001), postprandial glucose (PPG) 180-minute area under the curve (-3829.8 mg·min/dL, p = 0.0011), and 120-minute PPG (-23.0 mg/dL, p = 0.0016) at 24 weeks. Treatment with saxagliptin resulted in similar reductions in HBA(1c) relative to placebo, irrespective of metformin treatment. At 24 weeks, difference in adjusted mean fasting plasma glucose for saxagliptin versus placebo was -4.02 mg/dL (p = 0.3958); 17.3% and 6.7% of patients in the saxagliptin and placebo groups, respectively, achieved HbA(1c) < 7%. Mean change from baseline in body weight at week 24 was 0.39 kg for saxagliptin and 0.18 kg for placebo. Hypoglycemia was reported in 18.4% and 19.9% of patients in the saxagliptin and placebo groups, respectively (confirmed hypoglycemia: 5.3%, 3.3%). Other adverse events reported in at least 5% of patients were urinary tract infection (saxagliptin, placebo: 5.9%, 6.0%), influenza (3.0%, 6.6%), and pain in extremity (1.6%, 6.0%). Saxagliptin 5-mg once-daily add-on therapy improves glycemic control in T2D patients on insulin alone or combined with metformin and is generally well-tolerated. NCT00757588.


Imaging correlates of molecular signatures in oligodendrogliomas.
Molecular subsets of oligodendroglioma behave in biologically distinct ways. Their locations in the brain, rates of growth, and responses to therapy differ with their genotypes. Retrospectively, we inquired whether allelic loss of chromosomal arms 1p and 19q, an early molecular event and favorable prognostic marker in oligodendrogliomas, were reflected in their appearance on magnetic resonance imaging. Loss of 1p and 19q was associated with an indistinct border on T(1) images and mixed intensity signal on T(1) and T(2). Loss of 1p and 19q was also associated with paramagnetic susceptibility effect and with calcification, a common histopathological finding in oligodendrogliomas. These data encourage prospective evaluation of molecular alterations and magnetic resonance imaging characteristics of glial neoplasms.


Anisotropic diffraction from photorefractive gratings and Pockels tensor of Sn2P2S6.
The first observation of anisotropic diffraction and anisotropic self diffraction in low symmetry photorefractive crystal Sn(2)P(2)S(6) is reported. From comparison of the diffraction efficiency of isotropic and anisotropic diffraction the ratios of the Pockels tensor components are deduced, including some nondiagonal components that have never been evaluated until now. The particular orientation of the optical indicatrix in Sn(2)P(2)S(6) (roughly at 45 degrees to z- and x-axes at ambient temperature) has a paradoxical consequence: The efficiency of anisotropic diffraction depends solely on diagonal components of the Pockels tensor, while the efficiency of the isotropic diffraction is considerably affected by nondiagonal components. With already known results and data presented in this article we can state that all 10 nonvanishing Pockels tensor components of the m-symmetry class crystal like Sn(2)P(2)S(6) do manifest themselves in various types of nonlinear wave mixing.


Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary.
Combined immunosuppression by immunomodulators and biological therapy has become standard in the medical management of moderate-to-severe inflammatory bowel disease (IBD) because of clearly demonstrated efficacy. Clinical studies, registries, and case reports warn of the increased risk of infections, particularly opportunistic infections; however, already in the steroid monotherapy era, patients are at risk because it is accepted that a patient should be considered immunosuppressed when receiving a daily dose of 20 mg of prednisone for 2 weeks. Prescriptions increasingly involve azathioprine, methotrexate, and various biological agents. The TREAT registry evaluated safety in >6000 adult patients, half of them treated with infliximab (IFX) for about 1.9 years. IFX-treated patients had an increased risk of infections and this was associated with disease severity and concomitant prednisone use. The REACH study, evaluating the efficacy of IFX in children with moderate-to-severe Crohn disease, refractory to immunomodulatory treatment, reports serious infections as the major adverse events and their frequency is higher with shorter treatment intervals. The combination of immunosuppressive medications is a risk factor for opportunistic infections. Exhaustive guidelines on prophylaxis, diagnosis, and management of opportunistic infections in adult patients with IBD have been published by a European Crohn's and Colitis Organization working group, including clear evidence-based statements. We have reviewed the literature on infections in pediatric IBD as well as the European Crohn's and Colitis Organization guidelines to present a commentary on infection prophylaxis for the pediatric age group.


A single dose of tea with or without milk increases plasma antioxidant activity in humans.
To investigate the effect of black and green tea consumption, with and without milk, on the plasma antioxidant activity in humans. In a complete cross-over design, 21 healthy volunteers (10 male, 11 female) received a single dose of black tea, green tea (2 g tea solids in 300 ml water) or water with or without milk. Blood samples were obtained at baseline and at several time points up to 2 h post-tea drinking. Plasma was analysed for total catechins and antioxidant activity, using the ferric reducing ability of plasma (FRAP) assay. Consumption of black tea resulted in a significant increase in plasma antioxidant activity reaching maximal levels at about 60 min. A larger increase was observed after consumption of green tea. As anticipated from the higher catechin concentration in green tea, the rise in plasma total catechins was significantly higher after consumption of green tea when compared to black tea. Addition of milk to black or green tea did not affect the observed increases in plasma antioxidant activity. Consumption of a single dose of black or green tea induces a significant rise in plasma antioxidant activity in vivo. Addition of milk to tea does not abolish this increase. Whether the observed increases in plasma antioxidant activity after a single dose of tea prevent in vivo oxidative damage remains to be established. European Journal of Clinical Nutrition (2000) 54, 87-92


Nonlinearities and adaptation of color vision from sequential principal curves analysis.
Mechanisms of human color vision are characterized by two phenomenological aspects: the system is nonlinear and adaptive to changing environments. Conventional attempts to derive these features from statistics use separate arguments for each aspect. The few statistical explanations that do consider both phenomena simultaneously follow parametric formulations based on empirical models. Therefore, it may be argued that the behavior does not come directly from the color statistics but from the convenient functional form adopted. In addition, many times the whole statistical analysis is based on simplified databases that disregard relevant physical effects in the input signal, as, for instance, by assuming flat Lambertian surfaces. In this work, we address the simultaneous statistical explanation of the nonlinear behavior of achromatic and chromatic mechanisms in a fixed adaptation state and the change of such behavior (i.e., adaptation) under the change of observation conditions. Both phenomena emerge directly from the samples through a single data-driven method: the sequential principal curves analysis (SPCA) with local metric. SPCA is a new manifold learning technique to derive a set of sensors adapted to the manifold using different optimality criteria. Here sequential refers to the fact that sensors (curvilinear dimensions) are designed one after the other, and not to the particular (eventually iterative) method to draw a single principal curve. Moreover, in order to reproduce the empirical adaptation reported under D65 and A illuminations, a new database of colorimetrically calibrated images of natural objects under these illuminants was gathered, thus overcoming the limitations of available databases. The results obtained by applying SPCA show that the psychophysical behavior on color discrimination thresholds, discount of the illuminant, and corresponding pairs in asymmetric color matching emerge directly from realistic data regularities, assuming no a priori functional form. These results provide stronger evidence for the hypothesis of a statistically driven organization of color sensors. Moreover, the obtained results suggest that the nonuniform resolution of color sensors at this low abstraction level may be guided by an error-minimization strategy rather than by an information-maximization goal.


Space-time correlations in urban sprawl.
Understanding demographic and migrational patterns constitutes a great challenge. Millions of individual decisions, motivated by economic, political, demographic, rational and/or emotional reasons underlie the high complexity of demographic dynamics. Significant advances in quantitatively understanding such complexity have been registered in recent years, as those involving the growth of cities but many fundamental issues still defy comprehension. We present here compelling empirical evidence of a high level of regularity regarding time and spatial correlations in urban sprawl, unravelling patterns about the inertia in the growth of cities and their interaction with each other. By using one of the world's most exhaustive extant demographic data basis--that of the Spanish Government's Institute INE, with records covering 111 years and (in 2011) 45 million people, distributed among more than 8000 population nuclei--we show that the inertia of city growth has a characteristic time of 15 years, and its interaction with the growth of other cities has a characteristic distance of 80 km. Distance is shown to be the main factor that entangles two cities (60% of total correlations). The power of our current social theories is thereby enhanced.


PECAM-1 is expressed on hematopoietic stem cells throughout ontogeny and identifies a population of erythroid progenitors.
Platelet endothelial cell adhesion molecule-1 (PECAM-1) (CD31) is an adhesion molecule expressed on endothelial cells and subsets of leukocytes. Analysis of phenotypically defined hematopoietic stem cells (HSCs) from the yolk sac, fetal liver, and adult bone marrow demonstrates CD31 expression on these cells throughout development. CD31+ c-kit+ cells, but not CD31- c-kit+ cells, isolated from day-9.5 yolk sac give rise to multilineage hematopoiesis in vivo. Further evaluation of the CD31+ lineage marker-negative fraction of adult bone marrow reveals functionally distinct cell subsets. Transplantation of CD31+ Lin- c-kit- cells fails to protect lethally irradiated recipients, while CD31+ Lin- c-kit+ Sca-1- cells (CD31+ Sca-1-) provide radioprotection in the absence of long-term donor-derived hematopoiesis. Although donor-derived leukocytes were not detected in CD31+ Sca-1- recipients, donor-derived erythroid cells were transiently produced during the initial phases of bone marrow recovery. These results demonstrate CD31 expression on hematopoietic stem cells throughout ontogeny and identify a population of CD31+ short-term erythroid progenitors cells that confer protection from lethal doses of radiation.


Latitudinal Diversity of Culex pipiens Biotypes and Hybrids in Farm, Peri-Urban, and Wetland Habitats in Europe.
Despite the presence of Culex (Cx.) pipiens mosquitoes and circulation of West Nile virus (WNV), WNV outbreaks have so far not occurred in northern Europe. The species Cx. pipiens consists of two morphologically identical biotypes, pipiens and molestus, which can form hybrids. Until now, population dynamic studies of Cx. pipiens have not differentiated between biotypes and hybrids at the European scale, nor have they used comparative surveillance approaches. We therefore aimed to elucidate the relative abundance of Cx. pipiens biotypes and hybrids in three habitat types at different latitudes across Europe, using two different surveillance traps. BG-Sentinel and Mosquito-Magnet Liberty Plus traps were placed in three habitat types (farms, peri-urban, wetlands), in three European countries (Sweden, The Netherlands, Italy). Collected Cx. pipiens mosquitoes were identified to biotype with real-time PCR. Both trap types collected equal ratios of the biotypes and their hybrids. From northern to southern latitudes there was a significant decrease of pipiens and an increase of molestus. Habitat types influenced the relative ratios of biotypes and hybrids, but results were not consistent across latitudes. Our results emphasize the need to differentiate Cx. pipiens to the biotype level, especially for proper future WNV risk assessments for Europe.


Development and psychometric testing of the Swedish version of the Body Awareness Questionnaire.
This paper is a report of the development and psychometric testing of the Swedish version of the Body Awareness Questionnaire to measure bodily focus of attention. The Body Awareness Questionnaire has been identified as an instrument with excellent psychometric properties within the concept of body awareness. It has been used in both research and clinical settings in different contexts. However, a validated Swedish version is not available. A cross-sectional design was applied for adaptation of the Body Awareness Questionnaire and psychometric validation. Data were collected between autumn 2009 and spring 2011 from 120 patients diagnosed with rheumatoid arthritis, and from 120 students. The 'concurrent think aloud' method was used in a pre-test to determine the usability of the questionnaire. Cronbach's alpha was used to test the internal consistency, and confirmatory factor analysis was performed to test the construct validity. According to the confirmatory factor analysis, neither the one-factor model nor the four-factor model tested in this study fulfilled the pre-specified criteria in accordance with the Comparative Fit Index, Standardized Root Mean Squared Residual and the Root Mean Square Error of Approximation. The value of Cronbach's alpha for the Swedish version of the Body Awareness Questionnaire was satisfactory. Our results indicate that the two models tested in this study do not provide a good fit to the observed data. Further refinement and testing of the Swedish version of the Body Awareness Questionnaire is therefore required. The concept of body awareness may be useful in the management of chronic disease and can be addressed in nursing.


Toward real-time quantum imaging with a single pixel camera.
We present a workbench for the study of real-time quantum imaging by measuring the frame-by-frame quantum noise reduction of multi-spatial-mode twin beams generated by four wave mixing in Rb vapor. Exploiting the multiple spatial modes of this squeezed light source, we utilize spatial light modulators to selectively pass macropixels of quantum correlated modes from each of the twin beams to a high quantum efficiency balanced detector. In low-light-level imaging applications, the ability to measure the quantum correlations between individual spatial modes and macropixels of spatial modes with a single pixel camera will facilitate compressive quantum imaging with sensitivity below the photon shot noise limit.


Application of the fractional Fourier transform to image reconstruction in MRI.
The classic paradigm for MRI requires a homogeneous B(0) field in combination with linear encoding gradients. Distortions are produced when the B(0) is not homogeneous, and several postprocessing techniques have been developed to correct them. Field homogeneity is difficult to achieve, particularly for short-bore magnets and higher B(0) fields. Nonlinear magnetic components can also arise from concomitant fields, particularly in low-field imaging, or intentionally used for nonlinear encoding. In any of these situations, the second-order component is key, because it constitutes the first step to approximate higher-order fields. We propose to use the fractional Fourier transform for analyzing and reconstructing the object's magnetization under the presence of quadratic fields. The fractional fourier transform provides a precise theoretical framework for this. We show how it can be used for reconstruction and for gaining a better understanding of the quadratic field-induced distortions, including examples of reconstruction for simulated and in vivo data. The obtained images have improved quality compared with standard Fourier reconstructions. The fractional fourier transform opens a new paradigm for understanding the MR signal generated by an object under a quadratic main field or nonlinear encoding.


Functional Ulnar Nerve Paraganglioma: First Documented Occurrence in the Extremity With Hitherto Undescribed Associated Extensive Glomus Cell Hyperplasia and Tumorlet Formation.
Extra-adrenal paraganglioma has never been described in the extremities. A 34-year-old woman complained of an enlarging mass in the right forearm for 18 months. Imaging showed a circumscribed vascular tumor attached to the ulnar nerve; biopsy revealed features of paraganglioma. The resected tumor consisted of zellballen pattern of chief cells staining positively for chromogranin with surrounding S100-positive sustentacular cells. The chief cells contained many neurosecretory granules and mitochondria, whereas the sustentacular cells contained a large amount of rough endoplasmic reticulum and some microfilaments. There was adjacent extensive glomus cell hyperplasia and tumorlet formation. The intraoperative blood pressure dropped abruptly on tumor removal. The serum normetanephrine level decreased from a preoperative level of 1987 pg/mL (normal < 149 pg/mL) to normal after operation. The patient admitted on questioning to a history of paroxysmal attacks of transient palpitation, hand tremors, and sweating; imaging showed no evidence of tumor in other parts of the body, and there was no family history of similar tumor; she remained well 33 months after the operation. This occurrence of functional ulnar nerve paraganglioma with the hitherto undescribed associated glomus cell hyperplasia and tumorlet formation attests to the probable existence of normal sympathetic paraganglia in the extremity and their intimate functional relationship with glomus bodies.


Children eat their school lunch too quickly: an exploratory study of the effect on food intake.
Speed of eating, an important aspect of eating behaviour, has recently been related to loss of control of food intake and obesity. Very little time is allocated for lunch at school and thus children may consume food more quickly and food intake may therefore be affected. Study 1 measured the time spent eating lunch in a large group of students eating together for school meals. Study 2 measured the speed of eating and the amount of food eaten in individual school children during normal school lunches and then examined the effect of experimentally increasing or decreasing the speed of eating on total food intake. The time spent eating lunch was measured with a stop watch in 100 children in secondary school. A more detailed study of eating behaviour was then undertaken in 30 secondary school children (18 girls). The amount of food eaten at lunch was recorded by a hidden scale when the children ate amongst their peers and by a scale connected to a computer when they ate individually. When eating individually, feedback on how quickly to eat was visible on the computer screen. The speed of eating could therefore be increased or decreased experimentally using this visual feedback and the total amount of food eaten measured. In general, the children spent very little time eating their lunch. The 100 children in Study 1 spent on average (SD) just 7 (0.8) minutes eating lunch. The girls in Study 2 consumed their lunch in 5.6 (1.2) minutes and the boys ate theirs in only 6.8 (1.3) minutes. Eating with peers markedly distorted the amount of food eaten for lunch; only two girls and one boy maintained their food intake at the level observed when the children ate individually without external influences (258 (38) g in girls and 289 (73) g in boys). Nine girls ate on average 33% less food and seven girls ate 23% more food whilst the remaining boys ate 26% more food. The average speed of eating during school lunches amongst groups increased to 183 (53)% in the girls and to 166 (47)% in the boys compared to the speed of eating in the unrestricted condition. These apparent changes in food intake during school lunches could be replicated by experimentally increasing the speed of eating when the children were eating individually. If insufficient time is allocated for consuming school lunches, compensatory increased speed of eating puts children at risk of losing control over food intake and in many cases over-eating. Public health initiatives to increase the time available for school meals might prove a relatively easy way to reduce excess food intake at school and enable children to eat more healthily.


Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex.
Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.


Insulin-like growth factor 1 (IGF-1) enhances the protein expression of CFTR.
Low levels of insulin-like growth factor 1 (IGF-1) have been observed in the serum of cystic fibrosis (CF) patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR), whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL)- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET) assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.


Isolation of a family of organic anion transporters from human liver and kidney.
Five distinct organic anion transporter cDNAs, hOAT1-5, were isolated from human liver and kidney. hOAT1, 2, and 3 are homologous to their respective rat orthologues OAT1-3, whereas hOAT4 and 5 are novel clones that have not been identified in other species. hOAT1- and hOAT3-transfected cells showed uptake of p-aminohippurate and fluorescein. Cells expressing hOAT2 showed uptake of p-aminohippurate, methotrexate, cAMP, and alpha-ketoglutarate. Northern blot analysis indicated differential tissue distribution for the transporter transcripts. These results indicate the existence of a family of organic anion transporting proteins in humans distinct from the oatp-like family of transporters.