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Experimental Drug Improves Memory in Mice Models of Multiple Sclerosis

By MedImaging International staff writers
Posted on 05 Dec 2012

Investigators have reported the effective use of a form of magnetic resonance imaging (MRI) to identify what appears to be a key biochemical marker for cognitive impairment in the brains of individuals with multiple sclerosis (MS). More...

In follow-up research on mice with a rodent form of MS, researchers were able to use an experimental agent to modify that same marker, which resulted in greatly improving learning and memory.

Half of people with MS experience learning and memory difficulties—for which there is no approved treatment—along with movement abnormalities that characterize the debilitating autoimmune disorder. “We have a potentially novel treatment for cognitive impairment in MS, a devastating condition on the rise that affects at least 400,000 people in the United States,” said study leader Adam I. Kaplin, MD, PhD, an assistant professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine (Baltimore, MD, USA).

Dr. Kaplin warned that the treatment has so far been used only in mouse models of MS and is years away from clinical trials in people. Nevertheless, he noted, the research, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) published online in November 2012, has the potential to speed development of new drugs to treat cognitive impairment not only in MS patients, but also in patients with Alzheimer’s disease and other neurologic disorders.

MRI scan of brain lesions can frequently reveal how much damage the disease is doing to the brain, and those findings often correlate with physical disability. However, until now, according to Dr. Kaplin, there has been no way to link these image findings with cognitive impairment. For the study, Dr. Kaplin and his colleagues employed magnetic resonance spectroscopy (MRS), which uses conventional MRI scanners but adds tests to identify and compare various brain chemicals found on the images. The Johns Hopkins investigators performed the tests on nine occasions on the brains of subjects with MS, focusing on the hippocampus, looking at levels of various brain chemicals.

Levels of the neurotransmitter N-acetylaspartylglutamate (NAAG), the most plentiful peptide transmitter in the brain, stood out. At the same time patients came in for their MRI scan, they completed eight different cognitive tests. The researchers found a strong correlation between levels of NAAG in the right hippocampus and performance on six of the eight cognitive tests. The lower the levels of NAAG, the worse the subjects performed.

Dr. Kaplin noted that the availability of stronger MRI magnets in recent years made the NAAG-related findings possible. Buoyed by the strength of the correlation, Dr. Kaplin and his coworkers set about determining if the findings were more than incidental.

Dr. Kaplin then contacted Barbara S. Slusher, PhD, MAS, director of the Johns Hopkins Brain Science Institute NeuroTranslational Drug Discovery Program, who has spent years studying NAAG and its metabolism in the brain. Slusher and her colleagues had identified novel drugs that could block the breakdown of NAAG into its component parts by inhibiting the enzyme glutamate carboxypeptidase II (GCPII), including 2-PMPA. “For years, this has been a treatment in search of a disease,” Dr. Slusher stated.

Teaming up with Kristen A. Rahn, PhD, a psychiatry instructor at the Johns Hopkins University School of Medicine, the researchers bred mice with the rodent version of MS and treated them with 2-PMPA. “Before we could even consider progressing to human trials with this class of drugs, the key was to show that the finding of reduced NAAG in the brains of MS patients was causally related to, and not just correlated with, their cognitive impairment, and to do this we needed to test this out in an animal model of MS,” Dr. Rahn noted.

The scientists discovered that 2-PMPA was able to increase the NAAG levels in the MS mice close to those of a comparative set of mice without the disease. Although the mice still showed physical signs of MS, such as dragging limbs and an inability to run quickly, their learning and memory improved significantly.

To evaluate learning and memory, the mice were positioned in a maze with one escape hatch but a lot of dead ends. On day 1, all of the mice meandered bout and could not find the right escape hole. By day 4, healthy mice and mice with MS given 2-PMPA went directly to the escape hole. They were able to find the hole twice as quickly as those mice with MS but no drug.

The mice also were assessed for fear conditioning, a marker for memory. On day 1, a tone was played and then the mice were given a mild shock. Four days later, the researchers discovered that the healthy control mice and mice with MS given 2-PMPA froze in fear much longer when they heard the tone than other mice with untreated MS, signifying a stronger memory.

Dr. Kaplin reported that, historically, researchers have considered potential MS agents to be failures if they did not lessen physical symptoms in the mouse model. However, whereas 2-PMPA did not reduce physical disability, it is worth pursuing as a treatment for its extraordinary capacity for improving memory and learning.

Dr. Kaplin hopes that pharmaceutical companies will have a renewed interest in the development of drugs such as 2-PMPA for cognition improvement in MS and perhaps other neurodegenerative disorders. Because 2-PMPA is not orally active, the researchers are working on new nanotechnology-based delivery systems to get the agent to the brain. Moreover, Dr. Slusher is collaborating with the pharmaceutical company Eisai, Inc. (Woodcliff Lake, NJ, USA) to develop new drugs that could be taken orally.
“We are encouraged that there could be a way to enhance cognition in people with MS,” Dr. Kaplin concluded. “It’s something these patients desperately need.”

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Johns Hopkins University School of Medicine

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46 (175.95291137695): select journal.name,journal.id,dpcat.livesite,journal.code from jos_dp_categories dpcat join jos_journal journal on journal.id=dpcat.journalid where dpcat.id=10

47 (179.05235290527): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

48 (80.82389831543): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

49 (102.99682617188): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

50 (!!!!! 1867.0558929443): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

51 (138.0443572998): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

52 (74.863433837891): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

53 (!!!!! 1850.8434295654): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

54 (151.15737915039): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

55 (355.95893859863): SELECT name FROM jos_deeppockets WHERE id=294743682 LIMIT 1

56 (209.09309387207): SELECT name FROM jos_deeppockets_archive WHERE id=294743682 LIMIT 1

57 (85.830688476562): SELECT a.* FROM jos_components AS a WHERE ( a.admin_menu_link = 'option=com_syndicate' OR a.admin_menu_link = 'option=com_syndicate&hidemainmenu=1' ) AND a.option = 'com_syndicate'

58 (99.897384643555): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

59 (972.03254699707): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

60 (!!!!! 1785.9935760498): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

61 (101.08947753906): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

62 (182.15179443359): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

63 (74.863433837891): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

64 (151.8726348877): select cover from jos_number where journalid in (5) and cover is not null order by left(issue,2)+right(issue,2)*12 desc limit 1

65 (592.94700622559): SELECT fid FROM jos_deeppockets WHERE id=294743682 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294743682 AND published='1' LIMIT 1

66 (92.983245849609): SELECT id,name,sponsor_text FROM jos_deeppockets dp left outer join jos_channel_sponsor cs on dp.id=cs.fid WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id=212 ORDER BY `ordering`

67 (87.02278137207): select jos_twitters.link from jos_twitters where cat=10

68 (41.961669921875): select jos_facebook.link from jos_facebook where cat=10

69 (49.114227294922): select jos_google_plus.link from jos_google_plus where cat=10

70 (40.054321289062): select jos_linkedin.link from jos_linkedin where cat=10

71 (52.928924560547): SELECT fid FROM jos_deeppockets WHERE id=294743682 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294743682 AND published='1' LIMIT 1

72 (64.13459777832): SELECT id,name,sponsor_text FROM jos_deeppockets dp left outer join jos_channel_sponsor cs on dp.id=cs.fid WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id=212 ORDER BY `ordering`

73 (407.93418884277): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

74 (314.95094299316): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

75 (100.85105895996): SELECT id,name,title FROM jos_deeppockets WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id != 294743300 AND id != 294743301 AND id != 294743302 AND id != 294743303 AND id != 294743304 AND id != 294743305 AND id != 294743306 AND id != 294743307 AND id != 294743308 AND id != 294743309 AND id != 294743310 AND metakey != 'aacc' ORDER BY `ordering`

76 (84.161758422852): SELECT show_live FROM jos_com_show_setting LIMIT 1

77 (49.114227294922): SELECT show_live FROM jos_com_show_setting LIMIT 1

78 (44.822692871094): SELECT show_live FROM jos_com_show_setting LIMIT 1

79 (39.815902709961): SELECT show_live FROM jos_com_show_setting LIMIT 1

80 (41.007995605469): SELECT show_live FROM jos_com_show_setting LIMIT 1

81 (40.054321289062): SELECT show_live FROM jos_com_show_setting LIMIT 1

82 (44.107437133789): SELECT show_live FROM jos_com_show_setting LIMIT 1

83 (41.007995605469): SELECT show_live FROM jos_com_show_setting LIMIT 1

84 (41.007995605469): SELECT show_live FROM jos_com_show_setting LIMIT 1

85 (39.100646972656): SELECT show_live FROM jos_com_show_setting LIMIT 1

86 (41.007995605469): SELECT show_live FROM jos_com_show_setting LIMIT 1

87 (39.100646972656): SELECT show_live FROM jos_com_show_setting LIMIT 1

88 (43.869018554688): SELECT show_live FROM jos_com_show_setting LIMIT 1

89 (37.908554077148): SELECT show_live FROM jos_com_show_setting LIMIT 1

90 (93.936920166016): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

91 (45.061111450195): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

92 (49.829483032227): SELECT id,name,title FROM jos_deeppockets WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id != 294743300 AND id != 294743301 AND id != 294743302 AND id != 294743303 AND id != 294743304 AND id != 294743305 AND id != 294743306 AND id != 294743307 AND id != 294743308 AND id != 294743309 AND id != 294743310 AND metakey != 'aacc' ORDER BY `ordering`

93 (91.075897216797): SELECT show_live FROM jos_com_show_setting LIMIT 1

94 (46.968460083008): SELECT show_live FROM jos_com_show_setting LIMIT 1

95 (44.107437133789): SELECT show_live FROM jos_com_show_setting LIMIT 1

96 (38.862228393555): SELECT show_live FROM jos_com_show_setting LIMIT 1

97 (41.007995605469): SELECT show_live FROM jos_com_show_setting LIMIT 1

98 (38.14697265625): SELECT show_live FROM jos_com_show_setting LIMIT 1

99 (40.054321289062): SELECT show_live FROM jos_com_show_setting LIMIT 1

100 (39.100646972656): SELECT show_live FROM jos_com_show_setting LIMIT 1

101 (40.054321289062): SELECT show_live FROM jos_com_show_setting LIMIT 1

102 (37.908554077148): SELECT show_live FROM jos_com_show_setting LIMIT 1

103 (40.054321289062): SELECT show_live FROM jos_com_show_setting LIMIT 1

104 (38.862228393555): SELECT show_live FROM jos_com_show_setting LIMIT 1

105 (42.915344238281): SELECT show_live FROM jos_com_show_setting LIMIT 1

106 (40.054321289062): SELECT show_live FROM jos_com_show_setting LIMIT 1

107 (112.05673217773): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

108 (63.896179199219): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

109 (106.0962677002): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

110 (72.956085205078): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

111 (114.20249938965): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

112 (67.949295043945): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

113 (493.04962158203): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

114 (475.16822814941): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

115 (82.969665527344): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294743681 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

116 (434.87548828125): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294743681 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

117 (895.02334594727): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1

118 (612.02049255371): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1

119 (118.01719665527): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

120 (66.995620727539): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

121 (85.830688476562): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

122 (59.127807617188): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

123 (74.148178100586): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

124 (52.928924560547): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

125 (75.817108154297): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

126 (51.021575927734): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

127 (354.05158996582): SELECT * FROM trending_articles WHERE `journal_id` = 10 AND `timestamp` <= NOW() + INTERVAL 7 DAY ORDER BY `order`

128 (!!!!! 94892.978668213): SELECT * FROM jos_deeppockets WHERE jos_deeppockets.cat = 10 AND jos_deeppockets.type = 'deeppockets_item' AND jos_deeppockets.published = 1 AND jos_deeppockets.created + INTERVAL 14 DAY >= NOW() ORDER BY jos_deeppockets.hits DESC LIMIT 7

129 (756.97898864746): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294743682 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294743682 AND type='deeppockets_item' AND published='1' LIMIT 1

130 (!!!!! 25075.912475586): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3

131 (247.00164794922): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3

132 (209.09309387207): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1

133 (253.91578674316): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1

134 (474.92980957031): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1

135 (146.15058898926): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1

136 (512.83836364746): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1

137 (!!!!! 8965.9690856934): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1

138 (118.97087097168): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1

139 (53.882598876953): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1

140 (540.97175598145): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

141 (432.01446533203): SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

142 (67.949295043945): SELECT name FROM jos_deeppockets WHERE id=212

143 (45.061111450195): SELECT name FROM jos_deeppockets WHERE id=212

144 (830.17349243164): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))212((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3

145 (801.08642578125): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))212((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3

146 (99.18212890625): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

147 (66.995620727539): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

148 (!!!!! 8507.0133209229): TRUNCATE TABLE jos_trademed_module

149 (!!!!! 1810.0738525391): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

150 (143.05114746094): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294743682 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

151 (518.0835723877): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

152 (244.8558807373): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

153 (!!!!! 1209.9742889404): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

154 (104.90417480469): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

155 (!!!!! 1742.1245574951): SELECT jos_item.* FROM jos_item INNER JOIN jos_number ON jos_item.numberID=jos_number.id WHERE 1=1 AND (jos_item.imgMini<>'') AND jos_item.type='L' AND jos_item.numberID= ( SELECT jos_number.id FROM jos_number WHERE jos_number.journalID IN (10) and jos_number.id in (select distinct jos_number.id from jos_number join jos_item on jos_item.numberid=jos_number.id where jos_item.type='P') ORDER BY (CONVERT(SUBSTRING(issue,1,2),SIGNED) + (CONVERT(SUBSTRING(issue,3,2),SIGNED)*100)) DESC LIMIT 0,1 ) ORDER BY RAND() DESC LIMIT 6

156 (91.075897216797): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

157 (63.180923461914): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294743682 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294743682 AND published='1' LIMIT 1

158 (71.048736572266): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294743682 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294743682 AND type='deeppockets_item' AND published='1' LIMIT 1

159 (49.829483032227): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=0 or channel_id is null)

160 (41.007995605469): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=0 or channel_id is null)

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