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BioASQ
{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.
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69acbdb73b2c414cb48a711bb6da31f1
Selexipag is used for which disease?
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{ "text": [ "pulmonary arterial hypertension" ], "char_spans": [ { "start": [ 395 ], "end": [ 425 ] } ], "token_spans": [ { "start": [ 59 ], "end": [ 61 ] } ] }
[ "pulmonary arterial hypertension" ]
BioASQ
Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.
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796122644c79446f872e37f300157090
In which syndrome is the RPS19 gene most frequently mutated?
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{ "text": [ "Diamond-Blackfan Anemia", "DBA" ], "char_spans": [ { "start": [ 0 ], "end": [ 22 ] }, { "start": [ 25, 1049, 246, 1252, 1183, 376 ], "end": [ 27, 1051, 248, 1254, 1185, 378 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 2 ] }, { "start": [ 4, 172, 41, 206, 194, 63 ], "end": [ 4, 172, 41, 206, 194, 63 ] } ] }
[ "Diamond-Blackfan Anemia", "Diamond Blackfan anemia", "DBA" ]
BioASQ
Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.
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412a49803a00424099cd84a75d92bd63
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 1409, 172, 515, 362, 48, 1320, 1221 ], "end": [ 1415, 178, 521, 368, 54, 1326, 1227 ] } ], "token_spans": [ { "start": [ 295, 36, 101, 69, 10, 277, 259 ], "end": [ 297, 38, 103, 71, 12, 279, 261 ] } ] }
[ "BCR-ABL" ]
BioASQ
Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials (≤104 weeks' duration; typically 24 weeks' duration) and extension studies (typically ≥76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes.
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95f5fe67a6334781a72627254072209a
Which protein does empagliflozin inhibit?
{ "tokens": [ "Which", "protein", "does", "empagliflozin", "inhibit", "?" ], "offsets": [ 0, 6, 14, 19, 33, 40 ] }
{ "text": [ "SGLT2" ], "char_spans": [ { "start": [ 270, 69 ], "end": [ 274, 73 ] } ], "token_spans": [ { "start": [ 49, 14 ], "end": [ 49, 14 ] } ] }
[ "SGLT2" ]
BioASQ
Gaucher disease is an inborn recessive autosomal disease due to a partial deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient activity leads to accumulation of the lipid glucocerebroside in the liver, the spleen and bone marrow with concomitant anemia and thrombocytopenia. Patients with Gaucher disease have been classified in three types: type I is the more common, neurological manifestations occur in types II and III. Enzyme replacement therapy (ERT) with modified placental human glucocerebrosidase (ceredase) or recombinant glucocerebrosidase (cerezyme) is effective in most type I Gaucher disease and has become the current standard care administered to thousand of patients worldwide. ERT has obviated the need for bone marrow transplantation and virtually eliminated the need for splenectomy. We report here the French study including adults and children. ERT of 30 to 60 U/K every two weeks as starting dose was administrated to 108 patients with severe type I Gaucher disease. ERT fully reverse many of the manifestations of the disease. ERT regimen alleviated fatigue, and hematological and visceral signs and symptoms in nearly all severely-ill patients. Skeletal responses to treatment develop much more slowly than hematological or visceral responses. Studies in pediatrics show that the disease is more severe in children. These children should be treated early in the course of their disease to avoid irreparable damage. Hematological manifestation in type II cannot be reversed with enzyme replacement. In type III treatment can rarely reverse neurological deficit. Gaucher disease is also an excellent candidate for gene therapy.
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edb5b97a3a7341bdb6cfc2b80433d4f0
Which enzyme is deficient in Gaucher's disease?
{ "tokens": [ "Which", "enzyme", "is", "deficient", "in", "Gaucher", "'s", "disease", "?" ], "offsets": [ 0, 6, 13, 16, 26, 29, 36, 39, 46 ] }
{ "text": [ "Beta glucocerebrosidase" ], "char_spans": [ { "start": [ 109 ], "end": [ 131 ] } ], "token_spans": [ { "start": [ 17 ], "end": [ 18 ] } ] }
[ "Beta glucocerebrosidase" ]
BioASQ
The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.
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"dose", "deterioration", "and", "on", "-", "off", "phenomena", "." ], "offsets": [ 0, 4, 11, 14, 23, 24, 25, 26, 30, 31, 33, 39, 42, 45, 57, 62, 64, 75, 89, 99, 100, 103, 104, 106, 109, 116, 123, 126, 134, 135, 136, 137, 143, 148, 162, 163, 168, 170, 172, 177, 190, 191, 193, 194, 195, 199, 201, 204, 205, 211, 212, 217, 218, 223, 224, 226, 235, 236, 238, 239, 241, 254, 256, 267, 271, 280, 284, 285, 297, 301, 306, 313, 315, 318, 326, 335, 339, 342, 351, 356, 369, 376, 382, 388, 393, 399, 414, 417, 418, 419, 424, 426, 437, 439, 443, 452, 455, 464, 471, 478, 481, 484, 486, 489, 491, 496, 497, 507, 513, 519, 523, 531, 533, 535, 537, 543, 549, 551, 556, 560, 569, 574, 585, 597, 599, 607, 612, 617, 623, 625, 628, 629, 630, 635, 645, 646, 652, 653, 654, 656, 657, 658, 663, 669, 670, 676, 677, 678, 680, 681, 682, 687, 689, 701, 702, 709, 711, 712, 718, 719, 721, 725, 726, 727, 732, 734, 744, 745, 752, 754, 755, 761, 762, 763, 765, 772, 777, 779, 785, 789, 796, 799, 806, 808, 812, 813, 815, 819, 829, 836, 839, 846, 848, 852, 853, 855, 866, 871, 877, 881, 891, 894, 900, 903, 907, 909, 910, 925, 928, 931, 933, 941, 946, 956, 959, 964, 966, 969, 976, 978, 982, 983, 985, 990, 995, 999, 1005, 1006, 1007, 1012, 1017, 1026, 1031, 1037, 1038, 1040, 1047, 1048, 1049, 1054, 1058, 1064, 1071, 1076, 1078, 1084, 1090, 1092, 1098, 1105, 1108, 1115, 1120, 1124, 1133, 1135, 1139, 1141, 1142, 1143, 1144, 1149, 1155, 1159, 1169, 1176, 1179, 1185, 1187, 1191, 1199, 1202, 1209, 1211, 1215, 1217, 1220, 1229, 1234, 1240, 1241, 1243, 1251, 1257, 1264, 1268, 1273, 1274, 1275, 1276, 1281, 1288, 1299, 1304, 1308, 1319, 1322, 1324, 1325, 1329, 1341, 1343, 1346, 1348, 1361, 1367, 1370, 1376, 1385, 1393, 1396, 1404, 1414, 1418, 1428, 1431, 1438, 1444, 1448, 1454, 1457, 1463, 1473, 1478, 1479, 1480, 1482, 1487, 1489, 1497, 1506, 1522, 1530, 1533, 1540, 1544, 1558, 1564, 1568, 1577, 1580, 1586, 1589, 1599, 1607, 1611, 1617, 1627, 1630, 1634, 1638, 1641, 1649, 1652, 1656, 1661, 1664, 1673, 1682, 1685, 1697, 1705, 1708, 1713, 1722, 1726, 1730, 1733, 1736, 1744, 1747, 1750, 1751, 1753, 1754, 1759, 1773, 1777, 1779, 1780, 1784, 1793 ] }
5aad124ed6b3449e87579c5571aa6c64
Which drug is benserazide usually co-administered with?
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{ "text": [ "L-Dopa" ], "char_spans": [ { "start": [ 725, 1142, 417, 680, 1047, 24, 1005, 193, 1274, 628, 656 ], "end": [ 730, 1147, 422, 685, 1052, 29, 1010, 198, 1279, 633, 661 ] } ], "token_spans": [ { "start": [ 161, 258, 87, 148, 236, 5, 226, 42, 287, 130, 139 ], "end": [ 163, 260, 89, 150, 238, 7, 228, 44, 289, 132, 141 ] } ] }
[ "L-Dopa" ]
BioASQ
Determining clinical probability of pulmonary embolism (PE) with Wells scoring system is the first step towards diagnosis of PE. Definitive diagnosis of PE is confirmed by computed tomography pulmonary angiography (CTPA). This was a prospective study on 80 patients referred to the Institute for Pulmonary Diseases of Vojvodina with suspected PE between April 2010 and August 2012. Clinical probability of PE was determined according to the Wells and modified Wells scoring system. CTPA was performed in 60 patients. The degree of pulmonary vascular obstruction was quantified by the Qanadli index. Low clinical probability of PE was present in one patient (1.6%), moderate in 43 (71.6%) and high in 16 (26.6%) patients. PE was confirmed in 50 (83.3%) patients. There were 21 patients (42%) whose Quanadli index was <25%, 18 (36%) between 25%-50%, while Quanadli index was ≥50 in 11 patients (22%). When compared to CTPA findings, modified Wells scoring system showed 90% sensitivity [95% confidence interval (CI) 78.2%-96.6%], and 20% specificity (95% CI 3.11%-55.6%), positive predictive value (PPV) 84.9% (95% CI 72.4%-93.2%) and negative predictive value (NPV) 28.6% (95% CI 4.5%-70.7%). There was weak positive correlation between Wells score and Quanadli index (r = 0.14; P = 0.29), without statistical significance. Wells score was significantly higher in haemodynamically unstable than in haemodynamically stable patients (6.8 vs 5.6, P = 0.014). There was no statistically significant difference between the values of Quanadli index in these two groups (31.33% vs 26.64%, P = 0.062). Modified Wells criteria have high sensitivity but low specificity in PE diagnostics. The Wells score does not correlate well with the Quanadli index.
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862da8740a8c404c925e5d6116db47e5
What can be predicted with the Wells criteria?
{ "tokens": [ "What", "can", "be", "predicted", "with", "the", "Wells", "criteria", "?" ], "offsets": [ 0, 5, 9, 12, 22, 27, 31, 37, 45 ] }
{ "text": [ "pulmonary embolism" ], "char_spans": [ { "start": [ 36 ], "end": [ 53 ] } ], "token_spans": [ { "start": [ 4 ], "end": [ 5 ] } ] }
[ "pulmonary embolism" ]
BioASQ
We report the case of a Japanese boy whose dysmorphic features were consistent with those of Shprintzen-Goldberg syndrome. The radiological features were characterized by late-onset craniosynostosis, arachnodactyly, undermodeling of short tubular bones, mildly undermodeled and slightly bowed long bones, twisted ribs and tall vertebral bodies with elongated neural arches. Apart from the craniosynostosis, these skeletal changes resembled those of frontometaphyseal dysplasia, a well-known craniotubular dysplasia. Shprintzen-Goldberg syndrome also shares many clinical features with frontometaphyseal dysplasia.
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31b5228a9b2e43878afead6abaf040d4
Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?
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{ "text": [ "Craniosynostosis" ], "char_spans": [ { "start": [ 389, 182 ], "end": [ 404, 197 ] } ], "token_spans": [ { "start": [ 62, 30 ], "end": [ 62, 30 ] } ] }
[ "Craniosynostosis" ]
BioASQ
Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects. This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 x 200 μg tablets (reference: A) or 1 x 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated. 80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 μg b.i.d. The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCτ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679. Bioequivalence was demonstrated between 8 x 200 μg and 1 x 1,600 μg selexipag at steady state.
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990c3fbed6b34ba08dd9a7685e257613
Selexipag is used for which disease?
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{ "text": [ "pulmonary arterial hypertension" ], "char_spans": [ { "start": [ 120 ], "end": [ 150 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 23 ] } ] }
[ "pulmonary arterial hypertension" ]
BioASQ
To evaluate and compare outcomes for patients with vestibular schwannoma (VS) treated in a single institution with linac-based stereotactic radiosurgery (SRS) or by fractionated stereotactic radiotherapy (SRT). One hundred and nineteen patients (SRS = 78, SRT = 41) were treated. For both SRS and SRT, beam shaping is performed by a mini-multileaf collimator. For SRS, a median single dose of 12.5 Gy (range, 11-14 Gy), prescribed to the 80% isodose line encompassing the target, was applied. Of the 42 SRT treatments, 32 treatments consisted of 10 fractions of 3-4 Gy, and 10 patients received 25 sessions of 2 Gy, prescribed to the 100% with the 95% isodose line encompassing the planning target volume. Mean largest tumor diameter was 16.6 mm in the SRS and 24.6 mm in the SRT group. Local tumor control, cranial nerve toxicity, and preservation of useful hearing were recorded. Any new treatment-induced cranial nerve neuropathy was scored as a complication. Median follow-up was 62 months (range, 6-136 months), 5 patients progressed, resulting in an overall 5-year local tumor control of 95%. The overall 5-year facial nerve preservation probability was 88% and facial nerve neuropathy was statistically significantly higher after SRS, after prior surgery, for larger tumors, and in Koos Grade ≥3. The overall 5-year trigeminal nerve preservation probability was 96%, not significantly influenced by any of the risk factors. The overall 4-year probability of preservation of useful hearing (Gardner-Robertson score 1 or 2) was 68%, not significantly different between SRS or SRT (59% vs. 82%, p = 0.089, log rank). Linac-based RT results in good local control and acceptable clinical outcome in small to medium-sized vestibular schwannomas (VSs). Radiosurgery for large VSs (Koos Grade ≥3) remains a challenge because of increased facial nerve neuropathy.
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"remains", "a", "challenge", "because", "of", "increased", "facial", "nerve", "neuropathy", "." ], "offsets": [ 0, 3, 12, 16, 24, 33, 37, 46, 51, 62, 73, 74, 76, 78, 86, 89, 91, 98, 110, 115, 120, 121, 127, 140, 153, 154, 157, 159, 162, 165, 178, 191, 204, 205, 208, 209, 211, 215, 223, 227, 236, 245, 246, 250, 252, 254, 256, 260, 262, 264, 266, 271, 278, 280, 284, 289, 293, 297, 300, 302, 307, 315, 318, 328, 331, 333, 337, 338, 348, 358, 360, 364, 367, 369, 371, 378, 385, 390, 393, 398, 401, 402, 407, 409, 411, 412, 415, 417, 418, 420, 431, 434, 438, 440, 442, 450, 455, 468, 472, 478, 480, 484, 491, 493, 496, 500, 503, 507, 517, 519, 522, 533, 543, 546, 549, 559, 562, 563, 564, 566, 568, 570, 574, 577, 586, 595, 598, 607, 610, 612, 614, 616, 627, 630, 634, 637, 639, 644, 648, 650, 652, 660, 665, 678, 682, 691, 698, 704, 706, 711, 719, 725, 734, 738, 743, 746, 749, 753, 757, 761, 766, 769, 772, 776, 780, 785, 787, 793, 799, 806, 808, 816, 822, 830, 832, 836, 849, 852, 859, 867, 872, 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1750, 1751, 1753, 1766, 1770, 1776, 1780, 1781, 1786, 1792, 1794, 1796, 1804, 1806, 1816, 1824, 1827, 1837, 1844, 1850, 1860 ] }
212829ec9421495797a732770b08731b
Which disease can be categorized using the Koos grading system?
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{ "text": [ "vestibular schwannoma" ], "char_spans": [ { "start": [ 51 ], "end": [ 71 ] } ], "token_spans": [ { "start": [ 8 ], "end": [ 9 ] } ] }
[ "vestibular schwannoma" ]
BioASQ
Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.
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d941cbf53efb4218a8348c71b146a2d2
Mutation of which gene is implicated in the Christianson syndrome?
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{ "text": [ "SLC9A6" ], "char_spans": [ { "start": [ 1702, 833, 698, 554, 1065, 1312, 1434, 1850, 676, 284 ], "end": [ 1707, 838, 703, 559, 1070, 1317, 1439, 1855, 681, 289 ] } ], "token_spans": [ { "start": [ 291, 150, 118, 92, 185, 231, 247, 311, 114, 47 ], "end": [ 291, 150, 118, 92, 185, 231, 247, 311, 114, 47 ] } ] }
[ "SLC9A6" ]
BioASQ
The authors reported a 73-year-old alcoholic man with previously-unrecognized situs inversus totalis suffering from left upper quadrant pain. Acute myocardial infarction was diagnosed and coronary angioplasty was performed immediately. However, the massive bleeding from the previously-unfound hepatomas caused hypovolemic shock and fatal outcome. Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. Although being considered a benign entity, it would disturb diagnosis-making of the visceral diseases owing to the altered anatomy. To our knowledge, the coexistence of the coronary artery disease and ruptured hepatomas in situs inversus totalis, as in our patient, is never described. Recognition of any situs anomalies in time is the key to avoid misdiagnosis, inappropriate managements, and unwanted consequences.
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30297cdd9b004604bfbf3798dd6ebe86
What is situs inversus?
{ "tokens": [ "What", "is", "situs", "inversus", "?" ], "offsets": [ 0, 5, 8, 14, 22 ] }
{ "text": [ "Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs." ], "char_spans": [ { "start": [ 348 ], "end": [ 464 ] } ], "token_spans": [ { "start": [ 53 ], "end": [ 71 ] } ] }
[ "Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs." ]
BioASQ
Methylation of certain lysine residues in the N-terminal tails of core histone proteins in nucleosome is of fundamental importance in the regulation of chromatin structure and gene expression. Such histone modification is catalyzed by protein lysine methyltransferases (PKMTs). PKMTs contain a conserved SET domain in almost all of the cases and may transfer one to three methyl groups from S-adenosyl-L-methionine (AdoMet) to the epsilon-amino group of the target lysine residue. Here, quantum mechanical/molecular mechanical molecular dynamics and free-energy simulations are performed on human PKMT SET7/9 and its mutants to understand two outstanding questions for the reaction catalyzed by PKMTs: the mechanism for deprotonation of positively charged methyl lysine (lysine) and origin of product specificity. The results of the simulations suggest that Tyr-335 (an absolute conserved residue in PKMTs) may play the role as the general base for the deprotonation after dissociation of AdoHcy (S-adenosyl-L-homocysteine) and before binding of AdoMet. It is shown that conformational changes could bring Y335 to the target methyl lysine (lysine) for proton abstraction. This mechanism provides an explanation why methyl transfers could be catalyzed by PKMTs processively. The free-energy profiles for methyl transfers are reported and analyzed for wild type and certain mutants (Y305F and Y335F) and the active-site interactions that are of importance for the enzyme's function are discussed. The results of the simulations provide important insights into the catalytic process and lead to a better understanding of experimental observations concerning the origin of product specificity for PKMTs.
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f5801149c94f4f65b82ee302b13c0d29
What is the characteristic domain of histone methyltransferases?
{ "tokens": [ "What", "is", "the", "characteristic", "domain", "of", "histone", "methyltransferases", "?" ], "offsets": [ 0, 5, 8, 12, 27, 34, 37, 45, 63 ] }
{ "text": [ "SET domain" ], "char_spans": [ { "start": [ 304 ], "end": [ 313 ] } ], "token_spans": [ { "start": [ 48 ], "end": [ 49 ] } ] }
[ "SET domain" ]
BioASQ
Ehlers-Danlos syndrome is a complex hereditary connective tissue disorder that is characterized by abnormalities of the skin and joints and visceral and neurological manifestations. At present, at least 11 forms are recognized on the basis of their clinical characteristics, methods of transmission, and biochemical defect. The neurologic manifestations include cerebrovascular disease, peripheral neuropathy, plexopathy, periventricular subependymal heterotopias, and epilepsy. Previously, 2 females were reported to be affected with subependimal periventricular heterotopias and Ehlers-Danlos syndrome type 1. The authors report a new case of a 12-year-old girl with similar clinical and neuroradiological features.
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10de1ab61b0a47219444a92bc141d960
What tissue is most affected in Ehlers-Danlos syndromes?
{ "tokens": [ "What", "tissue", "is", "most", "affected", "in", "Ehlers", "-", "Danlos", "syndromes", "?" ], "offsets": [ 0, 5, 12, 15, 20, 29, 32, 38, 39, 46, 55 ] }
{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 47 ], "end": [ 63 ] } ], "token_spans": [ { "start": [ 8 ], "end": [ 9 ] } ] }
[ "connective tissue" ]
BioASQ
Periodic limb movement disorder (PLMD) is one of the commonest neurological disorders and causes significant disability, if left untreated. However, it is rarely diagnosed in clinical practice, probably due to lack of awareness and/or lack of necessary diagnostic facilities. Restless leg syndrome (RLS), aging, pregnancy, uraemia, iron deficiency, polyneuropathy are some of the common causes of secondary PLMD. Clinical presentation, polysomnographic findings and management of six patients of PLMD have been discussed in this report.
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f17066e29bca4700bcdd4b135925f533
Which deficiency is the cause of restless leg syndrome?
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{ "text": [ "iron" ], "char_spans": [ { "start": [ 332 ], "end": [ 335 ] } ], "token_spans": [ { "start": [ 59 ], "end": [ 59 ] } ] }
[ "iron" ]
BioASQ
Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.
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a636a925df634cada0c2d6964688e93a
Which is the receptor for substrates of Chaperone Mediated Autophagy?
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{ "text": [ "LAMP2A" ], "char_spans": [ { "start": [ 628, 312, 580, 237, 491, 682, 727, 454 ], "end": [ 633, 317, 585, 242, 496, 687, 732, 459 ] } ], "token_spans": [ { "start": [ 109, 54, 102, 38, 87, 119, 126, 81 ], "end": [ 109, 54, 102, 38, 87, 119, 126, 81 ] } ] }
[ "LAMP2A", "Lysosome-associated membrane protein 2 isoform A" ]
BioASQ
The focus of this article is acrokeratosis paraneoplastica, one of two disorders that have acquired the eponym Bazex syndrome. To date, all of the patients reported in the literature have had an underlying neoplasm, most commonly squamous cell carcinoma of the upper aerodigestive tract. In this review of 113 cases of acrokeratosis paraneoplastica (mean age, 61 years; 105 males, 8 females), the psoriasiform lesions preceded the diagnosis of the associated malignancy in 73 (67%) of 109 patients, whereas the cutaneous manifestations followed the diagnosis of the neoplasm in only 16 (15%) of 109; in the remainder, the onset of the skin lesions and the diagnosis of the tumor occurred simultaneously. Therefore, awareness of the cutaneous signs of Bazex syndrome is of obvious importance to dermatologists. Evidence in favor of the paraneoplastic nature of this disease is as follows: in 81 (93%) of 87 patients with adequate clinical descriptions, the skin lesions either improved significantly (or resolved) when the underlying neoplasm was treated or they remained unchanged in the setting of persistent disease. Occasionally, the reappearance of skin lesions has signaled a recurrence of the tumor.
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d451ee65e0e14baaa98a29b68092c5fc
Name synonym of Acrokeratosis paraneoplastica.
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{ "text": [ "Bazex syndrome" ], "char_spans": [ { "start": [ 751, 111 ], "end": [ 764, 124 ] } ], "token_spans": [ { "start": [ 139, 18 ], "end": [ 140, 19 ] } ] }
[ "Bazex syndrome" ]
BioASQ
To demonstrate the importance of preventive measures when a case of tuberculosis is detected, identify the causes that favored a tuberculosis outbreak in a school and determine the efficiency of obtaining induced sputum samples. Descriptive, study. The Santa Maria de la Providencia school, located in the municipality of Alcala de Henares in Spain. On April 11, 2005, a case of bacilliform pulmonary tuberculosis was notified in a teacher. Study of contacts in the collective was performed as a programmed intervention. Mantoux skin test and, if positive, chest radiograph were performed in contacts. Treatment of latent or active tuberculosis was recommended according to the result. School exposures were identified and underwent the Mantoux skin test (142 students in years 1, 2, 3, and 4 of compulsory secondary education and 22 teachers). The Mantoux test was positive in 68 students (48 %) and seven teachers (32 %). In seven students with results compatible with active tuberculosis disease, sputum induction was performed and treatment was started. A further two students, identified as contacts, were studied in another center and also started treatment for active tuberculosis disease. Due to the high risk of contagion, study of contacts was extended to the remaining students in compulsory secondary education. In this second phase, 134 students received the Mantoux skin test and seven were Mantoux positive (5.2 %). In all these students, active tuberculosis disease was ruled out. Latent tuberculosis treatment was recommended in all Mantoux-positive contacts.
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432d404973ba41318c6fe93752543d01
The Mantoux test detects what latent infection/disease?
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{ "text": [ "tuberculosis" ], "char_spans": [ { "start": [ 68, 129, 401, 1175, 1461, 1504, 978, 632 ], "end": [ 79, 140, 412, 1186, 1472, 1515, 989, 643 ] } ], "token_spans": [ { "start": [ 11, 21, 70, 210, 263, 270, 178, 110 ], "end": [ 11, 21, 70, 210, 263, 270, 178, 110 ] } ] }
[ "tuberculosis" ]
BioASQ
Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.
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dcbeada03bcb4f4d8ba89ab6cff60b0d
Which is the primary protein component of Lewy bodies?
{ "tokens": [ "Which", "is", "the", "primary", "protein", "component", "of", "Lewy", "bodies", "?" ], "offsets": [ 0, 6, 9, 13, 21, 29, 39, 42, 47, 53 ] }
{ "text": [ "α-synuclein" ], "char_spans": [ { "start": [ 481, 606, 694, 878, 325, 766, 1261, 76, 1178, 999, 565 ], "end": [ 491, 616, 704, 888, 335, 776, 1271, 86, 1188, 1009, 575 ] } ], "token_spans": [ { "start": [ 84, 108, 125, 157, 58, 138, 216, 11, 203, 176, 99 ], "end": [ 86, 110, 127, 159, 60, 140, 218, 13, 205, 178, 101 ] } ] }
[ "alpha-synuclein", "α-synuclein", "αSyn" ]
BioASQ
Phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) regulates protein synthesis in hippocampal dendrites. CPEB binds the 3' untranslated region (UTR) of cytoplasmic mRNAs and, when phosphorylated, initiates mRNA polyadenylation and translation. We report that, of the protein kinases activated in the hippocampus during synaptic plasticity, calcium/calmodulin-dependent protein kinase II (CaMKII) robustly phosphorylated the regulatory site (threonine 171) in CPEB in vitro. In postsynaptic density fractions or hippocampal neurons, CPEB phosphorylation increased when CaMKII was activated. These increases in CPEB phosphorylation were attenuated by a specific peptide inhibitor of CaMKII and by the general CaM-kinase inhibitor KN-93. Inhibitors of protein phosphatase 1 increased basal CPEB phosphorylation in neurons; this was also attenuated by a CaM-kinase inhibitor. To determine whether CaM-kinase activity regulates CPEB-dependent mRNA translation, hippocampal neurons were transfected with luciferase fused to a 3' UTR containing CPE-binding elements. Depolarization of neurons stimulated synthesis of luciferase; this was abrogated by inhibitors of protein synthesis, mRNA polyadenylation, and CaMKII. These results demonstrate that CPEB phosphorylation and translation are regulated by CaMKII activity and provide a possible mechanism for how dendritic protein synthesis in the hippocampus may be stimulated during synaptic plasticity.
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7d3d225c01ba4d0daa3bfa2341e0caf8
Which kinase is inhibited by the small molecule KN-93?
{ "tokens": [ "Which", "kinase", "is", "inhibited", "by", "the", "small", "molecule", "KN-93", "?" ], "offsets": [ 0, 6, 13, 16, 26, 29, 33, 39, 48, 53 ] }
{ "text": [ "The calcium/calmodulin-dependent protein kinase-II" ], "char_spans": [ { "start": [ 367 ], "end": [ 412 ] } ], "token_spans": [ { "start": [ 57 ], "end": [ 64 ] } ] }
[ "CAMK2", "calcium/calmodulin-dependent protein kinase II", "The calcium/calmodulin-dependent protein kinase-II", "CaM kinase II" ]
BioASQ
The natural phytoalexin resveratrol, found in grapes and red wine, recently rose to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the "pufferfishes" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.
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28273676388a4bd8b10c28cc78703649
What can Nothobranchius furzeri be used as a model system for?
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{ "text": [ "aging research" ], "char_spans": [ { "start": [ 1219 ], "end": [ 1232 ] } ], "token_spans": [ { "start": [ 212 ], "end": [ 213 ] } ] }
[ "aging research" ]
BioASQ
This study examined the accuracy of the 17-item Dutch version of the Davidson Trauma Scale (DTS) and the four-item SPAN (Startle, Physiological Arousal, Anger and Numbness) to detect survivors at risk for posttraumatic stress disorder (PTSD) within the first 2 weeks after the trauma. 203 civilian survivors of recent trauma with relatively mild symptoms completed the DTS a mean of 8.7 days after experiencing trauma. SPAN scores were computed from the DTS. At a mean of 64.6 days posttrauma, 160 respondents were assessed for diagnosis of PTSD with the Structured Interview for PTSD. Receiver operating characteristic curves showed that the DTS showed good overall screening accuracy (84%). At a cut-off value of 64, the DTS demonstrated a sensitivity of 0.86, a specificity of 0.70, a positive predictive value (PPV) of 0.12, and a negative predictive value (NPV) of 0.98. Overall accuracy of the SPAN was good (89%). At a cut-off of 10 the SPAN showed a sensitivity of 0.86, a specificity of 0.86, a PPV of 0.22, and a NPV of 0.98. The low PPVs were possibly due to the low of prevalence of PTSD in our sample (4.4%). This study shows that both the DTS and the SPAN are comparably accurate in screening early trauma survivors at risk for developing PTSD. The very brief four-item SPAN may be preferred over the longer 17-item DTS especially in settings in which time and resources are limited. Future studies should aim to cross-validate these results in random samples.
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f39ba0ef13d74fbbbee6b6a7495a7da1
Symptoms of which disorder are evaluated with the Davidson Trauma Scale?
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{ "text": [ "PTSD" ], "char_spans": [ { "start": [ 1095, 580, 236, 541, 1253 ], "end": [ 1098, 583, 239, 544, 1256 ] } ], "token_spans": [ { "start": [ 224, 106, 44, 100, 255 ], "end": [ 224, 106, 44, 100, 255 ] } ] }
[ "post-traumatic stress disorder", "PTSD" ]
BioASQ
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. Considerable clinical and genetic heterogeneity exists, and more than nine separate forms have been recognized. Recent advances in the molecular analysis of EDS have identify defects responsible for EDS VI (homozygous and compound heterozygous mutations in the lysyl-hydroxylase gene), EDS VIIA and EDS VIIB (mutations in the type I collagene genes), EDS VIIC (deficiency of procollagen N-proteinase), EDS IX (mutations in the MNK gene), and EDS IV (mutations in the type III collagen gene). Of the various types of Ehlers-Danlos syndrome the most severe is type IV (EDS IV). Early studies showed that fibroblasts from EDS IV patients secreted lower than normal amounts of type III procollagen (Pope et al., 1975). Later, the disease was linked to COL3A1, the gene encoding this protein. More recently, with the publication of full length cDNA and partial characterisation of the gene structure, detailed analysis of mutations in EDS IV patients has become possible. Nineteen different mutations in the type III procollagen gene have been reported in different families with EDS IV. Recent results support the hypothesis that in EDS IV, dominant inheritance should be assumed, in sporadic cases also, unless proven otherwise. Very little is known about the genetics or biochemicals defects responsible for the others EDS subtypes, but with the applications of the tools of molecular biology, analysis of these defects if now within reach.
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0fd48e8ecbbf4547af93df0c4d6ecfe0
What tissue is most affected in Ehlers-Danlos syndromes?
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{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 59 ], "end": [ 75 ] } ], "token_spans": [ { "start": [ 13 ], "end": [ 14 ] } ] }
[ "connective tissue" ]
BioASQ
Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use).
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6e72346d9baf4bee8b690349f4e87241
Which medication should be administered when managing patients with suspected acute opioid overdose?
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[ "naloxone" ]
BioASQ
We immunohistochemically investigated the degeneration processes of the nigro-striatal and nigro-amygdaloid pathways and the relationship between the loss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia nigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and TH-positive axonal terminals in the putamen decreased with a specific pattern. The substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that were almost evenly distributed, while the putamen exhibited diffuse or granular alpha-synuclein-immunostaining. Most of the granular stains were positive for anti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were negative. These findings suggest that the axonal terminals in the putamen undergo abnormal alpha-synuclein accumulation, but may not always originate from LB-bearing neurons in the substantia nigra. The central amygdaloid nucleus contained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive dystrophic axonal terminals, the degree of which was greater for cases with granular staining in the putamen, and which was proportional to the number of alpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal terminals in the central amygdaloid nucleus may have originated from LB-bearing neurons in the substantia nigra. The results of the present study indicate that the nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in DLB, and suggest that the degeneration of the nigro-amygdaloid pathway more strongly reflects LB formation in dopaminergic neurons of the substantia nigra than that of the nigro-striatal pathway. In addition, they indicate that there is no direct relationship between the loss of dopaminergic neurons and LB formation in the substantia nigra.
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838f259cf3d94ed1a4628e26a79fa183
Against which protein is the antibody used for immonostaining of Lewy bodies raised?
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{ "text": [ "alpha-Synuclein" ], "char_spans": [ { "start": [ 619, 1020, 1057, 717, 1236, 490, 866 ], "end": [ 633, 1035, 1071, 731, 1250, 504, 880 ] } ], "token_spans": [ { "start": [ 102, 170, 175, 119, 207, 80, 143 ], "end": [ 104, 172, 177, 121, 209, 82, 145 ] } ] }
[ "alpha-Synuclein" ]
BioASQ
To assess the efficacy and safety of tanezumab, a humanized monoclonal antibody directed against the pain-mediating neurotrophin, nerve growth factor, to treat pain and other symptoms of chronic prostatitis/chronic pelvic pain syndrome in a Phase IIa, proof-of-concept clinical trial powered to provide 2-sided 90% confidence interval around the primary endpoint. Patients received a single intravenous dose of tanezumab (20 mg) or placebo. The primary efficacy endpoint was the change from baseline to week 6 in average daily numerical rating scale pain score. The secondary endpoints included the change from baseline to week 6 in the National Institutes of Health Chronic Prostatitis Symptom Index and urinary symptoms. Safety was also assessed. Overall, 62 patients were randomized (30 to tanezumab and 32 to placebo). At week 6, tanezumab marginally improved the average daily pain (least-squares mean difference from placebo -0.47, 90% confidence interval -1.150-0.209) and urgency episode frequency (least-squares mean difference from placebo -1.37, 90% confidence interval -3.146-0.401). No difference was seen in the National Institutes of Health chronic prostatitis symptom index total score or micturition frequency at week 6. The most common adverse events were paresthesia and arthralgia. The odds of having a ≥ 30% reduction in pain were 1.75-fold greater (90% confidence interval 0.65-4.69) for patients receiving tanezumab versus placebo. Tanezumab might improve symptoms for some patients with chronic prostatitis/chronic pelvic pain syndrome. Although proof of concept was not demonstrated in the present study, additional studies with larger populations and stricter inclusion criteria according to patient phenotype might identify populations in which antinerve growth factor treatment will provide clinical benefit.
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53453018272b4cbaa4e322487a25246c
What is the target of tanezumab?
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{ "text": [ "nerve growth factor" ], "char_spans": [ { "start": [ 130 ], "end": [ 148 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 23 ] } ] }
[ "nerve growth factor", "NGF" ]
BioASQ
The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected ingestion of dextromethorphan by 1) describing the process by which an ingestion of dextromethorphan might be managed, 2) identifying the key decision elements in managing cases of dextromethorphan ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to the ingestion of dextromethorphan alone. Co-ingestion of additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions might be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) Patients who exhibit more than mild effects (e.g., infrequent vomiting or somnolence [lightly sedated and arousable with speaking voice or light touch]) after an acute dextromethorphan ingestion should be referred to an emergency department (Grade C). 3) Patients who have ingested 5-7.5 mg/kg should receive poison center-initiated follow-up approximately every 2 hours for up to 4 hours after ingestion. Refer to an emergency department if more than mild symptoms develop (Grade D). 4) Patients who have ingested more than 7.5 mg/kg should be referred to an emergency department for evaluation (Grade C). 5) If the patient is taking other medications likely to interact with dextromethorphan and cause serotonin syndrome, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, poison center-initiated follow-up every 2 hours for 8 hours is recommended (Grade D). 6) Patients who are asymptomatic and more than 4 hours have elapsed since the time of ingestion can be observed at home (Grade C). 7) Do not induce emesis (Grade D). 8) Do not use activated charcoal at home. Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of dextromethorphan within the preceding hour. Its administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grade D). 9) For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression (Grade C). 10) Use intravenous benzodiazepines for seizures and benzodiazepines and external cooling measures for hyperthermia (>104 degrees F, >40 degrees C) for serotonin syndrome. This should be done in consultation with and authorized by EMS medical direction, by a written treatment protocol or policy, or with direct medical oversight (Grade C). 11) Carefully ascertain by history whether other drugs, such as acetaminophen, were involved in the incident and assess the risk for toxicity or for a drug interaction.
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bb05ffd715264fdf8fc2a8c7edaf0d04
Which medication should be administered when managing patients with suspected acute opioid overdose?
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{ "text": [ "naloxone" ], "char_spans": [ { "start": [ 2918 ], "end": [ 2925 ] } ], "token_spans": [ { "start": [ 520 ], "end": [ 520 ] } ] }
[ "naloxone" ]
BioASQ
A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and a major component of the inclusion bodies commonly found with a wide variety of ALS. ALS-linked mutations in UBQLN2 are clustered in a unique proline-X-X repeat region, reportedly leading to impairment of the ubiquitin proteasome system. However, the molecular properties of mutant UBQLN2 remain unclear. To gain insight into the pathogenesis of UBQLN2-linked ALS/FTD, we examined the biochemical and cellular characteristics of mutant UBQLN2 in vitro. UBQLN2 localized in Rab11-positive endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN). These vesicles were ubiquitin- and p62-immunopositive and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN vesicles. UBQLN2 was found to be a potent regulator of the levels of the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. These data suggest a novel disease spectrum and provide new pathological insights into OPTN and UBQLN2, enhancing our understanding of the molecular basis of ALS/FTD.
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de7ad57d11e84ddf995786a4c2ecdfe5
Which human disease is associated with mutated UBQLN2
{ "tokens": [ "Which", "human", "disease", "is", "associated", "with", "mutated", "UBQLN2" ], "offsets": [ 0, 6, 12, 20, 23, 34, 39, 47 ] }
{ "text": [ "ALS", "amyotrophic lateral sclerosis" ], "char_spans": [ { "start": [ 246, 945, 880, 241, 1238, 1329, 1728, 682, 521 ], "end": [ 248, 947, 882, 243, 1240, 1331, 1730, 684, 523 ] }, { "start": [ 91 ], "end": [ 119 ] } ], "token_spans": [ { "start": [ 46, 170, 156, 44, 220, 233, 295, 120, 94 ], "end": [ 46, 170, 156, 44, 220, 233, 295, 120, 94 ] }, { "start": [ 20 ], "end": [ 22 ] } ] }
[ "ALS", "amyotrophic lateral sclerosis" ]
BioASQ
Cerebrolysin (Cere) is a peptidergic nootropic drug with neurotrophic properties which has been used to treat dementia and sequelae of stroke. Use of Cere prevents nuclear structural changes typical of apoptosis and significantly reduces the number of apoptotic cells after several apoptotic stimuli. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by mutations of the Notch3 gene encoding the Notch3 protein. Notch3 is involved in the regulation of apoptosis, modulating Fas-Ligand (Fas-L)- induced apoptosis. The aim of this study was to evaluate the in vitro protective effects of Cere against oxidative stress-induced apoptosis in cells from CADASIL patients. We used peripheral blood lymphocytes (PBLs) from 15 CADASIL patients (age range 34-70 years); 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analyzed by flow cytometry and fluorescence microscopy. Administration of Cere to PBLs from CADASIL patients cultured under standard conditions had no effect on the percentage of apoptotic cells. Administration of Cere to PBLs cultured with dRib caused a significant decrease in apoptosis after 48 h of culture in only 5 patients, whereas in the other 10 patients, Cere treatment was not associated with any significant difference in the percentage of apoptosis. This result showed a protective effect of Cere against oxidative stress-induced apoptosis only in 30 % of the CADASIL patients, suggesting that the Notch3 gene probably does not influence the anti-apoptotic properties of Cere in vitro.
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af0fd3f5bf9540ba8eb2d1ef50fc1544
Which gene is involved in CADASIL?
{ "tokens": [ "Which", "gene", "is", "involved", "in", "CADASIL", "?" ], "offsets": [ 0, 6, 11, 14, 23, 26, 33 ] }
{ "text": [ "Notch3 gene" ], "char_spans": [ { "start": [ 453, 1562 ], "end": [ 463, 1572 ] } ], "token_spans": [ { "start": [ 68, 270 ], "end": [ 69, 271 ] } ] }
[ "Notch3 gene" ]
BioASQ
To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. All publications reporting clinical trials of empagliflozin were eligible for inclusion. Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.
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8e4362d962304849af0e9a9cf344f780
Which protein does empagliflozin inhibit?
{ "tokens": [ "Which", "protein", "does", "empagliflozin", "inhibit", "?" ], "offsets": [ 0, 6, 14, 19, 33, 40 ] }
{ "text": [ "SGLT2" ], "char_spans": [ { "start": [ 621, 81 ], "end": [ 625, 85 ] } ], "token_spans": [ { "start": [ 108, 14 ], "end": [ 108, 14 ] } ] }
[ "SGLT2" ]
BioASQ
Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.
{ "tokens": [ "Interleukin-6", "(", "IL6", ")", "plays", "a", "central", "role", "in", "multiple", "myeloma", "pathogenesis", "and", "confers", "resistance", "to", "corticosteroid", "-", "induced", "apoptosis", ".", "We", "therefore", "evaluated", "the", "efficacy", "and", "safety", "of", "siltuximab", ",", "an", "anti", "-", "IL6", "monoclonal", "antibody", ",", "alone", "and", "in", "combination", "with", "dexamethasone", ",", "for", "patients", "with", "relapsed", "or", "refractory", "multiple", "myeloma", "who", "had", "≥", "2", "prior", "lines", "of", "therapy", ",", "one", "of", "which", "had", "to", "be", "bortezomib", "-", "based", ".", "Fourteen", "initial", "patients", "received", "siltuximab", "alone", ",", "10", "of", "whom", "had", "dexamethasone", "added", "for", "suboptimal", "response", ";", "39", "subsequent", "patients", "were", "treated", "with", "concurrent", "siltuximab", "and", "dexamethasone", ".", "Patients", "received", "a", "median", "of", "four", "prior", "lines", "of", "therapy", ",", "83", "%", "were", "relapsed", "and", "refractory", ",", "and", "70", "%", "refractory", "to", "their", "last", "dexamethasone", "-", "containing", "regimen", ".", "Suppression", "of", "serum", "C", "-", "reactive", "protein", "levels", ",", "a", "surrogate", "marker", "of", "IL6", "inhibition", ",", "was", "demonstrated", ".", "There", "were", "no", "responses", "to", "siltuximab", "but", "combination", "therapy", "yielded", "a", "partial", "(", "17", "%", ")", "+", "minimal", "(", "6", "%", ")", "response", "rate", "of", "23", "%", ",", "with", "responses", "seen", "in", "dexamethasone", "-", "refractory", "disease", ".", "The", "median", "time", "to", "progression", ",", "progression", "-", "free", "survival", "and", "overall", "survival", "for", "combination", "therapy", "was", "4.4", ",", "3.7", "and", "20.4", "months", "respectively", ".", "Haematological", "toxicity", "was", "common", "but", "manageable", ".", "Infections", "occurred", "in", "57", "%", "of", "combination", "-", "treated", "patients", ",", "including", "≥", "grade", "3", "infections", "in", "18", "%", ".", "Further", "study", "of", "siltuximab", "in", "modern", "corticosteroid", "-", "containing", "myeloma", "regimens", "is", "warranted", ",", "with", "special", "attention", "to", "infection", "-", "related", "toxicity", "." ], "offsets": [ 0, 14, 15, 18, 20, 26, 28, 36, 41, 44, 53, 61, 74, 78, 86, 97, 100, 114, 115, 123, 132, 134, 137, 147, 157, 161, 170, 174, 181, 184, 194, 196, 199, 203, 204, 208, 219, 227, 229, 235, 239, 242, 254, 259, 272, 274, 278, 287, 292, 301, 304, 315, 324, 332, 336, 340, 342, 344, 350, 356, 359, 366, 368, 372, 375, 381, 385, 388, 391, 401, 402, 407, 409, 418, 426, 435, 444, 455, 460, 462, 465, 468, 473, 477, 491, 497, 501, 512, 520, 522, 525, 536, 545, 550, 558, 563, 574, 585, 589, 602, 604, 613, 622, 624, 631, 634, 639, 645, 651, 654, 661, 663, 665, 667, 672, 681, 685, 695, 697, 701, 703, 705, 716, 719, 725, 730, 743, 744, 755, 762, 764, 776, 779, 785, 786, 787, 796, 804, 810, 812, 814, 824, 831, 834, 838, 848, 850, 854, 866, 868, 874, 879, 882, 892, 895, 906, 910, 922, 930, 938, 940, 948, 949, 951, 952, 954, 956, 964, 965, 966, 967, 969, 978, 983, 986, 988, 989, 991, 996, 1006, 1011, 1014, 1027, 1028, 1039, 1046, 1048, 1052, 1059, 1064, 1067, 1078, 1080, 1091, 1092, 1097, 1106, 1110, 1118, 1127, 1131, 1143, 1151, 1155, 1158, 1160, 1164, 1168, 1173, 1180, 1192, 1194, 1209, 1218, 1222, 1229, 1233, 1243, 1245, 1256, 1265, 1268, 1270, 1272, 1275, 1286, 1287, 1295, 1303, 1305, 1315, 1317, 1323, 1325, 1336, 1339, 1341, 1342, 1344, 1352, 1358, 1361, 1372, 1375, 1382, 1396, 1397, 1408, 1416, 1425, 1428, 1437, 1439, 1444, 1452, 1462, 1465, 1474, 1475, 1483, 1491 ] }
1e1ef110e6154949bc822e542fff38e2
Which interleukin is blocked by Siltuximab?
{ "tokens": [ "Which", "interleukin", "is", "blocked", "by", "Siltuximab", "?" ], "offsets": [ 0, 6, 18, 21, 29, 32, 42 ] }
{ "text": [ "interleukin-6" ], "char_spans": [ { "start": [ 0 ], "end": [ 12 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 0 ] } ] }
[ "interleukin-6" ]
BioASQ
The efficacy of the BD GeneOhm methicillin-resistant Staphylococcus aureus (MRSA) assay was assessed by analyzing nasal swabs and swabs from other body sites for the presence of MRSA in a low-prevalence area. From 681 patients with a high risk for MRSA carriage, 1,601 specimens were collected and transported in Amies agar. After discordant analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of the BD GeneOhm MRSA assay were 84.3%, 99.2%, 88.4%, and 98.9%, respectively, compared to culture.
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746d6125a1ae4b47b8868da9703ff04b
What is MRSA?
{ "tokens": [ "What", "is", "MRSA", "?" ], "offsets": [ 0, 5, 8, 12 ] }
{ "text": [ "MRSA" ], "char_spans": [ { "start": [ 457, 248, 76, 178 ], "end": [ 460, 251, 79, 181 ] } ], "token_spans": [ { "start": [ 81, 47, 12, 31 ], "end": [ 81, 47, 12, 31 ] } ] }
[ "methicillin-resistant S. aureus", "MRSA" ]
BioASQ
Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.
{ "tokens": [ "Objective", ".", "A", "study", "to", "determine", "if", "addition", "of", "palatal", "petechiae", "to", "Centor", "criteria", "adds", "more", "value", "for", "clinical", "diagnosis", "of", "acute", "strep", "pharyngitis", "in", "children", ".", "Hypothesis", ".", "In", "children", ",", "Centor", "Criteria", "does", "not", "cover", "all", "the", "symptoms", "and", "signs", "of", "acute", "strep", "pharyngitis", ".", "We", "hypothesize", "that", "addition", "of", "palatal", "petechiae", "to", "Centor", "Criteria", "will", "increase", "the", "possibility", "of", "clinical", "diagnosis", "of", "group", "A", "streptococcal", "pharyngitis", "in", "children", ".", "Methods", ".", "One", "hundred", "patients", "with", "a", "complaint", "of", "sore", "throat", "were", "enrolled", "in", "the", "study", ".", "All", "the", "patients", "were", "examined", "clinically", "using", "the", "Centor", "Criteria", ".", "They", "were", "also", "examined", "for", "other", "signs", "and", "symptoms", "like", "petechial", "lesions", "over", "the", "palate", ",", "abdominal", "pain", ",", "and", "skin", "rash", ".", "All", "the", "patients", "were", "given", "rapid", "strep", "tests", ",", "and", "throat", "cultures", "were", "sent", ".", "No", "antibiotics", "were", "given", "until", "culture", "results", "were", "obtained", ".", "Results", ".", "The", "sample", "size", "was", "100", "patients", ".", "All", "100", "had", "fever", ",", "sore", "throat", ",", "and", "erythema", "of", "tonsils", ".", "Twenty", "of", "the", "100", "patients", "had", "tonsillar", "exudates", ",", "85/100", "had", "tender", "anterior", "cervical", "lymph", "nodes", ",", "and", "86/100", "had", "no", "cough", ".", "In", "total", ",", "9", "out", "of", "the", "100", "patients", "had", "positive", "throat", "cultures", ".", "We", "observed", "that", "petechiae", "over", "the", "palate", ",", "a", "very", "significant", "sign", ",", "is", "not", "included", "in", "the", "Centor", "Criteria", ".", "Palatal", "petechiae", "were", "present", "in", "8", "out", "of", "the", "100", "patients", ".", "Six", "out", "of", "these", "8", "with", "palatal", "petechiae", "had", "positive", "throat", "culture", "for", "strep", "(", "75", "%", ")", ".", "Only", "7", "out", "of", "20", "with", "exudates", "had", "positive", "strep", "culture", ".", "Sixteen", "out", "of", "the", "100", "patients", "had", "rapid", "strep", "test", "positive", ".", "Those", "84/100", "who", "had", "negative", "rapid", "strep", "also", "had", "negative", "throat", "culture", ".", "Statistics", ".", "We", "used", "Fisher", "'s", "exact", "test", ",", "comparing", "throat", "culture", "positive", "and", "negative", "versus", "presence", "of", "exudates", "and", "palatal", "hemorrhages", "with", "positive", "and", "negative", "throat", "cultures", "and", "the", "resultant", "P", "value", "<", ".0001", ".", "Conclusion", ".", "Our", "study", "concludes", "that", "addition", "of", "petechiae", "over", "the", "palate", "to", "Centor", "Criteria", "will", "increase", "the", "possibility", "of", "diagnosing", "acute", "group", "A", "streptococcal", "pharyngitis", "in", "children", "." ], "offsets": [ 0, 9, 11, 13, 19, 22, 32, 35, 44, 47, 55, 65, 68, 75, 84, 89, 94, 100, 104, 113, 123, 126, 132, 138, 150, 153, 161, 163, 173, 175, 178, 186, 188, 195, 204, 209, 213, 219, 223, 227, 236, 240, 246, 249, 255, 261, 272, 274, 277, 289, 294, 303, 306, 314, 324, 327, 334, 343, 348, 357, 361, 373, 376, 385, 395, 398, 404, 406, 420, 432, 435, 443, 445, 452, 454, 458, 466, 475, 480, 482, 492, 495, 500, 507, 512, 521, 524, 528, 533, 535, 539, 543, 552, 557, 566, 577, 583, 587, 594, 602, 604, 609, 614, 619, 628, 632, 638, 644, 648, 657, 662, 672, 680, 685, 689, 695, 697, 707, 711, 713, 717, 722, 726, 728, 732, 736, 745, 750, 756, 762, 768, 773, 775, 779, 786, 795, 800, 804, 806, 809, 821, 826, 832, 838, 846, 854, 859, 867, 869, 876, 878, 882, 889, 894, 898, 902, 910, 912, 916, 920, 924, 929, 931, 936, 942, 944, 948, 957, 960, 967, 969, 976, 979, 983, 987, 996, 1000, 1010, 1018, 1020, 1027, 1031, 1038, 1047, 1056, 1062, 1067, 1069, 1073, 1080, 1084, 1087, 1092, 1094, 1097, 1102, 1104, 1106, 1110, 1113, 1117, 1121, 1130, 1134, 1143, 1150, 1158, 1160, 1163, 1172, 1177, 1187, 1192, 1196, 1202, 1204, 1206, 1211, 1223, 1227, 1229, 1232, 1236, 1245, 1248, 1252, 1259, 1267, 1269, 1277, 1287, 1292, 1300, 1303, 1305, 1309, 1312, 1316, 1320, 1328, 1330, 1334, 1338, 1341, 1347, 1349, 1354, 1362, 1372, 1376, 1385, 1392, 1400, 1404, 1410, 1411, 1413, 1414, 1415, 1417, 1422, 1424, 1428, 1431, 1434, 1439, 1448, 1452, 1461, 1467, 1474, 1476, 1484, 1488, 1491, 1495, 1499, 1508, 1512, 1518, 1524, 1529, 1537, 1539, 1545, 1552, 1556, 1560, 1569, 1575, 1581, 1586, 1590, 1599, 1606, 1613, 1615, 1625, 1627, 1630, 1635, 1641, 1644, 1650, 1654, 1656, 1666, 1673, 1681, 1690, 1694, 1703, 1710, 1719, 1722, 1731, 1735, 1743, 1755, 1760, 1769, 1773, 1782, 1789, 1798, 1802, 1806, 1816, 1818, 1824, 1825, 1830, 1832, 1842, 1844, 1848, 1854, 1864, 1869, 1878, 1881, 1891, 1896, 1900, 1907, 1910, 1917, 1926, 1931, 1940, 1944, 1956, 1959, 1970, 1976, 1982, 1984, 1998, 2010, 2013, 2021 ] }
345cc6f39eb0472ebb37229e6f4e34b1
Centor criteria are used for which disease?
{ "tokens": [ "Centor", "criteria", "are", "used", "for", "which", "disease", "?" ], "offsets": [ 0, 7, 16, 20, 25, 29, 35, 42 ] }
{ "text": [ "streptococcal pharyngitis" ], "char_spans": [ { "start": [ 1984, 406 ], "end": [ 2008, 430 ] } ], "token_spans": [ { "start": [ 356, 67 ], "end": [ 357, 68 ] } ] }
[ "streptococcal pharyngitis" ]
BioASQ
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients. Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis. Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet. CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML. However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML. In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors. A critical issue to resolve this problem is to fully understand the biology of LSCs, and to identify key genes that play significant roles in survival and self-renewal of LSCs. In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.
{ "tokens": [ "Chronic", "myeloid", "leukemia", "(", "CML", ")", "is", "a", "myeloproliferative", "disease", "characterized", "by", "the", "overproduction", "of", "granulocytes", ",", "which", "leads", "to", "high", "white", "blood", "cell", "counts", "and", "splenomegaly", "in", "patients", ".", "Based", "on", "clinical", "symptoms", "and", "laboratory", "findings", ",", "CML", "is", "classified", "into", "three", "clinical", "phases", ",", "often", "starting", "with", "a", "chronic", "phase", ",", "progressing", "to", "an", "accelerated", "phase", "and", "ultimately", "ending", "in", "a", "terminal", "phase", "called", "blast", "crisis", ".", "Blast", "crisis", "phase", "of", "CML", "is", "clinically", "similar", "to", "an", "acute", "leukemia", ";", "in", "particular", ",", "B", "-", "cell", "acute", "lymphoblastic", "leukemia", "(", "B", "-", "ALL", ")", "is", "a", "severe", "form", "of", "acute", "leukemia", "in", "blast", "crisis", ",", "and", "there", "is", "no", "effective", "therapy", "for", "it", "yet", ".", "CML", "is", "induced", "by", "the", "BCR", "-", "ABL", "oncogene", ",", "whose", "gene", "product", "is", "a", "BCR", "-", "ABL", "tyrosine", "kinase", ".", "Currently", ",", "inhibition", "of", "BCR", "-", "ABL", "kinase", "activity", "by", "its", "kinase", "inhibitor", "such", "as", "imatinib", "mesylate", "(", "Gleevec", ")", "is", "a", "major", "therapeutic", "strategy", "for", "CML", ".", "However", ",", "the", "inability", "of", "BCR", "-", "ABL", "kinase", "inhibitors", "to", "completely", "kill", "leukemia", "stem", "cells", "(", "LSCs", ")", "indicates", "that", "these", "kinase", "inhibitors", "are", "unlikely", "to", "cure", "CML", ".", "In", "addition", ",", "drug", "resistance", "due", "to", "the", "development", "of", "BCRABL", "mutations", "occurs", "before", "and", "during", "treatment", "of", "CML", "with", "kinase", "inhibitors", ".", "A", "critical", "issue", "to", "resolve", "this", "problem", "is", "to", "fully", "understand", "the", "biology", "of", "LSCs", ",", "and", "to", "identify", "key", "genes", "that", "play", "significant", "roles", "in", "survival", "and", "self", "-", "renewal", "of", "LSCs", ".", "In", "this", "review", ",", "we", "will", "focus", "on", "LSCs", "in", "CML", "by", "summarizing", "and", "discussing", "available", "experimental", "results", ",", "including", "the", "original", "studies", "from", "our", "own", "laboratory", "." ], "offsets": [ 0, 8, 16, 25, 26, 29, 31, 34, 36, 55, 63, 77, 80, 84, 99, 102, 114, 116, 122, 128, 131, 136, 142, 148, 153, 160, 164, 177, 180, 188, 190, 196, 199, 208, 217, 221, 232, 240, 242, 246, 249, 260, 265, 271, 280, 286, 288, 294, 303, 308, 310, 318, 323, 325, 337, 340, 343, 355, 361, 365, 376, 383, 386, 388, 397, 403, 410, 416, 422, 424, 430, 437, 443, 446, 450, 453, 464, 472, 475, 478, 484, 492, 494, 497, 507, 509, 510, 511, 516, 522, 536, 545, 546, 547, 548, 551, 553, 556, 558, 565, 570, 573, 579, 588, 591, 597, 603, 605, 609, 615, 618, 621, 631, 639, 643, 646, 649, 651, 655, 658, 666, 669, 673, 676, 677, 681, 689, 691, 697, 702, 710, 713, 715, 718, 719, 723, 732, 738, 740, 749, 751, 762, 765, 768, 769, 773, 780, 789, 792, 796, 803, 813, 818, 821, 830, 839, 840, 847, 849, 852, 854, 860, 872, 881, 885, 888, 890, 897, 899, 903, 913, 916, 919, 920, 924, 931, 942, 945, 956, 961, 970, 975, 981, 982, 986, 988, 998, 1003, 1009, 1016, 1027, 1031, 1040, 1043, 1048, 1051, 1053, 1056, 1064, 1066, 1071, 1082, 1086, 1089, 1093, 1105, 1108, 1115, 1125, 1132, 1139, 1143, 1150, 1160, 1163, 1167, 1172, 1179, 1189, 1191, 1193, 1202, 1208, 1211, 1219, 1224, 1232, 1235, 1238, 1244, 1255, 1259, 1267, 1270, 1274, 1276, 1280, 1283, 1292, 1296, 1302, 1307, 1312, 1324, 1330, 1333, 1342, 1346, 1350, 1351, 1359, 1362, 1366, 1368, 1371, 1376, 1382, 1384, 1387, 1392, 1398, 1401, 1406, 1409, 1413, 1416, 1428, 1432, 1443, 1453, 1466, 1473, 1475, 1485, 1489, 1498, 1506, 1511, 1515, 1519, 1529 ] }
eb81aaa1e4b44724821213505ab1015b
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
{ "tokens": [ "What", "tyrosine", "kinase", ",", "involved", "in", "a", "Philadelphia-", "chromosome", "positive", "chronic", "myelogenous", "leukemia", ",", "is", "the", "target", "of", "Imatinib", "(", "Gleevec", ")", "?" ], "offsets": [ 0, 5, 14, 20, 22, 31, 34, 36, 50, 61, 70, 78, 90, 98, 100, 103, 107, 114, 117, 126, 127, 134, 135 ] }
{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 765, 715, 673, 916 ], "end": [ 771, 721, 679, 922 ] } ], "token_spans": [ { "start": [ 142, 132, 122, 171 ], "end": [ 144, 134, 124, 173 ] } ] }
[ "BCR-ABL" ]
BioASQ
SECIS elements are stem-loop structures located in the 3' untranslated regions (UTRs) of eukaryotic selenoprotein mRNAs that are required for directing cotranslational selenocysteine incorporation at UGA codons. In prokaryotes, stem-loops mediating selenocysteine incorporation are located immediately downstream of the UGA selenocysteine codon, in the coding region. Previous characterization studies of the mammalian SECIS elements of type 1 deiodinase, glutathione peroxidase, and selenoprotein P showed that conserved nucleotides in the loops and unpaired bulges, and base pairing in the stems are required for SECIS function. These initial studies utilized approximately 175-230-nt segments of the 3'UTRs of the selenoprotein mRNAs. Here we define the minimal functional rat type 1 deiodinase SECIS element, a 45-nt segment, the 5' boundary of which corresponds precisely to the 5'-most critical conserved nucleotide identified previously. We also define base pairing requirements in the stem of this element. In view of the presence of SECIS elements in the open reading frames (ORFs) of bacterial selenoproteins, we examine the effects in the type 1 deiodinase of extending the ORF into the SECIS element, and find that this dramatically inhibits SECIS function. Finally, we define a minimal spacing requirement of 51-111 nt between a eukaryotic UGA selenocysteine codon and SECIS element.
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5798e357ab44416ea1ecd5323e3e7ae4
What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?
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[ "SECIS" ]
BioASQ
(i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65. Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis. The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR-pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone. The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR-pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation.
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4a5e280ba4534d708cd9a706f914288a
CURB65 score is used for stratification of which disease?
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[ "pneumonia" ]
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