Miracle-dz/UniFAR-FTUs huggingface dataset:
Interpreting myocardial perfusion scintigraphy using single-photon emission computed tomography. Part 1

This article discusses the protocol for myocardial perfusion scintigraphy performed with single-photon emission computed tomography (SPECT). Indications for SPECT are listed with consideration given to the results of the increasingly more common angio-CT examinations of the coronary arteries (multislice computed tomography). The paper also presents basic information about interpreting the results, including the scores of left ventricle myocardial perfusion using the 17-segment polar map, and explains the concept of total perfusion deficit.
Giant neurons in the rat reticular formation: a sensorimotor interface in the elementary acoustic startle circuit?

The mammalian acoustic startle response (ASR) is a relatively simple motor response that can be elicited by sudden and loud acoustic stimuli. The ASR shows several forms of plasticity, such as habituation, sensitization, and prepulse inhibition, thereby making it an interesting model for studying the underlying neuronal mechanisms. Among the neurons that compose the elementary startle circuit are giant neurons in the caudal pontine reticular nucleus (PnC), which may be good candidates for analyzing the neuronal basis of mammalian behavior. In a first step of this study, we employed retrograde and anterograde tracing techniques to identify the possible sources of input and the efferent targets of these neurons. In a second step, we performed intracellular recordings in vivo, followed by subsequent injections of HRP for morphological identification, thereby investigating whether characteristic features of the ASR are reflected by physiological properties of giant PnC neurons. Our observations demonstrate convergent, bilateral input from several auditory brainstem nuclei to the PnC, predominantly originating from neurons in the cochlear nuclear complex and the superior olivary complex. Almost no input neurons were found in the nuclei of the lateral lemniscus. As the relatively long neuronal response latencies in several of these auditory nuclei appear to be incompatible with the primary ASR, we conclude that neurons in the cochlear root nuclei most likely provide the auditory input to PnC neurons that is required to elicit the ASR. The giant PnC neurons have a remarkable number of physiological features supporting the hypothesis that they may be a neural correlate of the ASR: (1) they receive short- latency auditory input, (2) they have high firing thresholds and broad frequency tuning, (3) they are sensitive to changes in stimulus rise time and to paired-pulse stimulation, (4) repetitive acoustic stimulation results in habituation of their response, and (5) amygdaloid activity enhances their response to acoustic stimuli. Anterograde tracing showed that most giant PnC neurons are reticulospinal cells. Axon collaterals and terminal arbors were found in the reticular formation as well as in cranial and spinal motoneuron pools. The results of this study indicate that giant PnC neurons form a sensorimotor interface between the cochlear nuclear complex and cranial and spinal motoneurons. This neuronal pathway implies that the elementary acoustic startle circuit is composed of only three central relay stations and thus appears to be organized more simply than assumed in the past.
Discriminations of interaural phase differences.

Listeners were asked to discriminate between two pulsed sinusoids, one presented with an interaural phase delay θ and the other presented with a longer delay θ + Δθ. Frequency of the sinusoids ranged from 250 to 4000 Hz. The difference threshold for Δθ was defined as the dependent variable. This threshold increased as θ increased from zero degrees to half the period of the sinusoid, then decreased as θ was further increased to a full period of the sinusoid. As θ was increased to half the period of the sinusoid, the lateral image appeared to shift away from midline toward the ear leading in time; but as θ was increased beyond half a period of the sinusoid, the lateral image appeared to shift toward the midline from the ear lagging in time. These results were obtained at 250, 500, and 900 Hz. At 2000 Hz, the value of Δθ remained a constant as θ was varied, while at 4000 Hz the lateral image was not moved by any interaural delay. The results imply that (1) for frequencies less than 2000 Hz, lateral discrimin.
Association of Time‐Varying Clearance of Nivolumab With Disease Dynamics and Its Implications on Exposure Response Analysis

Nivolumab is a human monoclonal antibody that blocks the interaction between PD‐1 programmed death‐1 (PD‐1) and its ligands, PD‐L1 and PD‐L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time‐varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post‐treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure–response (E‐R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E‐R analysis. The results showed that E‐R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E‐R or dose–response relationship than the steady‐state PK metrics.
The Effects of Global Change on the Threat of Exotic Arthropods and Arthropod‐borne Pathogens to Livestock in the United States

Arthropod‐borne diseases are an important part of the group of foreign animal diseases that command attention from federal, state, and local animal health authorities in the United States because of the potential for adverse local and regional animal health impacts and also because of possible losses of export markets. Diseases of concern are listed by the US Animal Health Association and also by the Office International des Epizooties. Global change is causing the emergence of newly recognized diseases and altering enzootic and epizootic circumstances for known disease problems. Selected examples of arthropod‐borne diseases of importance are discussed in terms of their potential for introduction, spread, and impact on livestock and human health in the United States.
Circadian rhythms in effects of hypnotics and sleep inducers.

Chronopharmacology involves the investigation of drug effects as a function of biological time and the investigation of drug effects on rhythm characteristics. Three new concepts must be considered: (a) the chronokinetics of a drug, embracing rhythmic (circadian) changes in drug bioavailability (or pharmacokinetics) and its excretion (urinary among others); (b) the chronaesthesia of a biosystem to a drug, i.e. circadian changes in the susceptibility of any biosystem to a drug (including organ systems, parasites, etc.); skin and bronchial chronaesthesia to various agents have been documented in man; and (c) the chronergy of a drug, taking into consideration its chronokinetics and the chronaesthesia of the involved organismic biosystems. The term chronergy includes rhythmic changes in the overall effects and in the effectiveness of some drugs. Clinical chronopharmacology is useful for solving problems of drug optimization, i.e. enhancing the desired efficiency of a drug and reducing its undesired effects. Circadian rhythms can be demonstrated in various effects of drugs on sleep, anaesthesia and related processes. For example, in the rat the duration of sleep induced by substances such as pentobarbital, hexobarbital, Althesin (alphaxadone and alphadoline in castor oil) is circadian system stage-dependent. Time-dependent changes of liver enzymes (e.g. hexobarbital oxidase) play a role in these circadian rhythms. The clinical chronopharmacokinetics of benzodiazepines have been documented in man. Chronopharmacologic methods can be used to study desired and undesired hypnotic effects of substances. Such is the case of new antihistamines (anti-H1), which do not induce sleepiness, in either acute or chronic administration. Pertinent also is the problem of intolerance to shift-work. Intolerant shift-workers are subject to internal desynchronization between at least two rhythms (e.g. activity-rest cycle and body temperature). Clinically these workers suffer from sleep disturbances, persistent fatigue and are regular users of sleeping pills, which is also a symptom of intolerance. However, over the long-term, these drugs are of no help to intolerant shift-workers.
Health Care of Young Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

BACKGROUND We wanted to determine the type of outpatient medical care reported by young adult survivors of childhood cancer and to examine factors associated with limited medical care. METHODS We analyzed data from 9,434 adult childhood cancer survivors enrolled in a retrospective cohort study who completed a baseline questionnaire. They had a mean age of 26.8 years (range 18 to 48 years), 47% were female, 12% were minorities, and 16% were uninsured. Four self-reported outcome measures were used to determine outpatient medical care in a 2-year period: general contact with the health care system, general physical examination, cancer-related medical visit, and medical visit at a cancer center. RESULTS Eighty-seven percent reported general medical contact, 71.4% a general physical examination, 41.9% a cancer-related visit, and 19.2%, a visit at a cancer center. Factors associated with not reporting a general physical examination, a cancer-related visit, or a cancer center visit included no health insurance (odds ratio [OR] = 2.34; 95% confidence interval [CI], 1.97–2.77), male sex (OR = 1.65; 95% CI, 1.44–1.88), lack of concern for future health (OR = 1.57; 95% CI, 1.36–1.82), and age 30 years or older in comparison with those 18 to 29 years (OR = 1.56; 95% CI, 1.35–1.81). The likelihood of reporting a cancer-related visit or a general physical examination decreased significantly as the survivor aged or the time from cancer diagnosis increased. This trend was also significant for those treated with therapies associated with substantial risk for cardiovascular disease or breast cancer. CONCLUSIONS Primary care physicians provide health care for most of this growing high-risk population. To optimize risk-based care, it is critical that cancer centers and primary care physicians develop methods to communicate effectively and longitudinally.
Complex Propagation of Events: Design Patterns Comparison

Today’s applications require high level of interactivity and the applications are expected to update their state, and provide users with immediate correct results. In high complex applications this usually means updating states of a number of objects that are part of complex dependency network. To decouple these dependencies such systems usually employ implicit invocation mechanisms such as well-known Observer pattern. However, building efficient propagation system that will keep object states up-to-date is a challenging task, since a number of issues arise. In this paper we identified 18 qualitative criteria and compared 5 design patterns that can be used to build propagation system on top of applications’ business objects. The exhaustive comparison results are given along with discussion and remarks that should be taken in consideration when dealing with this challenging task.
Antifibrillatory Effects of Volatile Anesthetics in Acute Occlusion/Reperfusion Arrhythmias

Halothane, enflurane, and isoflurane were evaluated for antifibrillatory efficacy and compared with lidocaine, propranolol, procainamide, and verapamil in a canine acute left anterior descending (LAD) coronary artery occlusion/reperfusion model with basal pentobarbital anesthesia. Of the antiarrhythmic drugs, only verapamil prevented ventricular fibrillation during occlusion and reperfusion. Halothane 1% inspired after 15 min showed similar protection. Enflurane 2.5% inspired after 15 min resulted in significant protection but caused hypotension after occlusion in 4 of 17 dogs. Isoflurane 1.7% inspired after 15 min showed intermediate results. At inspired concentrations of 0.5% and 1.25%, respectively, halothane and enflurane protected against ventricular fibrillation without hypotension. It is concluded that the volatile anesthetics have antifibrillatory effects in this canine model but differ in their ability to cause hypotension in the presence of proximal LAD coronary artery occlusion.
GM Foods and the Misperception of Risk Perception

Public opposition to genetically modified (GM) food and crops is widely interpreted as the result of the public's misperception of the risks. With scientific assessment pointing to no unique risks from GM crops and foods, a strategy of accurate risk communication from trusted sources has been advocated. This is based on the assumption that the benefits of GM crops and foods are self‐evident. Informed by the interpretation of some qualitative interviews with lay people, we use data from the Eurobarometer survey on biotechnology to explore the hypothesis that it is not so much the perception of risks as the absence of benefits that is the basis of the widespread rejection of GM foods and crops by the European public. Some respondents perceive both risks and benefits, and may be trading off these attributes along the lines of a rational choice model. However, for others, one attribute—benefit—appears to dominate their judgments: the lexicographic heuristic. For these respondents, their perception of risk is of limited importance in the formation of attitudes toward GM food and crops. The implication is that the absence of perceived benefits from GM foods and crops calls into question the relevance of risk communication strategies for bringing about change in public opinion.
Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK

Heparin binds and activates the receptor tyrosine kinase ALK, which has no known ligand. De-Orphaning ALK Receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), are important during development and regeneration and are often aberrantly activated in cancer. ALK is an orphan RTK with no known ligand. Murray et al. found that heparin bound directly and with high affinity to a specific region in the extracellular domain of ALK. Heparin stimulated ALK activation and signaling in NB1 cells through a mechanism that required heparin sulfation and the ability of heparin to promote dimerization of ALK. Moreover, an antibody that competed with heparin for binding to ALK prevented heparin-mediated activation of ALK. These results define heparin as an ALK-binding agonist, thereby providing potential avenues for therapeutic intervention. Anaplastic lymphoma kinase (ALK) is one of the few remaining “orphan” receptor tyrosine kinases (RTKs) in which the ligands are unknown. Ligand-mediated activation of RTKs is important throughout development. ALK is particularly relevant to the development of the nervous system. Increased activation of RTKs by mutation, genetic amplification, or signals from the stroma contributes to disease progression and acquired drug resistance in cancer. Aberrant activation of ALK occurs in subsets of lung adenocarcinoma, neuroblastoma, and other cancers. We found that heparin is a ligand that binds specifically to the ALK extracellular domain. Whereas heparins with short chain lengths bound to ALK in a monovalent manner and did not activate the receptor, longer heparin chains induced ALK dimerization and activation in cultured neuroblastoma cells. Heparin lacking N- and O-linked sulfate groups or other glycosaminoglycans with sulfation patterns different than heparin failed to activate ALK. Moreover, antibodies that bound to the extracellular domain of ALK interfered with heparin binding and prevented heparin-mediated activation of ALK. Thus, heparin and perhaps related glycosaminoglycans function as ligands for ALK, revealing a potential mechanism for the regulation of ALK activity in vivo and suggesting an approach for developing ALK-targeted therapies for cancer.
Risk assessment of tuberculosis in immunocompromised patients. A TBNET study.

RATIONALE In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. OBJECTIVES This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. METHODS Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. MEASUREMENTS AND MAIN RESULTS Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. CONCLUSIONS Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials. gov (NCT 00707317).
Development of a simple and convenient feeding device to infect

It has become difficult in recent years to conduct the direct feeding of mosquitoes on animals because of ethical considerations related to animal experimentation. Thus, the artificial feeding of mosquitoes on blood meals is an important technique in studies on the oral infection of mosquitoes to agents. Since Rutledge et al. (1964) devised the artificial membrane-feeding technique, several artificial membrane-feeding methods have been developed to increase the feeding rates of mosquitoes on blood meals. The purpose of the present study is to develop a simple and convenient device for the artificial feeding of mosquitoes. We designed a device using Kimwipe , a coverglass, the lid of a plastic dish and a 50 ml Erlenmeyer flask. The efficacy was assessed by the infection rate of mosquitoes to Brugia pahangi microfilariae (MF) derived from the peritoneal cavity of Mongolian jirds. Immediately after the feeding of mosquitoes on MF by the new device, the MF infection rate of mosquitoes was 50 81%. On day 14 post-feeding, 51 94% of mosquitoes harbored third-stage infective larvae. The components needed to construct the device for artificial feeding of mosquitoes are generally available in laboratories. Furthermore, no elaborate modification of materials is necessary in making the feeding device. Therefore, this simple and convenient artificial feeding device promises to be applicable for experimental infection of mosquitoes not only with B. pahangi MF but also with other agents such as malaria and viruses.
DOPAMINE RELEASES ENDOTHELIUM‐DERIVED RELAXING FACTOR VIA α2‐ADRENOCEPTORS IN CANINE VESSELS: COMPARISONS BETWEEN FEMORAL ARTERIES AND VEINS

1. We investigated the role of vascular smooth muscle α‐adrenoceptor subtypes in the vasoconstrictor response of femoral arteries and veins to dopamine and whether the vasoconstriction is modified by endothelium‐dependent relaxation mediated via the activation of α2‐adrenoceptors in ring preparations of femoral arteries and veins from mongrel dogs.
Tolerable Hearing Aid Delays. III. Effects on Speech Production and Perception of Across-Frequency Variation in Delay

Objective Signal processing strategies that attempt to mimic the frequency resolution of the healthy cochlea require finer frequency resolution at low frequencies than at high. The filtering required will cause more delay to the low-frequency end of the spectrum than to the high-frequency end, which may have disturbing effects. In a real-time application, making the delay constant across frequency would require the higher frequency components to be subjected to a compensating delay, leading to a larger overall delay, which may also give rise to disturbing effects (Stone & Moore, 1999, 2002). This experiment assessed the effects of frequency-dependent delay on subjective and objective measures of speech production and perception. Design Digital filtering was used to introduce across-frequency delays of 0, 4, 9, 15, or 24 msec. The low frequencies were always more delayed than the high frequencies, with a smooth variation in delay between the low and the high frequencies. In addition, there was a 2.5 msec delay that did not vary with frequency arising from the processes of analog-digital-analog conversion and equalization. Ten subjects with symmetric, bilateral, moderate hearing impairment of cochlear origin were fitted binaurally with Phonak PicoNet2 BTE linear hearing aids. The aids were programmed to provide insertion gains closely approximating the NAL (RP) (Byrne & Dillon, 1986) prescription for each subject and ear. The output of an omnidirectional microphone, attached on top of each aid, fed a digital filtering unit that introduced the across-frequency delay. Audio shoes reintroduced the signal back into the BTE aids. Subjects were tested in a counterbalanced order for their identification of vowel-consonant-vowel (VCV) syllables. In a second session, the same subjects spoke from a script: their utterances were recorded on tape, speech production rates were measured and subjective ratings of the disturbance of the delay were obtained. Subjects required some training to recognize the effects of the delay and rate them consistently. Results Subjective disturbance increased progressively with increasing across-frequency delay. A 9-msec delay was significantly more disturbing than a 0-msec delay. A delay of about 20 msec led to a mean rating of “disturbing. ” VCV identification decreased significantly once the across-frequency delay was 15 msec or greater. However, word production rates were not significantly affected by across-frequency delay over the range tested. Conclusions Relatively small across-frequency delays (9 to 15 msec) give rise to significant changes in speech identification and subjective disturbance. A delay of 9 to 15 msec, constant across frequency, would have a smaller effect (Stone & Moore, 1999). It appears desirable to compensate, at least in part, for across-frequency delays introduced by any processing.