Pure Covalent-Organic Framework Membrane as a Label-Free Biomimetic Nanochannel for Sensitive and Selective Sensing of Chiral Flavor Substances.
Chiral flavor substances play an important role in the human perception of different tastes. Here, we report a pure covalent-organic framework (COF) membrane nanochannel in combination with a chiral gold nanoparticles (AuNPs) selector for sensing chiral flavor substances. The pure COF membrane with a proper pore size is selected as the nanochannel, while l-cysteine-modified AuNPs (l-Cys-AuNPs) are used as the chiral selector. l-Cys-AuNPs show stronger binding to the S-enantiomer than the R-enantiomer, causing current reduction to different degrees for the R- and S-enantiomer to achieve chiral sensing due to the synergistic effect of the size exclusion of the COF nanochannel and the chiral selectivity of l-Cys-AuNPs. The developed COF membrane nanochannel sensing platform not only allows an easy balance of the permeability and selectivity, which is difficult to achieve in traditional polymer membrane nanochannel sensors, but also exhibits better chiral performance than commercial artificial anodic aluminum oxide (AAO) nanochannel sensors. The developed nanochannel sensor is successfully applied for sensing flavor enantiomers such as limonene, propanediol, methylbutyric acid, and butanol with the enantiomer excess values of 55.2% (propanediol) and 72.4% (limonene) and the low detection limits of 36 (limonene) and 71 (propanediol) ng L-1. This study provides a new idea for the construction of nanochannel platforms based on the COF for sensitive and selective chiral sensing.


A pilot study for a screening trial of cervical fluorescence spectroscopy.
Fluorescence spectroscopy is a promising technology for detection of epithelial precancers and cancers. In preparation for a multicenter phase II screening trial, a pilot trial was conducted to test data collection and patient examination procedures, use data forms, time procedures, and identify problems with preliminary data analysis. Women 18 years of age and older underwent a questionnaire, a complete history, and a physical examination, including a pan-colposcopy of the lower genital tract. A fiber-optic probe measured fluorescence excitation-emission matrices at 1-3 cervical sites for 58 women. The data collection procedures, data forms, and procedure times worked well, although collection times for all the clinical data take an average of 28 min. The clinical team followed procedures well, and the data could be retrieved from the database at all sites. The multivariate analysis algorithm correctly identified squamous normal tissue 99% of the time and columnar normal tissue only 7%. The assessment of ploidy from monolayer samples was not accurate in this small sample. The study was successful as a pilot trial. We learned who participated, who withdrew, how often abnormalities were present, and that algorithms that have worked extremely well in previous studies do not work as well when a few study parameters are changed. The current algorithm for diagnosis identified squamous normal tissue very accurately and did less well for columnar normal tissue. Inflammation may be an explanation for this phenomenon. Fluorescence spectroscopy is a promising technology for the detection of epithelial precancers and cancers. The screening trial of fluorescence and reflectance spectroscopy was successful.


Coupling between endocytosis and sphingosine kinase 1 recruitment.
Genetic studies have suggested a functional link between cholesterol/sphingolipid metabolism and endocytic membrane traffic. Here we show that perturbing the cholesterol/sphingomyelin balance in the plasma membrane results in the massive formation of clusters of narrow endocytic tubular invaginations positive for N-BAR proteins. These tubules are intensely positive for sphingosine kinase 1 (SPHK1). SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals, which are cellular compartments specialized for exo/endocytosis. Membrane recruitment of SPHK1 involves a direct, curvature-sensitive interaction with the lipid bilayer mediated by a hydrophobic patch on the enzyme's surface. The knockdown of SPHKs results in endocytic recycling defects, and a mutation that disrupts the hydrophobic patch of Caenorhabditis elegans SPHK fails to rescue the neurotransmission defects in loss-of-function mutants of this enzyme. Our studies support a role for sphingosine phosphorylation in endocytic membrane trafficking beyond the established function of sphingosine-1-phosphate in intercellular signalling.


Efficacy of a psychoeducational intervention in caregivers of people with intellectual disabilities: A randomized controlled trial (EDUCA-IV trial).
People with intellectual disabilities (ID) are usually cared for by their own parents, families or informal caregivers. Caring for a person with ID can have a negative impact on caregivers' mental health (burden, depression, anxiety). The main aim of the EDUCA-IV trial was testing the efficacy of a psychoeducational intervention program (PIP) versus standard practice and to see whether the PIP intervention would reduce the caregiver's burden at post-intervention (4 months) and at follow-up (8 months). This was a multi-centre randomised controlled trial including 194 caregivers (96 randomised to PIP, 98 to control condition). PIP intervention consists of 12 weekly group sessions. The control group received treatment as usual. Primary outcomes measured included the Zarit Burden Interview (ZBI). Secondary outcomes were caregivers' mental health (GHQ-28), anxiety (STAI) and depression (CES-D). The decrease of ZBI scores was not significant at 4 months. There was significant decrease in the GHQ scores at 4 and 8 months. CES-D showed relevant results at follow-up. Intention to treat analyses showed similar results. The PIP intervention seems not to be effective reducing burden, but appears to have a positive result on general mental health. The program was well received and valued by caregivers.


New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential.
Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme required for hydroxylation of the aminobutyl side chain of deoxyhypusine in eukaryotic translation initiation factor 5A (eIF-5A), the second step in hypusine biosynthesis. DOHH has been recently identified in P. falciparum and P. vivax. Both enzymes have very peculiar features including E-Z type HEAT-like repeats and a diiron centre in their active site. Both proteins share only 26 % amino acid identity to the human paralogue. Hitherto, no X-ray structure exists from either enzyme. However, structural predictions based on the amino acid sequence of the active site in comparison to the human enzyme show that four conserved histidine and glutamate residues provide the coordination sites for chelating the ferrous iron ions. Recently, we showed that P. vivax DOHH is inhibited by zileuton (N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea), a drug that is known for inhibiting human 5-lipoygenase (5-LOX) by the complexation of ferrous iron. A novel discovery program was launched to identify inhibitors of the P. falciparum DOHH from the Malaria Box, consisting of 400 chemical compounds, which are highly active in the erythrocytic stages of Malaria infections. In a first visual selection for potential ligands of ferrous iron, three compounds from different scaffold classes namely the diazonapthyl benzimidazole MMV666023 (Malaria Box plate A, position A03), the bis-benzimidazole MMV007384 (plate A, position B08), and a 1,2,5,-oxadiazole MMV665805 (plate A, position C03) were selected and subsequently evaluated in silico for their potential to complex iron ions. As a proof of principle, a bioanalytical assay was performed and the inhibition of hypusine biosynthesis was determined by GC-MS. All tested compounds proved to be active in this assay and MMV665805 exhibited the strongest inhibitory effect. Notably, the results were in accordance with the preliminary quantum-mechanical calculations suggesting the strongest iron complexation capacity for MMV665805. This compound might be a useful tool as well as a novel lead structure for inhibitors of P. falciparum DOHH.


Quantitation of mRNA levels of steroid 5 alpha-reductase isoenzymes in the rat brain by "one-step" RT-PCR and capillary electrophoresis.
The enzyme 5alpha-reductase (5alpha-R) is present in many mammalian tissues, including the brain. The physiological importance of 5alpha-R in the brain derives from its capability to convert testosterone (T) to a more potent androgen, dihydrotestosterone (DHT), and to convert progesterone to its 5alpha-reduced derivative, precursors of allopregnanolone, potent allosteric modulator of the gamma-aminobutyric acid receptor (GABA(A)-R). 5alpha-R occurs as two isoforms, 5alpha-R type 1 (5alpha-R1) and 5alpha-R type 2 (5alpha-R2). We present an accurate, rapid, and modestly labor-intensive method to precisely quantitate 5alpha-R mRNA species in the cerebral cortex of the rat. This approach combines the high specificity of "one-step" reverse transcription-polymerase chain reaction (RT-PCR) with the sensitivity of laser-induced fluorescence capillary electrophoresis (LIF-CE). Both cDNA synthesis and PCR amplification are performed with the same enzyme and site-specific primers, improving the efficiency of cDNA synthesis. The specific target mRNA and a mimic DNA fragment, used as a competitive internal standard, were co-amplified in a single reaction in which the same primers are used. The method presented in this paper enables a more efficient quantitative determination of 5alpha-R mRNA isozymes, and may lead to a better understanding of the role of 5alpha-R isozymes in the physiology of the central nervous system.


Mitochondrial DNA stress primes the antiviral innate immune response.
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.


Introduction of UAG, UAA, and UGA nonsense mutations at a specific site in the Escherichia coli chloramphenicol acetyltransferase gene: use in measurement of amber, ochre, and opal suppression in mammalian cells.
We have used oligonucleotide-directed site-specific mutagenesis to convert serine codon 27 of the Escherichia coli chloramphenicol acetyltransferase (cat) gene to UAG, UAA, and UGA nonsense codons. The mutant cat genes, under transcriptional control of the Rous sarcoma virus long terminal repeat, were then introduced into mammalian cells by DNA transfection along with UAG, UAA, and UGA suppressor tRNA genes derived from a human serine tRNA. Assay for CAT enzymatic activity in extracts from such cells allowed us to detect and quantitate nonsense suppression in monkey CV-1 cells and mouse NIH3T3 cells. Using such an assay, we provide the first direct evidence that an opal suppressor tRNA gene is functional in mammalian cells. The pattern of suppression of the three cat nonsense mutations in bacteria suggests that the serine at position 27 of CAT can be replaced by a wide variety of amino acids without loss of enzymatic activity. Thus, these mutant cat genes should be generally useful for the quantitation of suppressor activity of suppressor tRNA genes introduced into cells and possibly for the detection of naturally occurring nonsense suppressors.


Recombination Signals In The rpoC1 Gene Indicate Gene-Flow Between Planktothrix (Cyanoprokaryota) Species.
The delineation of species boundaries in the potentially harmful cyanobacterium Planktothrix Anagnostidis et Komárek 1988 is particularly tangled. Genetic recombination has been invoked to explain the occurrence of overlapping biological traits among recognized species. Although horizontal gene transfer is shown as a driver of diversification in this genus, clear evidence for homologous recombination at the single gene level is still lacking. Several Planktothrix strains (n = 244) sampled in eight fresh water lakes in north Italy were characterized by sequencing the rpoC1 gene, a molecular marker previously proposed to discriminate between species. Six haplotypes were detected, four of which are newly described. A relevant number of rpoC1 sequences (n = 54) showed evidence of homologous recombination. By comparing the sequences produced in the work presented here to those available on GenBank for the genus, multiple recombination events were tracked between haplotypes associated to P. rubescens, P. suspensa and P. agardhii, the latter being a species not found in our survey. Recombination signals were in form of (i) a vast mosaic structure present in the alignment of rpoC1 haplotypes, (ii) multiple and statistically significant paths in the split decomposition network connecting these haplotypes and (iii) many individual crossing-over events detected by means of recombination detection tests. Data suggest that the molecular evolution of the rpoC1 gene in the genus Planktothrix appears as strongly influenced by homologous recombination. In addition, rpoC1 diversity effectively tracks recombinational processes among species in the complex made up by P. rubescens, P. agardhii and P. suspensa, which are not isolated in terms of gene-flow.


Fabrication of porous calcite using chopped nylon fiber and its evaluation using rats.
Although porous calcite has attracted attention as bone substitutes, limited studies have been made so far. In the present study, porous calcite block was fabricated by introducing chopped nylon fiber as porogen. Ca(OH)2 powder containing 10 wt% chopped nylon fiber was compacted at 150 MPa, and sintered to burn out the fiber and to carbonate the Ca(OH)2 under stream of 1:2 O2-CO2. Sintering of Ca(OH)2 at 750 °C or lower temperature resulted in incomplete burning out of the fiber whereas sintering at 800 °C or higher temperature resulted in the formation of CaO due to the thermal decomposition of Ca(OH)2. However, sintering at 770 °C resulted in complete burning out of the fiber and complete carbonation of Ca(OH)2 to calcite without forming CaO. Macro- and micro-porosities of the porous calcite were approximately 23 and 16%, respectively. Diameter of the macropores was approximately 100 μm which is suitable for bone tissue penetration. Porous calcite block fabricated by this method exhibited good tissue response when implanted in the bone defect in femur of 12-weeks-old rat. Four weeks after implantation, bone bonded on the surface of calcite. Furthermore, bone tissue penetrated interior to the macropore at 8 weeks. These results demonstrated the good potential value of porous calcite as artificial bone substitutes.


Protective effects of Punica granatum seeds extract against aging and scopolamine induced cognitive impairments in mice.
Dementia is one of the age related mental problems and characteristic symptom of various neurodegenerative diseases including Alzheimer's disease. This impairment probably is due to the vulnerability of the brain cells to increased oxidative stress during aging process. Many studies have shown that certain phenolic antioxidants attenuate neuronal cell death induced by oxidative stress. The present work was undertaken to assess the effect of ethanolic extract of Punica granatum seeds on cognitive performance of aged and scopolamine treated young mice using one trial step-down type passive avoidance and elevated plus maze task. Aged or scopolamine treated mice showed poor retention of memory in step-down type passive avoidance and in elevated plus maze task. Chronic administration (21 days) of Punica granatum extract and vitamin C significantly (p < 0.05) reversed the age induced or scopolamine induced retention deficits in both the paradigms. Punica granatum extract also significantly lowered lipid peroxidation level and increased antioxidant glutathione level in brain tissues. Punica granatum preparations could be protective in the treatment of cognitive disorders such as dementia and Alzheimer's disease.


Ideomotor apraxia in agrammatic and logopenic variants of primary progressive aphasia.
There are few studies examining praxis in subjects with primary progressive aphasia. The aim of this study was to examine the pattern and severity of ideomotor apraxia in subjects with logopenic and agrammatic variants of primary progressive aphasia and to determine if the presence of ideomotor apraxia correlated with specific neuroanatomical structural abnormalities. Subjects with primary progressive aphasia were prospectively recruited and classified according to published criteria. Using the apraxia subtest of the Western Aphasia Battery, pattern and severity of ideomotor apraxia was examined in all subjects diagnosed with agrammatic and logopenic variants of primary progressive aphasia. The study included 47 subjects, 21 diagnosed with agrammatic variant of primary progressive aphasia and 26 with logopenic variant primary progressive aphasia. Subjects with agrammatic aphasia were older at onset than the logopenic variant (67.2 vs. 61.7 years, p = 0.02), but there was no difference in illness duration prior to evaluation. Those with logopenic aphasia showed more cognitive impairment on the Mini-Mental Status Examination (agrammatic = 26.7/30, logopenic = 22/30, p = 0.002), and a trend for more severe language impairment as measured by the Western Aphasia Battery-Aphasia Quotient (agrammatic = 82.3, logopenic = 75.2, p = 0.11). Strong correlations were found between Western Aphasia Battery-Aphasia Quotient and total apraxia, instrumental apraxia, and complex apraxia, while average to modest correlations were seen with upper limb apraxia and facial apraxia. After adjusting for age, mental status performance, and Western Aphasia Battery-Aphasia Quotient score, those with agrammatic aphasia had a higher degree of total apraxia (p = 0.004), facial apraxia (p = 0.03), instrumental apraxia (p = 0.0006), and complex apraxia (p = 0.0006) than those with logopenic aphasia. The agrammatic variant of primary progressive aphasia was associated with greater praxis deficits but less cognitive impairment than the logopenic variant. The presence of ideomotor apraxia was associated with grey matter loss in the left lateral premotor cortex with extension into the motor cortex. These findings suggest that although some affected areas in the agrammatic and logopenic variants of primary progressive aphasia overlap, there exists an area that is more affected in the agrammatic variant than the logopenic variant that accounts for the greater association of agrammatic aphasia with ideomotor apraxia.


Riding posture affects quadriceps femoris oxygenation during an incremental cycle exercise in cycle-based athletes.
Although oxygenation levels and muscle recruitment patterns of the quadriceps femoris during an incremental cycling exercise has been reported, oxygenation and activation profiles of the quadriceps femoris in racing posture in cycle-based athletes remain unknown. This study aimed to examine the effects of riding posture on oxygenation and neuromuscular activation of quadriceps femoris during an incremental cycling exercise in cycle-based athletes. Nine cycle-based athletes and nine nonathletic subjects performed an incremental cycling exercise at a constant cadence of 90 rpm. Riding postures were the racing posture using an aero-handle bar (aero posture) and the usual upright racing posture as the control (upright posture). Near-infrared spectroscopy and surface electromyography were recorded from vastus lateralis and rectus femoris. Changes in the tissue oxygenation index of the near-infrared spectroscopy from baseline were calculated, and the amplitudes of electromyographic signals were normalized to the initial values of the exercise in each muscle. In cycle-based athletes, changes in the tissue oxygenation index of vastus lateralis and rectus femoris in the aero posture were significantly lower than those obtained in the upright posture throughout the exercise, whereas no significant differences between the postures were observed in the normalized electromyographic amplitudes of vastus lateralis and rectus femoris. A significant difference between the postures was only occurred in changes of the tissue oxygenation index of rectus femoris in the final phase of exercise in nonathletic subjects. It appears that riding posture affects the oxygenation pattern of quadriceps femoris during incremental cycling exercise in cycle-based athletes. The main results of this study suggest that aero posture during incremental cycle exercise enhanced the muscular oxygen consumption of the quadriceps femoris in the trained cyclists.


[First finding of Lutzomyia longipalpis (Lutz & Neiva, 1912) in the urban area of Uberlândia, MG, concomitant with the first reported autochthonous case of human visceral leishmaniasis].
The first occurrence of the vector for visceral leishmaniasis, Lutzomyia longipalpis, in the urban area of Uberlândia, State of Minas Gerais, and the first autochthonous case of human visceral leishmaniasis recorded in the same locality are reported. These were notified to the Zoonosis Control Center, through the Epidemiological Surveillance sector of the Municipal Health Department. The importance of these findings regarding transmission of the disease in this area is discussed.


Super-Resolved Microbubble Localization in Single-Channel Ultrasound RF Signals Using Deep Learning.
Recently, super-resolution ultrasound imaging with ultrasound localization microscopy (ULM) has received much attention. However, ULM relies on low concentrations of microbubbles in the blood vessels, ultimately resulting in long acquisition times. Here, we present an alternative super-resolution approach, based on direct deconvolution of single-channel ultrasound radio-frequency (RF) signals with a one-dimensional dilated convolutional neural network (CNN). This work focuses on low-frequency ultrasound (1.7 MHz) for deep imaging (10 cm) of a dense cloud of monodisperse microbubbles (up to 1000 microbubbles in the measurement volume, corresponding to an average echo overlap of 94%). Data are generated with a simulator that uses a large range of acoustic pressures (5-250 kPa) and captures the full, nonlinear response of resonant, lipid-coated microbubbles. The network is trained with a novel dual-loss function, which features elements of both a classification loss and a regression loss and improves the detection-localization characteristics of the output. Whereas imposing a localization tolerance of 0 yields poor detection metrics, imposing a localization tolerance corresponding to 4% of the wavelength yields a precision and recall of both 0.90. Furthermore, the detection improves with increasing acoustic pressure and deteriorates with increasing microbubble density. The potential of the presented approach to super-resolution ultrasound imaging is demonstrated with a delay-and-sum reconstruction with deconvolved element data. The resulting image shows an order-of-magnitude gain in axial resolution compared to a delay-and-sum reconstruction with unprocessed element data.


Is Old Age Just a Number in Language Skills? Language Performance and Its Relation to Age, Education, Gender, Cognitive Screening, and Dentition in Very Old Finnish Speakers.
This study reports on how very old (VO) Finnish people without dementia perform in the Western Aphasia Battery (WAB) and two verbal fluency tasks and which demographic factors predict the performance. The study included fifty 80- to 100-year-old community-dwelling Finnish speakers with no dementing illnesses or speech-language disabilities, who completed the WAB and two verbal fluency tasks. Multifactorial statistical analyses with recursive partitioning were carried out to determine the significant predictors out of five predictor variables (age, gender, education, dentition, and Mini-Mental State Examination [MMSE]) for four response variables (WAB Aphasia Quotient [AQ], Language Quotient [LQ], semantic, and phonemic word fluencies). Overall, individual variation was notable in VO speakers. All predictor variables were statistically significantly associated with one or more of the language skills. Age was the most significant predictor; the critical age of 85-86 years was associated with a decline in WAB-AQ and semantic fluency. Poor dentition and the MMSE score both predicted a decline in WAB-LQ and phonemic fluency. A high level of education was positively associated with the skills of the best-performing individuals in WAB-AQ, WAB-LQ, and semantic fluency. VO age is a significant factor contributing to language performance. However, a younger age, a good cognitive performance, intact teeth, and a higher educational level also seem to have a preservative power as regards language skills. Gender differences should be interpreted with caution. The results of this study provide culture- and language-specific normative data, which aids in differentiating typical aging from the signs of acute or degenerative neuropathology to ensure appropriate medical and therapeutic interventions.


Using the Federal Register.
The Federal Register provides official notice of the issuance and contents of agency regulations and proposed rule changes and gives citizens an opportunity for input into their development. Knowing how to use this publication should be part of any administrator's repertory of skills.


Mechanical stretch induces lung α-epithelial Na(+) channel expression.
ABSTRACT During fetal development physiological stretching helps drive lung growth and maturation. At birth, the α-subunit of the alveolar epithelial sodium channel (α-ENaC) is a critical factor in helping to facilitate clearance of lung fluid during the perinatal period. The effects of stretch, however, on α-ENaC expression in the fetal lung have yet to be elucidated. In an effort to explore this question, we used both an in vitro cell culture model that exposes cells to repetitive cyclic stretch (CS) as well as an in vivo preterm animal model of mechanical ventilation (MV). We found that murine lung epithelial (MLE-12) cells exposed to repetitive CS showed a significant rise in α-ENaC mRNA expression. Total and cell-surface protein abundance of α-ENaC were also elevated after 24 h of CS. Stretch-induced increases in α-ENaC expression were suppressed in the presence of either actinomycin D or cycloheximide. Pharmacological inhibition of the extracellular signal-regulated protein kinase (ERK1/2) did not attenuate stretch-induced increases in α-ENaC protein, whereas inhibition of p38 MAPK or c-Jun NH2-terminal kinase (JNK) did. In 29-day preterm rabbits, alveolar stretching secondary to postnatal MV markedly elevated fetal lung α-ENaC expression compared to spontaneously breathing counterparts. In summary, our findings indicate that mechanical stretch promotes α-ENaC expression.


Decreased responsiveness of vascular postjunctional alpha1-, alpha2-adrenoceptors and neuropeptide Y1 receptors in rats with heart failure.
Heart failure is associated with increased sympathetic nerve activity. We hypothesized that chronic sympathetic stimulation in heart failure resulted in decreased vascular sympathetic responsiveness. A pithed rat model was employed to evaluate peripheral vascular alpha-adrenoceptor and neuropeptide Y (NPY) receptor responsiveness. Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. Sham operated rats (Sham) served as controls. Two months after this surgical procedure, both heart failure (n = 30) and Sham (n = 30) rats underwent standard pithing procedure. Pressor responses to preganglionic sympathetic nerve stimulation (PNS) and activation of postjunctional alpha1- and alpha2-adrenoceptors as well as Y1 receptors were studied. In response to PNS, cardiac index was similar between heart failure and sham rats (P = n.s.). Mean arterial pressure (MAP) increased in a frequency-dependent fashion after PNS in heart failure rats as well as in control rats. All the agonists used, i.e. the alpha1-adrenoceptor agonist phenylephrine, the alpha2-adrenoceptor agonists clonidine and BHT933 as well as NPY, induced dose-dependent increases in MAP in heart failure and in sham rats. However, in rats with heart failure, the response to all the agonists studied was significantly decreased and the dose response curves were shifted to the right (P < 0.01). We conclude that in vivo vascular response to postjunctional alpha1- and alpha2-adrenoceptors as well as Y1 receptors are decreased in rats with heart failure.


IgE responsiveness to Dermatophagoides farinae in West Highland white terrier dogs is associated with region on CFA35.
Immunoglobulin E (IgE)-mediated hypersensitivity against environmental allergens, commonly including Dermatophagoides farinae, is associated with atopic diseases in both humans and dogs. We have recently identified a family of clinically healthy West Highland white terriers (WHWTs) with high-serum D. farinae-IgE levels. In this study, we investigated the genetic mechanism controlling IgE responsiveness in dogs by performing a genome-wide association study (GWAS) using the Affymetrix V2 Dog SNP array in 31 high-IgE and 24 low-IgE responder WHWTs. A gene-dropping simulation method, using SIB-PAIR software, showed significant allelic association between serum D. farinae-specific IgE levels and a 2.3-Mb area on CFA35 (best empirical P = 1 × 10(-5)). A nearby candidate gene, CD83, encodes a protein which has important immunological functions in antigen presentation and regulation of humoral immune responses. We sequenced this gene in 2 high-IgE responders and 2 low-IgE responders and identified an intronic polymorphic repeat sequence with a predicted functional effect, but the association was insufficient to explain the GWAS association signal in this population (P = 1 × 10(-3)). Further studies are necessary to investigate the significance of these findings for IgE responsiveness and atopic disease in the dog.


Participation of low-threshold calcium spikes in excitatory synaptic transmission in guinea pig medial frontal cortex.
We studied the activation of low-threshold calcium spikes (LTS) by excitatory postsynaptic potentials in pyramidal neurons from guinea pig medial frontal cortex with intracellular recording. We used extracellular bicuculline and phaclofen and intracellular QX-314 to block inhibitory synaptic potentials and sodium currents. Postsynaptic potentials were evoked by stimulation of layer I. We found that large (> 10-15 mV) excitatory synaptic potentials evoked from membrane potentials more negative than -75 mV were able to trigger LTS. The activation of LTS resulted in an increase of the rising slope or amplitude of the synaptic potentials depending on the size of the excitatory postsynaptic potential (EPSP). We used 100 microM NiCl2 to confirm the presence of LTS as part of the EPSPs. The N-methyl-D-aspartate (NMDA) and non-NMDA components of the excitatory synaptic potentials were isolated using (+/-)2-amino-5-phosphonovaleric acid (APV; 50 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM); both components could, independently, trigger an LTS. With recordings made with K+ acetate-filled electrodes, we show that the activation of LTS was critical to allow excitatory synaptic potentials to reach the threshold of action potential firing; also, this amplification of synaptic responses produced the firing of more than a single action potential by the postsynaptic cell. These results demonstrate that in cortical pyramidal neurons the activation of low-threshold calcium spikes results in the amplification of synaptic responses.


Maximizing peptide identification events in proteomic workflows using data-dependent acquisition (DDA).
Current analytical strategies for collecting proteomic data using data-dependent acquisition (DDA) are limited by the low analytical reproducibility of the method. Proteomic discovery efforts that exploit the benefits of DDA, such as providing peptide sequence information, but that enable improved analytical reproducibility, represent an ideal scenario for maximizing measureable peptide identifications in "shotgun"-type proteomic studies. Therefore, we propose an analytical workflow combining DDA with retention time aligned extracted ion chromatogram (XIC) areas obtained from high mass accuracy MS1 data acquired in parallel. We applied this workflow to the analyses of sample matrixes prepared from mouse blood plasma and brain tissues and observed increases in peptide detection of up to 30.5% due to the comparison of peptide MS1 XIC areas following retention time alignment of co-identified peptides. Furthermore, we show that the approach is quantitative using peptide standards diluted into a complex matrix. These data revealed that peptide MS1 XIC areas provide linear response of over three orders of magnitude down to low femtomole (fmol) levels. These findings argue that augmenting "shotgun" proteomic workflows with retention time alignment of peptide identifications and comparative analyses of corresponding peptide MS1 XIC areas improve the analytical performance of global proteomic discovery methods using DDA.


K+ transport by rat colon: adaptation to a low potassium diet.
Recent studies with the isolated perfused rat kidney have demonstrated the existence of an intrinsic renal adaptation to conserve K+ in response to ingestion of a low K+ diet for 3 days. To determine whether the colon alters its K+ transport properties in a similar fashion, we measured transmural 86Rb fluxes across sheets of distal colonic epithelium under short-circuit conditions. Preliminary studies using a double-isotope technique demonstrated that 86Rb and 42K fluxes were similar; therefore 86Rb flux was considered equivalent to K+ flux. The distal half of the colon from each rat was divided into two segments, referred to as early and late distal colon. Experiments were carried out using rats fed a K+ -free, control (0.15 mmol/g), and high K+ (1.13 mmol/g) powdered diet of otherwise identical electrolyte content. Net K+ secretion (Jnet) by the early distal colon was reduced from 0.45 in the controls to -0.02 mueq X cm-2 X h-1 by a low K+ diet as a result of a decrease in serosal-to-mucosal flux (Jsm), with no change in mucosal-to-serosal flux (Jms). Conductance (GT) and short-circuit current (Isc) were unchanged. Jnet by the late distal colon averaged 0.17 in the controls and 0.01 mueq X cm-2 X h-1 with a low K+ diet, but this difference was not significant statistically. In comparison with the controls, a high K+ diet had no effect on Jnet by the early distal colon (0.48 mueq X cm-2 X h-1) but increased Jnet by the late distal colon substantially (0.77 mueq X cm-2 X h-1).(ABSTRACT TRUNCATED AT 250 WORDS)


Aerobic exercise enhances neural correlates of motor skill learning.
Repetitive, in-phase bimanual motor training tasks can expand the excitable cortical area of the trained muscles. Recent evidence suggests that an acute bout of moderate-intensity aerobic exercise can enhance the induction of rapid motor plasticity at the motor hotspot. However, these changes have not been investigated throughout the entire cortical representation. Furthermore, it is unclear how exercise-induced changes in excitability may relate to motor performance. We investigated whether aerobic exercise could enhance the neural correlates of motor learning. We hypothesized that the combination of exercise and training would increase the excitable cortical area to a greater extent than either exercise or training alone, and that the addition of exercise would enhance performance on a motor training task. 25 young, healthy, right-handed individuals were recruited and divided into two groups and three experimental conditions. The exercise group performed exercise alone (EX) and exercise followed by training (EXTR) while the training group performed training alone (TR). The combination of exercise and training increased excitability within the cortical map of the trained muscle to a greater extent than training alone. However, there was no difference in performance between the two groups. These results indicate that exercise may enhance the cortical adaptations to motor skill learning.


Xanthomonas axonopodis pv. citri: factors affecting successful eradication of citrus canker.
SUMMARY Taxonomic status: Bacteria, Proteobacteria, gamma subdivision, Xanthomodales, Xanthomonas group, axonopodis DNA homology group, X. axonopodis pv. citri (Hasse) Vauterin et al. Microbiological properties: Gram negative, slender, rod-shaped, aerobic, motile by a single polar flagellum, produces slow growing, non-mucoid colonies in culture, ecologically obligate plant parasite. Causal agent of Asiatic citrus canker on most Citrus spp. and close relatives of Citrus in the family Rutaceae. Disease symptoms: Distinctively raised, necrotic lesions on fruits, stems and leaves. Bacteria exude from lesions during wet weather and are disseminated by splash dispersal at short range, windblown rain at medium to long range and human assisted movement at all ranges. Crop loss: Severe infections cause defoliation, blemished fruit, premature fruit drop, die-back of twigs and general debilitation of the tree. Distribution: Citrus canker is not present in all subtropical to tropical regions of citriculture in the world, so considerable regulatory efforts are expended to prevent the introduction and spread of X. axonopodis pv. citri into areas in the Americas, Australia and elsewhere, with climates conducive to the disease. Limited strategies exist for suppression of citrus canker on more susceptible cultivars. Blemished fruit are unmarketable and exposed fruit are restricted in market access. The economic impact of loss of markets is much greater than that from yield and quality reductions of the crop. http://doacs.state.fl.us/canker, http://www.apsnet.org/education/lessonsplantpath/citruscanker/top.htm, http://www.apsnet.org/online/feature/citruscanker/, http://www.plantmanagementnetwork.org/pub/php/review/citruscanker/, http://www.abecitrus.com.br/fundecitrus.html, http://www.biotech.ufl.edu/PlantContainment/canker.htm, http://www.aphis.usda.gov/oa/ccanker/.


eIF5A and EF-P: two unique translation factors are now traveling the same road.
Translational control is extremely important in all organisms, and some of its aspects are highly conserved among all primary kingdoms, such as those related to the translation elongation step. The previously classified translation initiation factor 5A (eIF5A) and its bacterial homologue elongation factor P (EF-P) were discovered in the late 70's and have recently been the object of many studies. eIF5A and EF-P are the only cellular proteins that undergo hypusination and lysinylation, respectively, both of which are unique posttranslational modifications. Herein, we review all the important discoveries related to the biochemical and functional characterization of these factors, highlighting the implication of eIF5A in translation elongation instead of initiation. The findings that eIF5A and EF-P are important for specific cellular processes and play a role in the relief of ribosome stalling caused by specific amino acid sequences, such as those containing prolines reinforce the hypothesis that these factors are involved in specialized translation. Although there are some divergences between these unique factors, recent studies have clarified that they act similarly during protein synthesis. Further studies may reveal their precise mechanism of ribosome activity modulation as well as the mRNA targets that require eIF5A and EF-P for their proper translation.


Clinical and histopathologic features of paraneoplastic granuloma annulare in association with solid organ malignancies: A case-control study.
Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy. To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA. Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment. Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved. Single-institution, retrospective review with a small sample size. Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm.


Frequency of extreme Sahelian storms tripled since 1982 in satellite observations.
The hydrological cycle is expected to intensify under global warming, with studies reporting more frequent extreme rain events in many regions of the world, and predicting increases in future flood frequency. Such early, predominantly mid-latitude observations are essential because of shortcomings within climate models in their depiction of convective rainfall. A globally important group of intense storms-mesoscale convective systems (MCSs)-poses a particular challenge, because they organize dynamically on spatial scales that cannot be resolved by conventional climate models. Here, we use 35 years of satellite observations from the West African Sahel to reveal a persistent increase in the frequency of the most intense MCSs. Sahelian storms are some of the most powerful on the planet, and rain gauges in this region have recorded a rise in 'extreme' daily rainfall totals. We find that intense MCS frequency is only weakly related to the multidecadal recovery of Sahel annual rainfall, but is highly correlated with global land temperatures. Analysis of trends across Africa reveals that MCS intensification is limited to a narrow band south of the Sahara desert. During this period, wet-season Sahelian temperatures have not risen, ruling out the possibility that rainfall has intensified in response to locally warmer conditions. On the other hand, the meridional temperature gradient spanning the Sahel has increased in recent decades, consistent with anthropogenic forcing driving enhanced Saharan warming. We argue that Saharan warming intensifies convection within Sahelian MCSs through increased wind shear and changes to the Saharan air layer. The meridional gradient is projected to strengthen throughout the twenty-first century, suggesting that the Sahel will experience particularly marked increases in extreme rain. The remarkably rapid intensification of Sahelian MCSs since the 1980s sheds new light on the response of organized tropical convection to global warming, and challenges conventional projections made by general circulation models.


Angiographic evaluation of the distance from the top of the jugular bulb to the inferior petrosal sinus-internal jugular vein junction: simple classification and identification method for the orifice of the non-visualized inferior petrosal sinus during neuroendovascular surgery.
The inferior petrosal sinus (IPS) is the transvenous access route for neurointerventional surgery that is occasionally undetectable on digital subtraction angiography (DSA) because of blockage by a clot or collapse. This study was aimed at analyzing the distance from the jugular bulb (JB) to the IPS-internal jugular vein (IJV) junction and proposing a new anatomical classification system for the IPS-IJV junction to identify the non-visualized IPS orifice. DSA of 708 IPSs of 375 consecutive patients were retrospectively investigated to calculate the distance from the top of the JB to the IPS-IJV junction, and a simple classification system based on this distance was proposed. The median distance from the top of the JB to the IPS-IJV junction was 20.8 ± 14.7 mm. Based on the lower (10.9 mm) and upper (31.1 mm) quartiles, IPS-IJV junction variants were: type I, 0-10 mm (22.3%); type II, 11-30 mm (45.8%); type III, > 31 mm (23.9%); and type IV, no connection to the IJV (8.0%). Bilateral distances showed a positive interrelationship, with a correlation coefficient of 0.86. The bilateral symmetry type (visualized IPSs bilaterally) according to our classification occurred in 267 of 300 (89.0%) patients. In this study, the IPS-IJV junction was located far from the JB (types II and III), with a higher probability (69.6%). This distance and the four-type classification demonstrated high degrees of homology with the contralateral side. These results would be useful for identifying the non-visualized IPS orifice.


Enhancing consolidation of a rotational visuomotor adaptation task through acute exercise.
We assessed the effect of a single bout of intense exercise on the adaptation and consolidation of a rotational visuomotor task, together with the effect of the order of exercise presentation relative to the learning task. Healthy adult participants (n = 29) were randomly allocated to one of three experimental groups: (1) exercise before task practice, (2) exercise after task practice, and (3) task practice only. After familiarization with the learning task, participants undertook a baseline practice set. Then, four 60° clockwise rotational sets were performed, comprising an adaptation set and three retention sets at 1 h, 24 h, and 7 days after the adaptation set. Depending on the experimental group, exercise was presented before or after the adaptation sets. We found that error reduction during adaptation was similar regardless of when exercise was presented. During retention, significant error reduction was found in the retention set at 1 h for both exercise groups, but this enhancement was not present during subsequent retention sets, with no differences present between exercise groups. We conclude that an acute bout of intense exercise could positively affect retention, although the order in which exercise is presented does not appear to influence its benefits during the early stages of consolidation.


Studies on a mammalian hepatic binding protein specific for asialoglycoproteins. Evidence for receptor recycling in isolated rat hepatocytes.
Freshly isolated rat hepatocytes attained maximal ability to bind, internalize, and degrade 125I-asialo-orosomucoid after 5 h in suspension culture at 37 degrees C. Comparison of the number and distribution of the asialoglycoprotein binding sites of these cells revealed that 5% (6.7 x 10(4) receptors/cell) were on the external cell membrane with an average residency time of slightly less than 3 min. The remaining 95% were located intracellularly, as determined with detergent-solubilized hepatocytes. Binding of ligand (asialo-orosomucoid) was time-dependent, saturable, and dissociable. The dissociation constant for the single high affinity binding site was calculated to be 3.4 x 10(-8) M. The amount of asialo-orosomucoid metabolized by these cells over a period of 3 h at 37 degrees C was reduced 50% by the inclusion of 1 mM cycloheximide in the incubation medium. However, even in the absence of protein synthesis, 34 times more asialo-orosomucoid was metabolized than could be bound by the cell surface receptors, or twice the total capacity of the intact hepatocyte. These results provide clear evidence for the stability of the binding receptor under conditions where the ligand is being continually destroyed and support the previously proposed recycling hypothesis (Tanabe, T., Pricer, W.E., Jr., and Ashwell, G. (1979) J. Biol. Chem. 254, 1038-1043).


MiR-15a-5p negatively regulates cell survival and metastasis by targeting CXCL10 in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a common malignant disease from hematopoietic system. Aberrant expression of microRNAs (miRNAs) has been found in CML, however, the roles of many miRNAs including miR-15a-5p in CML are still unknown. In this study, the expression and roles of miR-15a-5p in CML were investigated. We found that restoration miR-15a-5p expression in CML cells decreased cell growth, metastasis and enhanced cell apoptosis. Chemokine ligand 10 (CXCL10) was predicted as a target gene of miR-15a-5p, which was verified by luciferase assay. CXCL10 mRNA and protein was down-regulated in the CML cells with miR-15a-5p overexpression by real time RT-PCR and western blotting. We also found that there were low levels of miR-15a-5p companied with high levels of CXCL10 in blood samples from CML patients. In a conclusion, miR-15a-5p suppresses cell survival and metastasis of CML by targeting CXCL10, which is a therapeutic option for CML patients.


Fc-fusion proteins: new developments and future perspectives.
Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas.


[Tubal choriocarcinoma: a case].
The authors report a case history of a tubal choriocarcinoma occurring in a woman of 38 years of age. This was 6 years after her second and last pregnancy and was diagnosed before operation. A summary of the complementary examinations is presented: An ultrasound showing a non-specific mass whose value therefore was somewhat limited; A hysterosalpingogram which showed an irregular tubal image suggestive of a cancer of the tube; Pelvic arteriography that made the signs of choriocarcinoma fairly clear. Discussion then developed in looking at the literature of those diagnostic features that are usually made. Most often this is by laparatomy when a ruptured extra-uterine pregnancy is suspected or when suspicion rests on a twisted ovarian cyst, a uterine fibroid, a tubo-ovarian abscess or blood in the peritoneal cavity in the third trimester of pregnancy, treatment, which is best given as a combination of surgery and chemotherapy, and pathogenic aetiology. It does seem that there are two principal mechanisms, the first being a malignant transformation of a tubal pregnancy, or a choriocarcinoma arising de novo without an ectopic pregnancy.


Antiphospholipid syndrome: state of the art on clinical practice guidelines.
Antiphospholipid syndrome (APS) is a rare disease characterised by venous and/or arterial thrombosis, pregnancy complications and the presence of specific autoantibodies called antiphospholipid antibodies. This review aims to identify existing clinical practice guidelines (CPG) as part of the ERN ReCONNET project, aimed at evaluating existing CPGs or recommendations in rare and complex diseases. Seventeen papers providing important data were identified; however, the literature search highlighted the scarceness of reliable clinical data to develop CPGs. With no formal clinical guidelines in place, diagnosis and treatment of APS is largely based on consensus and expert opinion. Patients' unmet need refers to the understanding of the disease and its clinical picture and implications, the need of education for patients, family members and healthcare providers, as well as to the development of monitoring pathways involving multiple healthcare providers.


Cysteine is the initial site of modification of alpha-crystallin by kynurenine.
Tryptophan metabolites, such as kynurenine, are spontaneously unstable at neutral pH. They undergo side-chain deamination yielding reactive alpha, beta unsaturated ketones. In the lens, where these compounds act as UV filters, reaction of the breakdown products with lens proteins (crystallins) may be largely responsible for age-dependent colouration of this tissue. In previous research, where high pH (pH 9) was used to promote deamination and conjugation with lens protein, histidine, lysine, and cysteine residues were found to be modified. In this study we show that, at pH 7, site of reaction with the major lens chaperone alpha-crystallin, is the single cysteine residue of the alphaA subunit. This apparent selectivity has important ramifications because the cysteine-kynurenine adduct is itself unstable under physiological conditions.


Serologic-based investigation of leptospirosis in a population of free-ranging eastern grey kangaroos (Macropus giganteus) indicating the presence of Leptospira weilii serovar Topaz.
Eastern grey kangaroos (Macropus giganteus) are one of the most abundant large macropodids sharing the landscape with humans. Despite this, little is known about the prevalence of Leptospira carriage within this species and the role that they may partake in the transmission of this disease in Australia. The sera of 87 free-ranging eastern grey kangaroos, captured in the Warragamba Catchment Area, Sydney, Australia, from June 2004 to November 2006, were screened against a reference panel of 22 Leptospira serovars using the microscopic agglutination test (MAT). Leptospiral antibodies were detected in 47% (41 of 87) of serum samples collected. Leptospira weilii Topaz, a newly emergent serovar in Australia, was detected in all seropositive kangaroos (41 of 41; 100%). The sex and tail-fat body condition index of kangaroos appeared to have no significant effect on the exposure to the disease. This serologic-based study is the first reported for L. weilii serovar Topaz in New South Wales, to our knowledge, having previously been isolated only in humans and two other animal species (bovine and long-nosed bandicoot [Perameles nasuta]) in Western Australia and Queensland. The potential role of eastern grey kangaroos in the maintenance and zoonotic spread of the disease to livestock and humans is discussed.


Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461.
CX-5461 is a G-quadruplex (G4) ligand currently in trials with initial indications of clinical activity in cancers with defects in homologous recombination repair. To identify more genetic defects that could sensitize tumors to CX-5461, we tested synthetic lethality for 480 DNA repair and genome maintenance genes to CX-5461, pyridostatin (PDS), a structurally unrelated G4-specific stabilizer, and BMH-21, which binds GC-rich DNA but not G4 structures. We identified multiple members of HRD, Fanconi Anemia pathways, and POLQ, a polymerase with a helicase domain important for G4 structure resolution. Significant synthetic lethality was observed with UBE2N and RNF168, key members of the DNA damage response associated ubiquitin signaling pathway. Loss-of-function of RNF168 and UBE2N resulted in significantly lower cell survival in the presence of CX-5461 and PDS but not BMH-21. RNF168 recruitment and histone ubiquitination increased with CX-5461 treatment, and nuclear ubiquitination response frequently co-localized with G4 structures. Pharmacological inhibition of UBE2N acted synergistically with CX-5461. In conclusion, we have uncovered novel genetic vulnerabilities to CX-5461 with potential significance for patient selection in future clinical trials.


Endurance training remodels skeletal muscle phospholipid composition and increases intrinsic mitochondrial respiration in men with Type 2 diabetes.
The effects of exercise training on the skeletal muscle (SKM) lipidome and mitochondrial function have not been thoroughly explored in individuals with Type 2 diabetes (T2D). We hypothesize that 10 wk of supervised endurance training improves SKM mitochondrial function and insulin sensitivity that are related to alterations in lipid signatures within SKM of T2D (males n = 8). We employed integrated multi-omics data analyses including ex vivo lipidomics (MS/MS-shotgun) and transcriptomics (RNA-Seq). From biopsies of SKM, tissue and primary myotubes mitochondrial respiration were quantified by high-resolution respirometry. We also performed hyperinsulinemic-euglycemic clamps and blood draws before and after the training. The lipidomics analysis revealed that endurance training (>95% compliance) increased monolysocardiolipin by 68.2% (P ≤ 0.03), a putative marker of mitochondrial remodeling, and reduced total sphingomyelin by 44.8% (P ≤ 0.05) and phosphatidylserine by 39.7% (P ≤ 0.04) and tended to reduce ceramide lipid content by 19.8%. Endurance training also improved intrinsic mitochondrial respiration in SKM of T2D without alterations in mitochondrial DNA copy number or cardiolipin content. RNA-Seq revealed 71 transcripts in SKM of T2D that were differentially regulated. Insulin sensitivity was unaffected, and HbA1c levels moderately increased by 7.3% despite an improvement in cardiorespiratory fitness (V̇o2peak) following the training intervention. In summary, endurance training improves intrinsic and cell-autonomous SKM mitochondrial function and modifies lipid composition in men with T2D independently of alterations in insulin sensitivity and glycemic control.


Economic evaluation of a participatory ergonomics intervention in a textile plant.
In this study we report on the economic evaluation of a participatory ergonomics process undertaken at a clothing manufacturer in Southwestern Ontario, Canada that employs approximately 300 workers. We undertake a cost-benefit analysis from the company perspective. Intervention costs amounted to $65,787 and intervention benefits $360,614 (2011 Canadian dollars). The net present value was $294,827, suggesting that the intervention was worth undertaking based on the costs and consequences over the measurement period spanning more than four years. Based on these costs and benefits, the benefit-to-cost ratio is 5.5. Overall, the findings from this study suggest that participatory ergonomics interventions can be cost beneficial from the company perspective. Even though the changes were typically low-cost and low-tech interventions implemented by the plant mechanics and maintenance personnel, benefits were realized on both the health and financial fronts.


Has medical history importance for surgeons?
Surgeons will do well to remember that the two most important contributions to the growth and extension of surgery came from two disciplines, not then regarded as the most innovative. Anesthesia came from dentistry, the work primarily of W.T.G. Morton of Boston; prophylactic surgical antisepsis originated with the obstetrician Semmelweis, who developed a scheme of prophylactic chemical antisepsis that still remains the core of surgical antisepsis. In the mid 1880's, largely as a result of the work of Chamberland and others of the Pasteur school, surgeons in France and Germany substituted thermal for chemical antisepsis, whenever applicable. Whereas Lister's influence was tremendous in fostering acceptance of antisepsis by surgeons, by the end of his professorial career he had begun his capitulation to prophylactic antisepsis, which was complete by 1896 to the very practices that Semmelweis had proved the value of almost five decades previously. These were 19th century innovations. The greatest boon to surgery's advance in this century has been control of cellulitic infections through chemotherapeutic agencies, the sulfonamides and antibiotics. The tremendous upsurge of interest in research at the end of World War II brought surgeons to a fuller realization of the significant part they could play in the advance of their discipline. Intimate alignment of surgeons with physiologists of the circulation begot intracardiac surgery, a significant innovation with consequences of tremendous import for greater medicine's advance. Today, surgeons attacking the problem of tissue transplantation are aligning themselves with biochemists, geneticists, immunologists, experimental pathologists, and pharmacologists in their broad approach to the phenomenon of allograft rejection. The great extension of vascular surgery since World War II has made jewelers of surgeons of small tubular structures. The technical phases of these demanding operative procedures have largely been overcome. Solution of the biologic rejection phenomenon is awaited eagerly by all investigators, a discovery that will greatly enhance predictable success of transfer of skin as well as of organs. When will surgery experience another great catalytic forward thrust like that achieved through anesthesia, prophylactic antisepsis, and the antibiotics? No discipline in medicine can exist alone without privation. For its continuing advancement, surgery is dependent upon close and intimate relationships with many other medical disciplines. Apart from the enlightenment provided by a searching examination of the origins of our surgical discipline, the earnest and persistent pursuer will discover a lively pleasure and satisfaction that accrues as a special dividend.


Small bowel obstruction due to disease of epiploic appendage.
Primary disease of an epiploic appendage is rare. Small bowel obstruction is an unusual complication of such disease due to bands or adhesions caused by torsion or inflammation. A 49-year old man presented with small bowel obstruction and was found to have a band from a necrotic epiploic appendage adherent to mesentery, obstructing the ileum. The band was released and the epiploic appendage removed.


Gefitinib (Iressa) trials in non-small cell lung cancer.
Gefitinib (Iressa) is a synthetic anilinoquinazoline capable of inhibiting the epidermal growth factor receptor tyrosine kinase in vitro at nanomolar concentrations. In phase I trials, gefitinib was well tolerated at doses above that required to induce antitumor effects in vitro. Notably, antitumor activity was observed in lung cancer patients. These findings resulted in the initiation of phase II trials employing gefitinib monotherapy in patients with recurrent non-small cell lung cancer (the so-called IDEAL trials). Study participants were randomized to 250 mg or 500 mg of gefitinib per day. Objective response rates between 10 and 20% were achieved with minimal host related toxicity (mainly acne like rash and mild diarrhea). Median survivals ranged between 6 and 8 months. Subsequently, phase III trials (the so-called INTACT trials) combined gefitinib and chemotherapy in chemonaive patients with advanced non-small cell lung cancer. These trials failed to demonstrate a survival advantage with the addition of gefitinib to standard platinum-based chemotherapy regimens. However, overall host related toxicities were not substantially worsened with the addition of gefitinib to chemotherapy. Further studies employing single agent gefitinib as well as regimens employing a different sequencing of chemotherapy and gefitinib are planned in recurrent and previously untreated lung cancer patients.


Involvement of EZH2 inhibition in lenalidomide and pomalidomide-mediated growth suppression in HTLV-1-infected cells.
Immunomodulatory imide drugs (IMiDs), such as lenalidomide and pomalidomide, exert pleiotropic effects, e.g., antitumor effects in multiple myeloma, by binding the protein Cereblon and altering its substrate specificity. Lenalidomide is approved for the treatment of adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1), although the precise mechanisms responsible for its effectiveness have not been fully elucidated. Here, we used HTLV-1-infected cell lines to investigate how IMiDs exert anti-ATL effects. In three of four tested HTLV-1-infected cell lines, the cells treated with lenalidomide or pomalidomide exhibited mild growth suppression without apoptosis, which was associated with decreased IRF4, c-Myc, and phosphorylated STAT3 levels as well as enhanced SOCS3 expression. Additionally, the levels of enhancer of zeste homolog 2 (EZH2) and trimethyl histone 3 Lys27 (H3K27me3) were decreased following IMiD treatment in all three susceptible cell lines. An IMiD-mediated reduction of EZH2 and H3K27me3 levels was also observed in a multiple myeloma cell line. Furthermore, treatment with an EZH2-inhibitor reproduced the IMiD-mediated effects in HTLV-1-infected cells and multiple myeloma cells. These findings strongly suggest that a reduction of EZH2 expression is involved in the mechanism underlying the antitumor effects of IMiD.


Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data.
The Escherichia coli genome-scale metabolic model (GEM) is an exemplar systems biology model for the simulation of cellular metabolism. Experimental validation of model predictions is essential to pinpoint uncertainty and ensure continued development of accurate models. Here, we quantified the accuracy of four subsequent E. coli GEMs using published mutant fitness data across thousands of genes and 25 different carbon sources. This evaluation demonstrated the utility of the area under a precision-recall curve relative to alternative accuracy metrics. An analysis of errors in the latest (iML1515) model identified several vitamins/cofactors that are likely available to mutants despite being absent from the experimental growth medium and highlighted isoenzyme gene-protein-reaction mapping as a key source of inaccurate predictions. A machine learning approach further identified metabolic fluxes through hydrogen ion exchange and specific central metabolism branch points as important determinants of model accuracy. This work outlines improved practices for the assessment of GEM accuracy with high-throughput mutant fitness data and highlights promising areas for future model refinement in E. coli and beyond.


[Age-related and etiological features of severe injury in children].
A comparative retrospective analysis of condition severity was made in different age groups: 61 road traffic injured children (Group 1) and 63 children with injuries of another etiology (Group 2) on admission. There no substantial differences in their condition severity: severe and extremely severe conditions were seen in 77.8 and 11.5% in Group 1 and 79.4 and 6.35% in Group 2, respectively. The age-related features of the pattern of traumatic injuries were established in relation to their etiology.


A designer peptide as a template for growing Au nanoclusters.
A peptide was designed to generate a sub-nanometric template that guides the growth of fluorescent gold nanoclusters. The peptide was endorsed with nucleating moieties and a three-dimensional structure that arrests the growth of ultrasmall nanoparticles. The nanoclusters are not cytotoxic and can be found in the cytosol of cells.


Drugs and sport. Research findings and limitations.
Many types of drugs are used by athletes to improve performance. This paper reviews the literature on 3 categories of drugs: those that enhance performance as stimulants (amphetamines, ephedrine, and cocaine), those that are used to reduce tremor and heart rate (beta-blockers) and those involved in bodyweight gain or loss (anabolic-androgenic steroids, growth hormone, beta 2-agonists, and diuretics). Limitations of research on these drugs as they relate to performance enhancement are also discussed. The numerous studies that have assessed the effects of amphetamines on performance report equivocal results. This may be due to the large interindividual variability in the response to the drug and the small sample sizes used. Most studies, however, show that some individuals do improve exercise performance when taking amphetamines, which may be attributed to their role in masking fatigue. As a stimulant, ephedrine has not been found to improve performance in the few studies available. More recently, ephedrine has been purported to be effective as a fat burner and used by athletes to maintain or improve muscle mass. Although research on individuals with obesity supports the use of ephedrine for fat loss, no studies have been done on athletes. The few studies of cocaine and exercise suggest that little to no performance gains are incurred from cocaine use. Moreover, the sense of euphoria may provide the illusion of better performance when, in actuality, performance was not improved or was impaired. beta-Blockers have been found to reduce heart rate and tremor and to improve performance in sports that are not physiologically challenging but require accuracy (e.g. pistol shooting). However, there is evidence that some individuals may be high responders to beta-blockers to the extent that their heart rate response is so blunted as to impair performance. Although equivocal, several studies have reported that anabolic-androgenic steroids increase muscle size and strength. However, most studies are not well controlled and use insufficient drug doses. One recent well controlled study did find an increase in muscle mass and strength with supraphysiological doses, and the improvements were greater in participants who were also resistance training. There is little information available on the effects of growth hormone on muscle mass or performance in athletes, although data suggest that growth hormone administration does not increase muscle protein synthesis. beta 2-Agonists, such as clenbuterol and salbutamol, when administered orally appear to improve muscular strength due to their potential role in increasing muscle mass. However, studies have not been done using athletes. Diuretics results in a loss of body water and hence bodyweight that can be advantageous for sports with strict bodyweight classifications. There is insufficient evidence on possible performance decrements in the field that could result from dehydration induced by the diuretics. Overall, the most significant concern in studies of drug use is the large inter-individual variability in responses to a drug. Further studies are needed to understand why some individuals are more responsive than others and to assess whether the responses are consistent for a given individual. Most studies of drug effectiveness have not used athletes. The effectiveness of many drugs may be reduced in highly trained athletes because there is a lower margin for improvement.


Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein.
SHP-1 is a cytoplasmic SH2 domain containing protein-tyrosine phosphatase (PTP) involved in the negative regulation of multiple signaling pathways in hematopoietic, nervous, and epithelial cells. The thyroid TRK-T3 oncogene consists of the NTRK1 tyrosine kinase domain fused in-frame with sequences of the TFG (TRK-fused gene), encoding a protein of unknown function. TFG contains a coiled-coil domain responsible for TRK-T3 oligomerization. In addition, recent analysis of the sequences outside of the coiled-coil domain suggested possible interactions with other proteins. Based on the presence of a putative SHP-1 SH2-binding site within the TFG sequences, we have investigated the role of the SHP-1 phosphatase in TRK-T3 oncoprotein signaling. In this study we show that SHP-1 interacts with and down-regulates TRK-T3. We provide evidence that SHP-1 SH2 and catalytic domains, respectively, associate with the TFG- and NTRK1-derived portions of TRK-T3. Our data contribute to the definition of cellular mechanisms involved in thyroid tumorigenesis. Moreover, it reveals TFG as a novel protein able to modulate SHP-1 activity.


Do chronic pain and comorbidities affect brain function in sickle cell patients? A systematic review of neuroimaging and treatment approaches.
Sickle cell disease (SCD) is a medical condition in which chronic pain is common and negatively impacts psychosocial function and quality of life. Although the brain mechanisms underlying chronic pain are well studied in other painful conditions, the brain mechanisms underlying chronic pain and the associated psychosocial comorbidities are not well established in SCD. A growing literature demonstrates the effect of treatment of chronic pain, including pharmacological and nonpharmacological treatments, on brain function. The present systematic review aimed to (1) determine the effects of chronic pain and psychosocial comorbidities on brain function of patients with SCD; (2) summarize pharmacological and nonpharmacological approaches to treat these symptoms; and (3) identify areas for further investigation of potential beneficial effects of treatments on brain function. Titles were screened using predefined criteria, including SCD, and abstracts and full texts were reviewed by 2 independent reviewers. A total of 1167 SCD articles were identified, and 86 full articles were included covering 3 sections: chronic pain (4 studies), psychosocial comorbidities (11 studies), and pharmacological and nonpharmacological treatments (71 studies). Neuroimaging evidence demonstrates aberrant neural processing related to chronic pain and psychosocial comorbidities in SCD beyond ischemic stroke and cerebral hemorrhage. Although neuroimaging studies show an important role for psychological factors, pain management is nearly exclusively based on opioids. Behavior therapy seems useful to improve psychological symptoms as well as chronic pain and quality of life. Further investigation is required with larger cohorts, matched controls, and examination of treatment-related neural mechanisms.


Population fraction of Parkinson's disease attributable to preventable risk factors.
Parkinson's disease is the fastest-growing neurologic disease with seemingly no means of prevention. Intrinsic risk factors (age, sex, and genetics) are inescapable, but environmental factors are not. We identified repeated blows to the head in sports/combat as a potential new risk factor. 23% of PD cases in females were attributable to pesticide/herbicide exposure, and 30% of PD in males were attributable to pesticides/herbicides, military-related chemical exposures, and repeated blows to the head, and therefore could have potentially been prevented.


The digital divide: David vs. Goliath.
There is a global danger that hides in the shadows and is changing the way continuing care operators care for residents. Today, to provide that same historical level of resident care, a group of techno-soldiers are not just a nice-to-have, but are a must, to protect our critical Information Technology (IT) infrastructure. There is little doubt that technology has enabled us to provide better care. Electronic medical records, human resources information systems, and voice over internet communications systems have created great efficiencies in operations. However, global cybercriminals lurk in the same technologies that support us. Continuously attempting to rob our private information and hold us ransom, or play havoc with our IT systems impeding our provision of care. How can a continuing care operator, an already funding-challenged industry balance the costs of protecting their IT infrastructure against this growing massive threat? Compounding the issue, rising insurance expectations for continuing care operators to continuously enhance their IT safety controls against evolving cyberterrorism. This is the story of the Good Samaritan Society/Canada (Good Samaritan) digital transformation journey. Our digital roadmap sets Good Samaritan up to rise above the ongoing barrage of cyberattacks and loss of insurance. This is a digital divide story of David vs. Goliath.


[The sanitary preventive direction of Zemstvo medicine of Ekaterinoslav Gubernia].
The article analyzes, for the reason of archive and literary sources, the historic medical characteristics of formation of sanitary antiepidemic organization of Yekaterinoslav gubernia. The historic stages are established and the essence and basic principles of formation of preventive direction oa Zemstvo medicine are revealed. It is demonstrated that the achievements of sanitary organization of Yekaterinoslav Zemstvo became possible due to the efforts of progressive Zemstvo sanutary physicians who developed a comprehensive system of sanitary epidemiologic service, the most advanced in Ukraine.


Sensory adaptation of Dictyostelium discoideum cells to chemotactic signals.
Postvegetative Dictyostelium discoideum cells react chemotactically to gradients of cAMP, folic acid, and pterin. In the presence of a constant concentration of 10(-5) M cAMP cells move at random. They still are able to respond to superimposed gradients of cAMP, although the response is less efficient than without the high background level of cAMP. Cells which are accommodated to 10(-5) M cAMP do not react to a gradient of cAMP if the mean cAMP concentration is decreasing with time. This indicates the involvement of adaptation in the detection of chemotactic gradients: cells adapt to the mean concentration of chemoattractant and respond to positive deviations from the mean concentration. Cells adapted to high cAMP concentrations react normally to gradients of folic acid or pterin. Adaptation to one of these compounds does not affect the response to the other attractants. This suggests that cAMP, folic acid, and pterin are detected by different receptors, and that adaptation is localized at a step in the transduction process before the signals from these receptors coincide into one pathway. I discuss the implications of adaptation for chemotaxis and cell aggregation.


Antithrombotic effect of captopril and enalapril in old rats.
In the present study, we have shown considerably accelerated thrombosis in old rats in comparison with adult rats, which may be related to the impaired hemostatic balance in these animals. In old rats, captopril and enalapril caused a marked reduction of venous thrombus weight. The mechanism of antithrombotic action of these drugs seems to be dependent on the suppression of coagulation cascade and the enhancement of the fibrinolytic processes.


Routing information flow by separate neural synchrony frequencies allows for "functionally labeled lines" in higher primate cortex.
Efficient transfer of sensory information to higher (motor or associative) areas in primate visual cortical areas is crucial for transforming sensory input into behavioral actions. Dynamically increasing the level of coordination between single neurons has been suggested as an important contributor to this efficiency. We propose that differences between the functional coordination in different visual pathways might be used to unambiguously identify the source of input to the higher areas, ensuring a proper routing of the information flow. Here we determined the level of coordination between neurons in area MT in macaque visual cortex in a visual attention task via the strength of synchronization between the neurons' spike timing relative to the phase of oscillatory activities in local field potentials. In contrast to reports on the ventral visual pathway, we observed the synchrony of spikes only in the range of high gamma (180 to 220 Hz), rather than gamma (40 to 70 Hz) (as reported previously) to predict the animal's reaction speed. This supports a mechanistic role of the phase of high-gamma oscillatory activity in dynamically modulating the efficiency of neuronal information transfer. In addition, for inputs to higher cortical areas converging from the dorsal and ventral pathway, the distinct frequency bands of these inputs can be leveraged to preserve the identity of the input source. In this way source-specific oscillatory activity in primate cortex can serve to establish and maintain "functionally labeled lines" for dynamically adjusting cortical information transfer and multiplexing converging sensory signals.


Planning the interview for a clinical nurse researcher.
The number of clinical nurse researcher positions seems to be increasing in healthcare agencies today. There are some unique features of the clinical nurse researcher role, including the complexities of a research position, the relatively recent introduction of the role in some clinical settings, and the frequency with which the position is coupled with other major clinical, administrative, or educational responsibilities. To increase the effectiveness of both the chief nurse executive and the clinical nurse researcher during the employment interview, the authors discuss five lines of inquiry that the interviewer or candidate can use.


Defining early mycosis fungoides: validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas.
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and is often difficult to diagnose. Early-stage disease is particularly challenging and requires clinical and histopathologic correlation to make an accurate diagnosis. In order to facilitate the diagnosis of early MF, an algorithm has been proposed by the International Society for Cutaneous Lymphomas (ISCL) whereby clinical and histopathologic characteristics as well as immunohistochemistry and T-cell receptor gene rearrangement studies may be applied to suspected cases of MF. The diagnostic utility of this algorithm has not yet been validated. We sought to determine the validity of the proposed algorithm via an investigator-blinded, retrospective, case-control study. A total of 34 cases were randomly selected from the database of a clinic for cutaneous T-cell lymphomas and included patients with MF and patients with clinicopathologic mimics. The proposed diagnostic algorithm was systematically applied to the entire cohort. Each case was assigned a composite score based on the parameters in the proposed algorithm. Among the 24 cases of MF, 21 cases achieved four or more points through application of the algorithm. Among the 10 cases of MF mimics, only four achieved four or more points. This difference was significant (Fisher's exact test, p = 0.009). The sensitivity of the 4-point threshold for a diagnosis of MF was 87.5% and the specificity was 60%. The diagnostic algorithm proposed by the ISCL is a statistically valid method for defining cases of early MF and distinguishing these cases from other benign dermatoses. However, the clinical utility of the algorithm may be limited by its low specificity. Further refinement of the algorithm may improve its accuracy.


Serious Games for Improving Technical Skills in Medicine: Scoping Review.
Serious games are being used to train specific technical skills in medicine, and most research has been done for surgical skills. It is not known if these games improve technical skills in real life as most games have not been completely validated. This scoping review aimed to evaluate the current use of serious games for improving technical skills in medicine and to determine their current validation state using a validation framework specifically designed for serious games. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A multidatabase search strategy was adopted, after which a total of 17 publications were included in this review. These 17 publications described five different serious games for improving technical skills. We discuss these games in detail and report about their current validation status. Only one game was almost fully validated. We also discuss the different frameworks that can be used for validation of serious games. Serious games are not extensively used for improving technical skills in medicine, although they may represent an attractive alternative way of learning. The validation of these games is mostly incomplete. Additionally, several frameworks for validation exist, but it is unknown which one is the best. This review may assist game developers or educators in validating serious games.


Distribution of 21-Gene Recurrence Scores Among Breast Cancer Histologic Subtypes.
- The 21-gene recurrence score (RS) provides a probability of distant recurrence for estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. The utility of RS for rarer histologic subtypes of breast cancer is uncertain. - To determine the distribution of RS among various histologic subtypes using a population database. - Women between the ages of 18 and 75 with estrogen receptor-positive, HER2-negative breast cancer and known RS results were identified using the Surveillance, Epidemiology, and End Results database. Recurrence scores were categorized into risk groups using both traditional and Trial Assigning Individualized Options for Treatment cutoffs. Multivariable logistic regression was used to determine factors associated with high-risk RS. - We identified 45 618 patients with stage I to III, estrogen receptor-positive, HER2-negative breast cancer who had RS available. Overall, 3087 (7%) and 6337 (14%) of cancers were classified as high risk based on traditional and Trial Assigning Individualized Options for Treatment RS cutoffs, respectively. The proportion of high-risk RS ranged from 1% (tubular, 2 of 225) to 68% (medullary, 13 of 19) and 4% (tubular, 10 of 225) to 79% (medullary, 15 of 19) for traditional and Trial Assigning Individualized Options for Treatment cutoffs, respectively. Based on multivariable logistic regression (excluding medullary), subtypes other than invasive ductal carcinoma and papillary carcinoma were significantly associated with lower RS. The strongest predictors of a high-risk RS were higher tumor grade and negative progesterone receptor status. - We identified distinct distributions of RS among different histologic subtypes of breast cancer. Excluding medullary carcinoma, histologic subtypes other than invasive ductal carcinoma and papillary carcinoma all predict lower RS.


Acute anti-hyperglycaemic effects of an unripe apple preparation containing phlorizin in healthy volunteers: a preliminary study.
The health-promoting properties of apples are directly related to the biologically active compounds that they contain, such as polyphenols. The objective of this study was to prepare a low-sugar, fibre- and phlorizin-enriched powder from unripe apples and to gain insight regarding its anti-hyperglycaemic activity in healthy volunteers. The unripe apples (Malus domestica Borkh.) were collected 30 days after the full bloom day; blanched and pressed to obtain apple pomace which was then processed with a food cutter, oven-dried and milled to prepare apple powder. The concentrations of total sugars, water-soluble pectin and phlorizin in the apple preparation were 153.44 ± 2.46, 27.73 ± 0.51 and 12.61 ± 0.15 g kg(-1), respectively. Acute ingestion of the apple preparation improved glucose metabolism in the oral glucose tolerance test (OGTT) in six healthy volunteers by reducing the postprandial glucose response at 15 to 30 min by approximately two-fold (P < 0.05) and by increasing urinary glucose excretion during the 2- to 4-h interval of the OGTT by five-fold (P < 0.05). The results obtained indicate that the dried and powdered pomace of unripe apples can be used as a health-promoting natural product for the reduction of postprandial glycaemia and to improve the health of patients with diabetes.


Moderate alcohol consumption and cognitive risk.
We reviewed 143 papers that described the relationship between moderate drinking of alcohol and some aspect of cognition. Two types of papers were found: (1) those that provided ratios of risk between drinkers and nondrinkers (74 papers in total) and (2) those that, although they did not provide such ratios, allowed cognition in drinkers to be rated as "better," "no different," or "worse" than cognition in nondrinkers (69 papers in total). The history of research on moderate drinking and cognition can be divided into two eras: 1977-1997 and 1998-present. Phase I (1977-1997) was the era of neuropsychological evaluation involving mostly young to middle-aged (18-50 years old) subjects. Although initial studies indicated moderate drinking impaired cognition, many later studies failed to confirm this, instead finding no difference in cognition between drinkers and nondrinkers. Phase II (1998-present) was and is the era of mental status exam evaluation involving mostly older (≥55 years old) subjects. These studies overwhelmingly found that moderate drinking either reduced or had no effect on the risk of dementia or cognitive impairment. When all the ratios of risk from all the studies in phase II providing such ratios are entered into a comprehensive meta-analysis, the average ratio of risk for cognitive risk (dementia or cognitive impairment/decline) associated with moderate "social" (not alcoholic) drinking of alcohol is 0.77, with nondrinkers as the reference group. The benefit of moderate drinking applied to all forms of dementia (dementia unspecified, Alzheimer's disease, and vascular dementia) and to cognitive impairment (low test scores), but no significant benefit against cognitive decline (rate of decline in test scores) was found. Both light and moderate drinking provided a similar benefit, but heavy drinking was associated with nonsignificantly higher cognitive risk for dementia and cognitive impairment. Although the meta-analysis also indicated that wine was better than beer or spirits, this was based on a relatively small number of studies because most studies did not distinguish among these different types of alcohol. Furthermore, a number of the studies that did make the distinction reported no difference among the effects of these different types of alcohol. Therefore, at present this question remains unanswered. Analysis also showed that the presence of the apolipoprotein E epsilon 4 allele eliminated the benefit of moderate drinking. However, this was based on a relatively small number of studies and several other studies have found a beneficial effect of the epsilon e4 allele. Further studies are necessary to settle this question. The benefit of moderate alcohol for cognition was seen in both men and women, although the amount and pattern of drinking is very different between the two sexes. Lastly, the finding of unaffected or significantly reduced cognitive risk in light to moderate drinkers was seen in 14/19 countries for which country-specific ratio data were available, with three of the five remaining countries showing nonsignificant reductions as well. Overall, light to moderate drinking does not appear to impair cognition in younger subjects and actually seems to reduce the risk of dementia and cognitive decline in older subjects.


Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied. We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma. We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI. Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22-8.68; P = 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15-8.04; OR for active smoking, 2.77; 95% CI, 1.28-5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse. Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.


Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology.
Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor family. It actually functions as endocrine hormones but does not regulate cell growth and differentiation. It is demonstrated that FGF21 acts on multiple tissue to coordinate carbohydrate and lipid metabolism, including enhancing insulin sensitivity, decreasing triglyceride concentrations, causing weight loss, ameliorating obesity-associated hyperglycemia and hyperlipidemia. Moreover, FGF21 also plays important roles in some physiological processes, such as fasting and feeding, growth hormone axis and thermogenic function of brown adipose tissue. Clinical relevance of FGF21 in humans is still unclear, and the basis and consequences of increased FGF21 in metabolic disease remain to be determined. Both the pharmacological actions and physiological roles make FGF21 attractive drug candidates for treating metabolic disease, but some questions remain to be answered. This article concentrates on recent advances in our understanding of FGF21.


Pituicytoma: report of three cases with review of literature.
Pituicytoma is a rare low-grade tumor (WHO Grade I) of pituicytes involving the sellar-suprasellar region, and originating from the specialized glial cells of the neurohypophysis. Clinically and radiologically, they closely mimic pituitary adenoma or meningioma. Diagnosis requires histopathological examination of the resected tissue. This uncommon glial neoplasm is a rarity, with only 57 cases reported in the literature so far. We report three cases of pituicytoma (aged between 7 and 24 years) presenting with reduced vision, headache and features of hypercortisolism in one case. Radiologically, these lesions mimicked meningioma, hypothalamic chiasmatic glioma and pituitary microadenoma, respectively. The second case is a 7-year-old girl, the youngest case on record. Since this tumor is uncommon, it is frequently misdiagnosed. Awareness of this entity is essential for planning management and treatment. We present a brief review of all cases reported in the medical literature, and describe the clinical symptomatology, associated endocrinological abnormalities, imaging characteristics, behavior and outcome.


Fetal craniofacial morphometrics: in utero evaluation at 16 weeks' gestation.
Although ultrasound has proved useful in the diagnosis of fetal craniofacial malformations, its success has been based primarily on subjective clinical observations of apparent abnormal fetal structures, their proportions, and unusual features. However, such clinical observations may be misleading and ideally should be validated by standardized quantitative measurements. We describe here an ultrasonographic methodology that has provided quantitative data describing the normal fetal craniofacies at 16 weeks of gestation. This report is part of an ongoing research project directed at describing fetal facial morphology in utero at different gestational ages. Such data can be used to construct growth curves to which observations from suspected abnormal fetuses can be compared. A total of 53 patients were evaluated at 16 weeks of gestation, at which time 24 craniofacial linear and angular measurements were made. The landmarks employed for these measurements were those used in roentgencephalometry so that this fetal data base could be related to postnatal populations. Such data will contribute not only to a description of facial dysmorphogenesis but also to a better understanding of normal facial growth and development. Furthermore, they constitute a useful tool for prenatal diagnosis, gestational aging, growth predictions, and perhaps for as yet relatively unexplored fields such as fetal therapy.