Background. Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent ...tuberculosis infection LTBI). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods. A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results. Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions. These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.
Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection ...LTBI). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain.
A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional.
These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.
While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains ...poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely to be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.
Painful and painless channelopathies Bennett, David L H, Dr; Woods, C Geoffrey, Prof
Lancet neurology,
06/2014, Letnik:
13, Številka:
6
Journal Article
Recenzirano
Summary The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and ...transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav 1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A , which encodes Nav 1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1 , which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav 1.8 ( SCN10A ) and Nav 1.9 ( SCN11A ) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development—eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development.
Simple reaction time (SRT), the minimal time needed to respond to a stimulus, is a basic measure of processing speed. SRTs were first measured by Francis Galton in the 19th century, who reported ...visual SRT latencies below 190 ms in young subjects. However, recent large-scale studies have reported substantially increased SRT latencies that differ markedly in different laboratories, in part due to timing delays introduced by the computer hardware and software used for SRT measurement. We developed a calibrated and temporally precise SRT test to analyze the factors that influence SRT latencies in a paradigm where visual stimuli were presented to the left or right hemifield at varying stimulus onset asynchronies (SOAs). Experiment 1 examined a community sample of 1469 subjects ranging in age from 18 to 65. Mean SRT latencies were short (231, 213 ms when corrected for hardware delays) and increased significantly with age (0.55 ms/year), but were unaffected by sex or education. As in previous studies, SRTs were prolonged at shorter SOAs and were slightly faster for stimuli presented in the visual field contralateral to the responding hand. Stimulus detection time (SDT) was estimated by subtracting movement initiation time, measured in a speeded finger tapping test, from SRTs. SDT latencies averaged 131 ms and were unaffected by age. Experiment 2 tested 189 subjects ranging in age from 18 to 82 years in a different laboratory using a larger range of SOAs. Both SRTs and SDTs were slightly prolonged (by 7 ms). SRT latencies increased with age while SDT latencies remained stable. Precise computer-based measurements of SRT latencies show that processing speed is as fast in contemporary populations as in the Victorian era, and that age-related increases in SRT latencies are due primarily to slowed motor output.
The trail making test (TMT) is widely used to assess speed of processing and executive function. However, normative data sets gathered at different sites show significant inconsistencies. Here, we ...describe a computerized version of the TMT (C-TMT) that increases the precision and replicability of the TMT by permitting a segment-by-segment analysis of performance and separate analyses of dwell-time, move-time, and error time. Experiment 1 examined 165 subjects of various ages and found that completion times on both the C-TMT-A (where subjects connect successively numbered circles) and the C-TMT-B (where subjects connect circles containing alternating letters and numbers) were strongly influenced by age. Experiment 2 examined 50 subjects who underwent three test sessions. The results of the first test session were well fit by the normative data gathered in Experiment 1. Sessions 2 and 3 demonstrated significant learning effects, particularly on the C-TMT-B, and showed good test-retest reliability. Experiment 3 examined performance in subjects instructed to feign symptoms of traumatic brain injury: 44% of subjects produced abnormal completion times on the C-TMT-A, and 18% on the C-TMT-B. Malingering subjects could be distinguished from abnormally slow controls based on (1) disproportionate increases in dwell-time on the C-TMT-A, and (2) greater deficits on the C-TMT-A than on the C-TMT-B. Experiment 4 examined the performance of 28 patients with traumatic brain injury: C-TMT-B completion times were slowed, and TBI patients showed reduced movement velocities on both tests. The C-TMT improves the reliability and sensitivity of the trail making test of processing speed and executive function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer treatments are often more successful when the disease is detected early. We evaluated the feasibility and safety of multicancer blood testing coupled with positron emission tomography-computed ...tomography (PET-CT) imaging to detect cancer in a prospective, interventional study of 10,006 women not previously known to have cancer. Positive blood tests were independently confirmed by a diagnostic PET-CT, which also localized the cancer. Twenty-six cancers were detected by blood testing. Of these, 15 underwent PET-CT imaging and nine (60%) were surgically excised. Twenty-four additional cancers were detected by standard-of-care screening and 46 by neither approach. One percent of participants underwent PET-CT imaging based on false-positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multicancer blood testing combined with PET-CT can be safely incorporated into routine clinical care, in some cases leading to surgery with intent to cure.
We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are ...currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.
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Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic ...pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans.
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► We describe a novel human autosomal-dominant pain syndrome (FEPS) ► We demonstrate linkage of FEPS to a TRPA1 N855S point mutation ► FEPS patients show debilitating pain on fasting and physical stress ► N855S TRPA1 channels show enhanced inward currents but unaltered pharmacology
We meta-analyzed 115 functional magnetic resonance imaging (fMRI) studies reporting auditory-cortex (AC) coordinates for activations related to active and passive processing of pitch and spatial ...location of non-speech sounds, as well as to the active and passive speech and voice processing. We aimed at revealing any systematic differences between AC surface locations of these activations by statistically analyzing the activation loci using the open-source Matlab toolbox VAMCA (Visualization and Meta-analysis on Cortical Anatomy). AC activations associated with pitch processing (e.g., active or passive listening to tones with a varying vs. fixed pitch) had median loci in the middle superior temporal gyrus (STG), lateral to Heschl's gyrus. However, median loci of activations due to the processing of infrequent pitch changes in a tone stream were centered in the STG or planum temporale (PT), significantly posterior to the median loci for other types of pitch processing. Median loci of attention-related modulations due to focused attention to pitch (e.g., attending selectively to low or high tones delivered in concurrent sequences) were, in turn, centered in the STG or superior temporal sulcus (STS), posterior to median loci for passive pitch processing. Activations due to spatial processing were centered in the posterior STG or PT, significantly posterior to pitch processing loci (processing of infrequent pitch changes excluded). In the right-hemisphere AC, the median locus of spatial attention-related modulations was in the STS, significantly inferior to the median locus for passive spatial processing. Activations associated with speech processing and those associated with voice processing had indistinguishable median loci at the border of mid-STG and mid-STS. Median loci of attention-related modulations due to attention to speech were in the same mid-STG/STS region. Thus, while attention to the pitch or location of non-speech sounds seems to recruit AC areas less involved in passive pitch or location processing, focused attention to speech predominantly enhances activations in regions that already respond to human vocalizations during passive listening. This suggests that distinct attention mechanisms might be engaged by attention to speech and attention to more elemental auditory features such as tone pitch or location.
This article is part of a Special Issue entitled <Human Auditory Neuroimaging>.
•The results of 115 auditory fMRI studies were meta-analyzed.•Pitch processing and spatial processing have different median auditory-cortex loci.•Processing of infrequent pitch changes is separable from other types of pitch processing.•Auditory attention modulates activity in the superior temporal gyrus and sulcus.•Speech and voice processing activate similar regions of the auditory cortex.
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