Miracle-dz/UniFAR-FTUs huggingface dataset:
The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation

1 The aim of the present study was to investigate the in vivo pharmacological profile of CP‐122, 288, an indole‐derivative with a conformationally restricted N‐methylpyrrolidinyl basic side chain in the C‐3 position. This C‐3 substituent structurally differentiates CP‐122, 288 from the 5‐HT1D receptor agonist sumatriptan, which possesses an N, N‐dimethylaminoethyl group. 2 When administered prior to electrical stimulation of the trigeminal ganglion, CP‐122, 288 (0.3–300 ng kg−1, i.v.) produced a dose‐related inhibition of plasma protein extravasation in rat dura mater (minimum effective dose, MED, 3 ng kg−1 i.v., P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg−1 i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 μg kg−1 i.v., P < 0.05). Thus, CP‐122, 288 is of the order of 104 fold more potent than sumatripan. 3 At all doses tested, CP‐122, 288 did not inhibit plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4 In a separate series of studies in the anaesthetized rat, CP‐122, 288 (0.003‐3 μg kg−1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of CP‐122, 288 which inhibit plasma protein leakage in rat dura, are devoid of haemodynamic effects. 5 Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically‐driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of CP‐122, 288 on an ongoing and established inflammatory event. CP‐122, 288 (30 and 300 ng kg−1, i.v., P < 0.01 and P < 0.05, respectively) produced a complete inhibition of plasma protein leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6 In the anaesthetized dog, CP‐122, 288 and sumatriptan, at 1–300 μg kg−1, i.v. , produced a dose‐dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that sumatriptan inhibits neurogenic inflammation in the rat (MED, 100 μg kg−1, i.v.), and produces vasoconstriction in the dog, over a similar dose‐range. Interestingly, doses of CP‐122, 288 that inhibit neurogenic inflammation in rat dura mater (0.3–300 ng kg−1) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7 These data demonstrate that in the rat, CP‐122, 288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog. Potentially, CP‐122, 288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side‐effects.
Repeat HIV Testing, Risk Behaviors, and HIV Seroconversion Among Young Men Who Have Sex With Men: A Call to Monitor and Improve the Practice of Prevention

&NA; Objectives: We compared recent risk behaviors and HIV seroconversion among young men who have sex with men (MSM) who were first‐time, infrequent, and repeat HIV testers. Methods: Male adolescents and young men aged 15 to 22 years were randomly sampled, interviewed, counseled, and tested for HIV at 194 gay‐identified venues in seven U.S. cities from 1994 through 1998. Analyses were restricted to MSM who reported having never tested or last tested HIV‐negative. Results: Of 3430 participants, 36% tested for the first time, 39% had tested infrequently (one or two times), and 26% had tested repeatedly (≥ three times). Compared with first‐time testers, repeat testers were more likely to report recent risk behaviors and to acquire HIV (7% versus 4%). Over 75% of repeat testers who seroconverted acquired HIV within 1 year of their last test. Compared with repeat testers, first‐time testers reported similar use of health care but delayed testing for nearly 2 additional years after initiating risk. Conclusions: Many young MSM soon acquire HIV after repeated use of HIV counseling and testing services. Providers must strengthen practices to identify, counsel, and test young MSM and provide enhanced behavioral interventions for those with persistent risks.
Having A “Safe Delivery”: Conflicting Views from Tibet

In the Tibetan Autonomous Region (TAR) of the People's Republic of China (PRC) maternal mortality ratios remain among the highest in the world. Although traditional Tibetan medical theory, practice, and pharmacology include information on maternal and child health care, Tibet is one of the few societies in the world that does not have traditional birth attendants or midwives. Using ethnographic methods, we gathered data from individual interviews with rural Tibetan women (N = 38) about their beliefs and behaviors surrounding pregnancy and childbirth. Additional data were gathered through interviews with prefecture, county, and township health care providers. These data were used to develop a culturally appropriate village birth attendant training program in rural Tibet. We describe Tibetan women's perspectives of “having a safe delivery” in relation to concepts about “safe delivery” according to evidence-based medicine in the West. Our work also provides an example of the benefits and challenges that arise when ethnographic research methods are used to design and implement health care interventions.
Profitably Bundling Information Goods: Evidence From the Evolving Video Library of Netflix

ABSTRACT Using a unique dataset of the Netflix video on demand library, this article measures the characteristics of information goods important when employing a strategic bundling strategy. By matching the titles entering and exiting the library to their relevant properties, I use a characteristic approach to determine when the value to Netflix of adding a title exceeds the licensing fee and when the displacement effect associated with presence in the library dictates that the title will not be offered. Results show that titles of median commercial success are bundled more frequently than the most and least successful, and the number of similar films exiting the library is important to how likely a film is to enter, indicating strategic bundling. These results are generalizable to the streaming video industry and any information goods with rapidly diminishing marginal utility.
New Predictive Marker for Hemodialysis Vascular Access Dysfunction

To examine the relationship between intra‐access pressures and vascular stenosis, we measured the total (pT) and static (pS) pressures and the severity of stenosis before and after percutaneous transluminal angioplasty (PTA). The dynamic pressure (△p) and static intra‐access pressure ratios (SIAPR) were calculated. We analyzed the clinical correlation of △p and SIAPR with the severity and location of stenosis, and searched potential predictive factors for the severity of stenosis using multivariate regression. While SIAPR was significantly decreased only in outflow stenosis after PTA (p < 0.0001), △p was significantly increased in both inflow and in outflow stenosis (p < 0.05). SIAPR was negatively correlated with the severity of stenosis only in outflow stenosis (p < 0.0001), and △p was significantly correlated with both inflow and outflow stenosis (p < 0.05). △p was an independent predictor for the severity of stenosis in both inflow and outflow stenosis (p < 0.05). Thus, our study suggests that △p may be more clinically useful than SIAPR not only in detecting access stenosis regardless of its location, but also providing information about the severity of stenosis.
S1P1-Selective Agonist SEW2871 Exacerbates Reperfusion Arrhythmias

Sphingosine-1-phosphate (S1P) has been considered to play an important role in ischemia/reperfusion (I/R) injury. We used SEW2871 (SEW), a novel receptor-selective agonist for S1P1, to elucidate the role of S1P1 in myocardial I/R. Isolated perfused rat hearts exposed to S1P (1 and 10 mM) or SEW (1 and 0.1 mM) were subjected to 30 minutes of global no-flow ischemia and 2 hours of reperfusion. S1P at 1 and 10 mM significantly reduced infarct size and CK release compared with vehicle-control. The effect of 0.1 μM SEW on infarct size was modest. After I/R, S1P at both doses and SEW at 0.1 μM improved developed pressure (LVDP). SEW at 1 mM significantly prolonged the duration of ventricular tachycardia and ventricular fibrillation, leading to irreversible reperfusion tachyarrhythmias in 60% of the hearts. This is the first demonstration of the critical role of the S1P1 receptor in I/R injury.
Music therapy with disorders of consciousness: current evidence and emergent evidence‐based practice

Patients with prolonged disorders of consciousness (PDOC) stemming from acquired brain injury present one of the most challenging clinical populations in neurological rehabilitation. Because of the complex clinical presentation of PDOC patients, treatment teams are confronted with many medicolegal, ethical, philosophical, moral, and religious issues in day‐to‐day care. Accurate diagnosis is of central concern, relying on creative approaches from skilled clinical professionals using combined behavioral and neurophysiological measures. This paper presents the latest evidence for using music as a diagnostic tool with PDOC, including recent developments in music therapy interventions and measurement. We outline standardized clinical protocols and behavioral measures to produce diagnostic outcomes and examine recent research illustrating a range of benefits of music‐based methods at behavioral, cardiorespiratory, and cortical levels using video, electrocardiography, and electroencephalography methods. These latest developments are discussed in the context of evidence‐based practice in rehabilitation with clinical populations.
Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress

Serum erythropoietin (Epo) levels are influenced by the integrity of renal function, the severity and etiology of anemia, the percentage of hemoglobin F and other factors. We aimed to create a parametric expression for the response to anemic/hypoxic stress and we evaluated serum Epo levels in 1096 subjects with normal renal function, of whom 837 were anemic (Hb 16.5 g/dl). Hb ranged between 3.6 and 23.8 g/dl and the corresponding Epo between <3.4 and 2670 mIU/ml. Between log-Epo and Hb the correlation co-efficient r was ? 0.706. The function linking Hb and log-Epo was determined as log(Epo) = 3.05 - 0.131 × Hb. Investigating various mathematic models, which could parametrically express the “response to anemia/hypoxia”, we found that the Hb × log(Epo) product was a stable parameter and fitted a normal distribution. Arbitrarily defining as normal range about one SD between the mean (12 - 21) we found that only 224 patients (20.8%) exhibited a Response to Anemia Index (RAI) beyond these limits. Below the lower limit there were 106 patients, diagnosed with polycythemia vera (12/38, 31.6%) anemia of chronic disease (10/34, 29.4%), megaloblastic anemia (17/56, 30.4%) and β-thalassemia trait (11/41, 26.8%). Forty-eight patients (45.3%) were diabetic. Above the defined upper normal RAI limit there were 118 patients, mainly diagnosed with secondary erythrocytosis (24/34, 70.6%), aplastic anemia (8/20, 40%), hemolytic anemia (3/14, 21.4%) and myelodysplastic syndromes (46/326, 14.1%). RAI was a rather constant parameter for each individual, with minimal variation in different evaluations, when Epo was estimated in the absence of inflammatory conditions. We have validated the superiority of RAI for the prediction of response to Epo in a cohort of 669 patients, who received Epo treatment. It is concluded that RAI is a reliable parameter describing the response to hypoxic/anemic stress.
Fetal neural grafts for Huntington's disease: A prospective view

Intrastriatal transplantation of striatal neuroblasts from human fetuses is a promising approach for treatment of Huntington's disease, on the basis of many experimental animal studies and, most recently, pilot clinical trials. Technically, several issues remain to be resolved (e.g., the precise site of dissection of the fetal tissue; the number and location of the fetal striatal implants; or the use of immunosuppressive therapy), and await larger‐scale trials and purposely designed protocols. Further clinical data must also be obtained, and preliminary promising results must be replicated in a patient group large enough to provide conclusive results. It is important to establish (1) the amount of clinical benefit provided to the patient by the grafted cells; (2) the anticipated duration of clinical benefits; and (3) the secondary rate of decline after the benefit of the graft has been overbalanced. Evaluation of these parameters will require very long‐term follow‐up of the patients involved, over several years after grafting, before the technique can eventually be proposed widely to patients. © 2002 Movement Disorder Society
Hottest pixel segmentation based thermal image analysis for children

In this paper, the first order statistics for gray level intensity defined from thermal image is implemented to govern the significant and distinguishable characteristic pattern in thermal image of affective states. The impact of thresholding mechanism is studied to differentiate between positive affective states (happy) and negative affective states (sad) analysis in response to the stimuli adopted from International Affective Pictures System (IAPS) database. The hottest pixel segmentation technique is applied where it identifies the threshold level in a way to classify the hottest pixel area. The region of interest is narrowed to a forehead region with result of separation analysis made to left and right area. Two experiments have been conducted by using different set of stimuli and the results depicts of asymmetry and differed in culmination pattern for these two affective states. This conclusive result from this study suggests that this feature can be used as one of the important feature to give information of affective states on individuals with autism spectrum disorder (ASD) with least of facial expressions and perhaps would-be use in non-verbal means.
Increased antipsychotic sensitivity in elderly patients: evidence and mechanisms.

OBJECTIVE The primary objective of this article is to review the literature regarding clinical effects, pharmacokinetics, and pharmacodynamics of antipsychotics in older people and to examine potential mechanisms underlying the age-related antipsychotic sensitivity. DATA SOURCES Data for this review were identified by searches of PubMed (1950-2007) and references from relevant articles and books. Search terms included antipsychotic, neuroleptic, elderly, aging, pharmacokinetics, pharmacodynamics, and dopamine, and only articles written in English or Japanese were consulted. DATA SELECTION Studies, reviews, and books pertaining to the clinical effects, pharmacokinetics, and pharmacodynamics with regard to the use of antipsychotics in older patients were selected. DATA SYNTHESIS The prevailing practices and clinical guidelines suggest that elderly patients can obtain therapeutic benefits at a lower dose and experience adverse effects from antipsychotics more often than younger patients, although there are still few trials that have directly compared elderly patients with the young. The literature suggests an age-related increase in brain access of drugs and demonstrates a decrease with age in the principal components in the dopaminergic system, including endogenous dopamine level and dopamine receptor density. CONCLUSIONS While clinicians conclusively hold that patients become more sensitive to antipsychotics as they become older, this proposition has only modest empirical support and warrants further investigation. Age-related functional decline in the dopaminergic system predicts lower antipsychotic doses for older patients. We propose a hierarchical series of testable hypotheses to address the relative contribution of age-related pharmacokinetic and pharmacodynamic changes to antipsychotic drug sensitivity.
The anti‐migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel

The mechanism of the anti‐migraine action of extracts of butterbur [Petasites hybridus (L.) Gaertn. ] is unknown. Here, we investigated the ability of isopetasin, a major constituent of these extracts, to specifically target TRPA1 channel and to affect functional responses relevant to migraine.
Oxytocin Facilitation of Maternal Behavior in Sheep a

Although human and nonhuman primates exhibit spontaneous maternal care, this is a relatively rare event among most mammalian species. Invariably, pregnancy and parturition, or the endocrine and neural mechanisms that they collectively represent, are required for the immediate and successful onset of maternal behavior. ' Sheep belong to this general category, and ewes are only maternally responsive towards a lamb after the onset of parturition. Fostering of lambs outside the peripartum period does not usually occur. Indeed, ewes positively avoid lambs, and if confronted by an approaching lamb, nonparturient ewes aggressively reject their approach by head butting the lamb into a retreat. When maternal, the ewe actively licks the lamb, continuously emits low-pitched bleats, and suckling usually takes place within an hour of birth, with the ewe actively orientating her posture to maximize the lamb's discovery of the udder.2 Following suckling, and usually within two hours of parturition, the ewe establishes an exclusive bond with her lamb. Although her behavior toward her own lamb is very maternal, strange lambs are rejected by the ewe should they attempt suckling, and this occurs even following the loss of her own lamb. In this paper we investigate the significance of parturition or vaginocervical stimulation (VCS) for the rapid onset of proceptive and receptive maternal behavior in sheep, together with its effectiveness in the release of central oxytocin. The importance of the pregnancy hormones (estrogen, and progesterone + estrogen) are taken into account in this context, and also for their requirement in facilitating central oxytocin effects on inducing maternal behavior. Other peptides, and drugs that promote or block the central release of oxytocin, are also examined for their effects on maternal behavior.
Saccharomyces cerevisiae Aqr1 Is an Internal-Membrane Transporter Involved in Excretion of Amino Acids

ABSTRACT Excretion of amino acids by yeast cells was reported long ago but has not been characterized in molecular terms. It is typically favored by overproduction of the amino acid and/or impairment of its uptake. Here we describe the construction of a yeast strain excreting threonine and homoserine. Using this excretor strain, we then applied a reverse-genetics approach and found that the transporter encoded by the YNL065w/AQR1 gene, a protein thought to mediate H+ antiport, is involved in homoserine and threonine excretion. Furthermore, overexpression of AQR1 led to increased excretion of several amino acids (alanine, aspartate, and glutamate) known to be relatively abundant in the cytosol. Transcription of the AQR1 gene is induced severalfold by a number of amino acids and appears to be under the negative control of Gcn4. An Aqr1-green fluorescent protein fusion protein is located in multiple internal membrane structures and appears to cycle continuously between these compartments and the plasma membrane. The Aqr1 sequence is significantly similar to the vesicular amine transporters of secretory vesicles of neuronal cells. We propose that Aqr1 catalyzes transport of excess amino acids into vesicles, which then release them in the extracellular space by exocytosis.
Overexpression of α‐synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α‐synuclein and activation of caspase‐9: resemblance to pathogenetic changes in Parkinson's disease

To elucidate the role of α‐synuclein in the pathogenesis of Parkinson's disease, both human α‐synuclein transgenic mice and targeted overexpression of human α‐synuclein in rat substantia nigra using viral vector‐based methods have been studied, however, little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in brains with Parkinson's disease are recapitulated in these models. Here, we used the recombinant adeno‐associated viral (rAAV) vector system for human α‐synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after infection, which was comparably slower than the progression of neurodegeneration reported in other studies. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of Parkinson's disease, such as phosphorylation of α‐synuclein at Ser129 and activation of caspase‐9. Both findings were also evident in cortical tissues overexpressing α‐synuclein via rAAV. Our results indicate that overexpression of α‐synuclein via rAAV apparently recapitulates several important features of brains with Parkinson's disease and dementia with Lewy bodies, and thus α‐synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of Parkinson's disease and dementia with Lewy bodies.
Regional cerebral blood flow in apoplexy due to occlusion of the middle cerebral artery

THE XENON 133 INJECTION METHOD allows simultaneous measurement of the blood flow in many areas of the brain.l. 2 It has been used for determination of the regional cerebral blood flow in several small series of patients with cerebrovascular diseases of various types.3-7a The regional flow responses of the braip to changes of arterial blood pressure and arterial pC0, have also been studied, and focal loss of autoregulation and of pC0,-induced vasodilatation in cases of cerebral apoplexy have been reported. "6y7a In the present study, a group of apoplectics with a single pathogenesis, i.e., with acute occlusion of the middle cerebral artery, has been studied with the aim of collecting information on the regional cerebral blood flow (rCBF) and its regulation in a well-defined type of apoplexy. The results obtained in apoplexy without occlusion of a major cerebral artery and in transient ischemic attacks will be reported in subsequent paper^. ^. ^
Gene therapy with novel adeno‐associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia

Familial hypercholesterolemia is an inherited disease caused by mutations in the LDL receptor gene leading to severe hypercholesterolemia and atherosclerosis. The LDL receptor is predominantly expressed in the liver, making it a preferred target organ for somatic gene therapy. We recently isolated a new family of vectors based on adeno‐associated viruses (AAVs) isolated from nonhuman primates, which enable efficient and stable transgene expression following in vivo gene delivery to liver.