1
00:00:05,185 --> 00:00:07,554
OKAY. LET'S GO AHEAD
AND GET

2
00:00:07,554 --> 00:00:09,256
STARTED. THANK YOU ALL FOR BEING

3
00:00:09,256 --> 00:00:11,625
HERE AND ALSO FOR ALL OF YOU WHO

4
00:00:11,625 --> 00:00:14,127
ARE ATTENDING VIRTUALLY. WELCOME

5
00:00:14,127 --> 00:00:17,397
TO THE CLINICO PATHOLOGIC GRAND

6
00:00:17,397 --> 00:00:18,331
ROUNDS OF THE 9TH CLINICAL

7
00:00:18,331 --> 00:00:20,901
CENTER. A SERIES THAT IS MEANT

8
00:00:20,901 --> 00:00:23,203
TO REALLY HIGHLIGHT VERY

9
00:00:23,203 --> 00:00:24,304
INTERESTING CLINICAL CASES AS

10
00:00:24,304 --> 00:00:27,908
YOU WILL SEE TODAY BUT ALSO IN

11
00:00:27,908 --> 00:00:33,213
THE BROADER SCHEME, VERY

12
00:00:33,213 --> 00:00:34,748
INTERESTING AND MONUMENT

13
00:00:34,748 --> 00:00:36,450
CHANGING, I DON'T THINK THAT'S

14
00:00:36,450 --> 00:00:40,353
ANYTHING WRONG YET. BUT MIND

15
00:00:40,353 --> 00:00:41,621
CHANGING RESEARCH CLINICAL

16
00:00:41,621 --> 00:00:43,924
RESEARCH PROGRAMS THAT I THINK

17
00:00:43,924 --> 00:00:46,960
THIS CASE TODAY HIGHLIGHTS BOTH

18
00:00:46,960 --> 00:00:49,796
AT THE HIGHEST LEVEL. WE WILL

19
00:00:49,796 --> 00:00:51,731
HEAR TODAY ABOUT

20
00:00:51,731 --> 00:00:52,966
HYPERPHOSPHATEMIC FAMILIAL

21
00:00:52,966 --> 00:00:54,835
TUMORAL CALCINOSIS AND DEFINING

22
00:00:54,835 --> 00:00:56,269
PATHOMECHANISMS FOR TREATMENT. 

23
00:00:56,269 --> 00:00:59,406
WE HAVE A GREAT ROSTER OF

24
00:00:59,406 --> 00:01:01,341
SPEAKERS, MIKE COLLINS HEAD OF

25
00:01:01,341 --> 00:01:03,610
THE SKELETAL DISORDERS AND

26
00:01:03,610 --> 00:01:06,079
MINERAL HOMEOSTASIS SECTION

27
00:01:06,079 --> 00:01:08,748
NIDCR. DR. ROSZKO, A RESEARCH

28
00:01:08,748 --> 00:01:11,751
PHYSICIAN AT THE SAME SECTION AT

29
00:01:11,751 --> 00:01:14,287
NIDCR. WE WILL SEE RADIOLOGY

30
00:01:14,287 --> 00:01:16,156
FROM DR. SABOURY FROM THE

31
00:01:16,156 --> 00:01:18,158
RADIOLOGY AND IMAGING SCIENCES

32
00:01:18,158 --> 00:01:21,128
AT THE NIH CLINICAL CENTER. WE

33
00:01:21,128 --> 00:01:22,996
WILL HEAR FROM DR. KLEINER, HEAD

34
00:01:22,996 --> 00:01:25,398
OF THE HISTOPATHOLOGY AND

35
00:01:25,398 --> 00:01:28,101
AUTOPSY PATHOLOGY SECTION AT THE

36
00:01:28,101 --> 00:01:30,003
NCI FOR THE PATHOLOGY FINDINGS.

37
00:01:30,003 --> 00:01:31,771
AND THEN WE WILL ALSO HEAR FROM

38
00:01:31,771 --> 00:01:35,642
DR. GOURH, ASSISTANT CLINICAL

39
00:01:35,642 --> 00:01:37,878
INVESTIGATOR HEAD OF SCLERODERMA

40
00:01:37,878 --> 00:01:39,946
GENOME EX AND HEALTH DISPARITIES

41
00:01:39,946 --> 00:01:41,148
UNIT AT NATIONAL INSTITUTE OF

42
00:01:41,148 --> 00:01:42,883
MINORITY HEALTH AND HEALTH

43
00:01:42,883 --> 00:01:44,317
DISPARITIES.  THE LAST THING I

44
00:01:44,317 --> 00:01:45,685
WILL SAY BEFORE WE START YOU

45
00:01:45,685 --> 00:01:49,089
WILL SEE ON THE SCREEN THE PHONE

46
00:01:49,089 --> 00:01:50,924
CALL -- PHONE NUMBER NEEDED IN

47
00:01:50,924 --> 00:01:54,461
ORDER TO OBTAIN CME FOR TODAY

48
00:01:54,461 --> 00:01:59,132
AND THE CME CODE IS 50533. 

49
00:01:59,132 --> 00:02:03,803
50533. WE HAVE ALSO DONE

50
00:02:03,803 --> 00:02:05,805
THOROUGH EVALUATION OF THE

51
00:02:05,805 --> 00:02:07,174
LIGHTS IN ROOM AND WE ARE READY

52
00:02:07,174 --> 00:02:15,749
TO GET STARTED. MIKE.

53
00:02:15,749 --> 00:02:17,884
>> THANK YOU FOR YOUR

54
00:02:17,884 --> 00:02:18,919
INTRODUCTION. I HAVE BEEN

55
00:02:18,919 --> 00:02:25,192
CHARGED WITH PRESENTING THE CASE

56
00:02:25,192 --> 00:02:27,327
WHICH I WILL GO RIGHT INTO. SO

57
00:02:27,327 --> 00:02:29,029
THIS NOW 42-YEAR-OLD MAN FIRST

58
00:02:29,029 --> 00:02:31,565
CAME TO THE NIH IN 2011 AT THE

59
00:02:31,565 --> 00:02:33,233
AGE OF 21. HE WAS ONE OF THE

60
00:02:33,233 --> 00:02:34,367
FIRST PATIENTS WITH THIS

61
00:02:34,367 --> 00:02:37,437
CONDITION THAT WE SAW. HIS

62
00:02:37,437 --> 00:02:39,339
PERTINENT MEDICAL HISTORY

63
00:02:39,339 --> 00:02:41,107
STARTED AROUND AGE 10 WHEN HE

64
00:02:41,107 --> 00:02:43,143
DEVELOPED BILATERAL SHIN PAIN

65
00:02:43,143 --> 00:02:50,050
AND ON X-RAY HAD DIAPHYSEAL

66
00:02:50,050 --> 00:02:51,851
THICKENING SUGGESTIVE OF OSTEO

67
00:02:51,851 --> 00:02:54,821
MYELITIS. AT 14 HE NOTICE AD 2

68
00:02:54,821 --> 00:02:56,890
BY 2 SOFT PAINFUL RED WATCH

69
00:02:56,890 --> 00:03:00,260
LUNCH OVER HIS HIP, THIS GREW 6

70
00:03:00,260 --> 00:03:02,262
MONTHS TO 17-CENTIMETERS

71
00:03:02,262 --> 00:03:04,164
RESECTED AT AGE 15, IT

72
00:03:04,164 --> 00:03:07,968
IMMEDIATELY RECURRED AND HAD

73
00:03:07,968 --> 00:03:10,203
MULTIPLE RESECTIONS SINCE. HE

74
00:03:10,203 --> 00:03:11,638
DEVELOPED MULTIPLE LARGE PAINFUL

75
00:03:11,638 --> 00:03:13,907
LEAGUES THAT YOU SEE HERE ON HIS

76
00:03:13,907 --> 00:03:18,044
SHOULDERS, HANDS, HE ELBOWS AN

77
00:03:18,044 --> 00:03:22,916
HIPS.S.  LESIONS WOULD LEAK A

78
00:03:22,916 --> 00:03:24,150
THICK WHITE LIQUIDITY CALLED

79
00:03:24,150 --> 00:03:26,820
MILK OF CALCIUM. THE BIGGEST

80
00:03:26,820 --> 00:03:28,922
PROBLEM WAS CHRONIC DEBILITATING

81
00:03:28,922 --> 00:03:30,257
PAIN AND PROGRESSIVE LOSS OF

82
00:03:30,257 --> 00:03:32,692
FUNCTIFUNCTION. SO THIS CAN BE A

83
00:03:32,692 --> 00:03:33,927
DEVASTATING DISEASE AND HE HAD A

84
00:03:33,927 --> 00:03:35,895
VERY DIFFICULT COURSE WITH THIS 

85
00:03:35,895 --> 00:03:37,731
HIS PERTINENT FAMILY HISTORY,

86
00:03:37,731 --> 00:03:39,933
HIS PARENTS ARE FIRST COUSINS,

87
00:03:39,933 --> 00:03:42,369
NOT INFECTED.  THREE OF SEVEN

88
00:03:42,369 --> 00:03:44,471
SIBLINGS HAVE SIMILAR BUT LESS

89
00:03:44,471 --> 00:03:46,806
SEVERE FINDINGS AS DOES HE. HE

90
00:03:46,806 --> 00:03:48,508
RESIDES IN SAUDI ARABIA BUT IS

91
00:03:48,508 --> 00:03:50,710
NOT A CITIZEN AND HAS NO HEALTH

92
00:03:50,710 --> 00:03:54,648
INSURANCE UNFORTUNATELY. HIS

93
00:03:54,648 --> 00:03:56,783
PERTINENT LABORATORY VALUES AT

94
00:03:56,783 --> 00:03:58,551
PRESENTATION ARE THAT HE HAD AN

95
00:03:58,551 --> 00:04:00,987
ELEVATED BLOOD PHOSPHATE, HIS

96
00:04:00,987 --> 00:04:03,757
BLOOD CALCIUM WAS UPPER LIMIT

97
00:04:03,757 --> 00:04:06,126
NORMAL ELEVATED CALCIUM TIMES

98
00:04:06,126 --> 00:04:07,427
PHOSPHATE PRODUCT. HIS KIDNEY

99
00:04:07,427 --> 00:04:09,529
FUNCTION WAS NORMAL WHEN HE

100
00:04:09,529 --> 00:04:13,400
FIRST CAME. HIS 125 DIHYDROXY

101
00:04:13,400 --> 00:04:15,735
VITAMIN D, THE ACTIVE FORM WAS

102
00:04:15,735 --> 00:04:18,038
ELEVATED, PARATHYROID HORMONE

103
00:04:18,038 --> 00:04:20,473
LOW NORMAL. C REACTIVE PROTEIN A

104
00:04:20,473 --> 00:04:23,343
MEASURE OF INFLAMMATION WAS

105
00:04:23,343 --> 00:04:25,345
ELEVATED. YOU WILL LEARN MORE

106
00:04:25,345 --> 00:04:28,014
ABOUT THE LOW INTACT FGF 23 AND

107
00:04:28,014 --> 00:04:30,617
HIGH C TERMINAL FGF 23 IN A

108
00:04:30,617 --> 00:04:32,952
LITTLE BIT FROM DR. ROSZKO WHEN

109
00:04:32,952 --> 00:04:34,454
SHE GOES OVER THE

110
00:04:34,454 --> 00:04:36,056
PATHOMECHANISM. HE UNDERWENT

111
00:04:36,056 --> 00:04:37,957
GENETIC TESTS AND SHOWS A

112
00:04:37,957 --> 00:04:41,061
HOMOZYGOUS LOSS OF FUNCTION

113
00:04:41,061 --> 00:04:44,631
VARIANT IN GALLANT T 3 A SERE

114
00:04:44,631 --> 00:04:47,934
ANINE AND 3 ANINE

115
00:04:47,934 --> 00:04:48,868
GALACTOTRANSFERASE AND THE NAME

116
00:04:48,868 --> 00:04:52,372
IS SHOWN THERE. SO THE HOSPITAL

117
00:04:52,372 --> 00:04:54,407
COURSE YOU HAVE SEEN HERE, HE'S

118
00:04:54,407 --> 00:04:55,742
BEEN HERE SEVERAL TIMES OVER THE

119
00:04:55,742 --> 00:04:57,510
YEARS FROM HIS HOSPITAL STAYS

120
00:04:57,510 --> 00:04:59,079
QUITE LENGTHY. HE'S HAD

121
00:04:59,079 --> 00:05:02,649
RESECTIONS OF HIP, SHOULDER AND

122
00:05:02,649 --> 00:05:04,617
BUTTOCKS LEAGUES AND HE HAD --

123
00:05:04,617 --> 00:05:06,186
LESIONS AND DRAINAGE OF THE

124
00:05:06,186 --> 00:05:07,087
LARGE FLUID COLLECTION THAT WAS

125
00:05:07,087 --> 00:05:10,957
OVER THE CHEST, YOU CAN SEE THAT

126
00:05:10,957 --> 00:05:12,726
THERE WAS A FLUID, FLUID LEVEL

127
00:05:12,726 --> 00:05:14,160
THERE IDENTIFIED BY THESE

128
00:05:14,160 --> 00:05:16,996
ARROWS. THIS IS A ONE LITER

129
00:05:16,996 --> 00:05:18,765
BOTTLE, THIS WAS DRAINED OFF OF

130
00:05:18,765 --> 00:05:21,101
THERE. AND THIS CHALKY SUBSTANCE

131
00:05:21,101 --> 00:05:27,574
IN THE BOTTOM IS SHOWN HERE. HE

132
00:05:27,574 --> 00:05:28,575
ALSO AT PRESENTATION YOU WILL

133
00:05:28,575 --> 00:05:31,778
SEE THIS ON THE X-RAYS FROM DR.

134
00:05:31,778 --> 00:05:35,115
SABOURY, HAD THESE LESIONS OR

135
00:05:35,115 --> 00:05:37,884
CALCIFICATIONS ON X-RAY AND AT

136
00:05:37,884 --> 00:05:40,653
FIRST WE SAID DID HE HAVE ORAL

137
00:05:40,653 --> 00:05:42,455
CONTRAST? I DIDN'T GIVE HIM, DID

138
00:05:42,455 --> 00:05:44,991
YOU? I SAID SURE LOOKED LIKE HE

139
00:05:44,991 --> 00:05:47,560
HAD ORAL CONTRAST IN THE BOWEL.

140
00:05:47,560 --> 00:05:49,496
BUT ON ENDOSCOPY THESE WERE

141
00:05:49,496 --> 00:05:51,231
COLLECTIONS OF CALCIFICATION

142
00:05:51,231 --> 00:05:54,100
THAT WERE SUB MUCOSAL AND

143
00:05:54,100 --> 00:05:55,602
AMAZINGLY EVEN WITH THIS DEGREE

144
00:05:55,602 --> 00:05:56,770
OF ALMOST OBSTRUCTION OF THE

145
00:05:56,770 --> 00:05:58,738
BOWEL HE HAD NO GI SYMPTOMS BUT

146
00:05:58,738 --> 00:06:01,074
THIS IS REMARKABLE FINDING, I

147
00:06:01,074 --> 00:06:02,041
HAVE NEVER SEEN ANYTHING LIKE IT

148
00:06:02,041 --> 00:06:07,881
SINCE. WE DID TRY AND TREAT HIM

149
00:06:07,881 --> 00:06:09,983
AND OTHER PATIENTS WITH

150
00:06:09,983 --> 00:06:11,251
MULTIPLE, MULTIPLE MEDICATIONS

151
00:06:11,251 --> 00:06:14,387
AS YOU CAN SEE HERE. WE TRIED TO

152
00:06:14,387 --> 00:06:15,855
INHIBIT ABSORPTION OF PHOSPHATE

153
00:06:15,855 --> 00:06:17,257
FROM THE GUT AND HE WAS ON TWO

154
00:06:17,257 --> 00:06:19,492
MEDICATIONS FOR THAT. WE TRIED

155
00:06:19,492 --> 00:06:20,927
TO PROMOTE EXCRETION OF

156
00:06:20,927 --> 00:06:22,829
PHOSPHATE INTO THE URINE. WE

157
00:06:22,829 --> 00:06:24,130
USED THESE THREE MEDICATIONS

158
00:06:24,130 --> 00:06:27,534
SHOWN HERE. WE TRIED TO REDUCE

159
00:06:27,534 --> 00:06:29,569
CALCIFICATIONS WITH TOPICAL

160
00:06:29,569 --> 00:06:33,206
DISULFATE. THIS IS A GRAPH OF A

161
00:06:33,206 --> 00:06:35,842
RATHER LENGTHY COURSE THAT HE

162
00:06:35,842 --> 00:06:37,911
HAD HERE. SHOWN IN THE TOP IS

163
00:06:37,911 --> 00:06:39,746
THE TUBULAR REABSORPTION OF

164
00:06:39,746 --> 00:06:41,648
PHOSPHORUS AND YOU CAN SEE HIS

165
00:06:41,648 --> 00:06:42,649
TUBULAR REABSORPTION OF

166
00:06:42,649 --> 00:06:44,117
PHOSPHORUS IS QUITE HIGH. SO IN

167
00:06:44,117 --> 00:06:46,553
SPITE OF HAVING HIGH BLOOD

168
00:06:46,553 --> 00:06:47,887
PHOSPHATE HIS KIDNEY WAS

169
00:06:47,887 --> 00:06:49,155
INAPPROPRIATELY REABSORBING OR

170
00:06:49,155 --> 00:06:50,957
HOLDING ON TO AS MUCH PHOSPHATE

171
00:06:50,957 --> 00:06:54,661
AS IT COULD. THE SEQUENTIAL

172
00:06:54,661 --> 00:06:59,132
THERAPIES THAT WE GAVE HIM ARE

173
00:06:59,132 --> 00:07:02,268
SHOWN DOWN HERE. SO THESE WERE

174
00:07:02,268 --> 00:07:04,037
TO INHIBIT PHOSPHATE ABSORPTION

175
00:07:04,037 --> 00:07:08,007
TO PROMOTE EXCRETI EXCRETI EXCRT

176
00:07:08,007 --> 00:07:11,044
OOH PROMOTE ABSORPTION AND

177
00:07:11,044 --> 00:07:13,112
SECRETION AND THIOSULFATE WITH

178
00:07:13,112 --> 00:07:14,347
NO EFFICACY AT ALL FOR THIS

179
00:07:14,347 --> 00:07:17,417
PATIENT.  SO THIS WAS A

180
00:07:17,417 --> 00:07:20,520
THERAPEUTIC FAILURE. AS MANY OF

181
00:07:20,520 --> 00:07:21,654
THESE HAVE BEEN. IT WAS CLEAR WE

182
00:07:21,654 --> 00:07:24,557
NEEDED TO DO BETTER AND YOU WILL

183
00:07:24,557 --> 00:07:25,492
SEE WHAT WE HAVE BEEN TRYING TO

184
00:07:25,492 --> 00:07:29,696
DO SINCE THEN.  WITH THAT NOW I

185
00:07:29,696 --> 00:07:31,564
WILL INTRODUCE MY COLLEAGUE, DR.

186
00:07:31,564 --> 00:07:34,434
KELLY ROSZKO WHO IS A STAFF

187
00:07:34,434 --> 00:07:36,236
CLINICIAN IN THE UNIT, AND SHE

188
00:07:36,236 --> 00:07:38,137
WILL TALK TO YOU ABOUT THE

189
00:07:38,137 --> 00:07:44,444
PATHOMECHANISM OF DISEASE. 

190
00:07:44,444 --> 00:07:54,921
>> THANK YOU. SO AS YOU
HAVE

191
00:07:57,090 --> 00:07:58,558
SEEN HYPERPHOSPHATEMIC FAMILIAL

192
00:07:58,558 --> 00:08:00,560
TUMORAL CALCINOSIS OR ATEFTC IS

193
00:08:00,560 --> 00:08:03,596
A DISORDER WHICH PRESENTS WITH

194
00:08:03,596 --> 00:08:05,265
LARGE TUMOR LIKE GROWTHS OF

195
00:08:05,265 --> 00:08:09,569
ABOUT NORMAL CALCIUM DEPOSIT DE 

196
00:08:09,569 --> 00:08:10,537
DEBILITATING CALCIFICATION

197
00:08:10,537 --> 00:08:11,604
AROUND THE SHOULDER AND

198
00:08:11,604 --> 00:08:12,839
CALCIFICATION AROUND THE

199
00:08:12,839 --> 00:08:15,308
BILATERAL HIPS IN THIS 3-D

200
00:08:15,308 --> 00:08:19,946
RECONSTRUCTED CT PHOTO HERE. 

201
00:08:19,946 --> 00:08:22,315
HFTC IS INHERITED IN AUTOSOME

202
00:08:22,315 --> 00:08:24,651
A.M. RECESSIVE PATTERN AND

203
00:08:24,651 --> 00:08:25,685
PATIENTS HAVE HIGH BLOOD

204
00:08:25,685 --> 00:08:27,487
PHOSPHATE LEVELS. 

205
00:08:27,487 --> 00:08:29,756
MECHANISTICALLY HFTC IS PA

206
00:08:29,756 --> 00:08:32,392
DISORDER OF DEFICIENT FGF 23

207
00:08:32,392 --> 00:08:35,595
SIGNALING. SO FGF 23 IS A

208
00:08:35,595 --> 00:08:37,463
HORMONE WHICH IS MADE BY BONE

209
00:08:37,463 --> 00:08:39,032
CELLS, IT CIRCULATES THROUGH THE

210
00:08:39,032 --> 00:08:41,034
BODY AND ACT AS THE KIDNEY WHERE

211
00:08:41,034 --> 00:08:44,904
IT BINDS TO FGF 1 RECEPTOR AND

212
00:08:44,904 --> 00:08:46,839
CORECEPTOR P. UPON SIGNALING IT

213
00:08:46,839 --> 00:08:49,609
DECREASES NAPY 28 EXPRESSION AND

214
00:08:49,609 --> 00:08:51,077
EXPRESSION OF 1 ALPHA

215
00:08:51,077 --> 00:08:55,148
HYDROXYLASE.  THIS LEADS TO A

216
00:08:55,148 --> 00:08:56,516
DECREASED FORM OF -- SORRY THIS

217
00:08:56,516 --> 00:09:00,753
LEADS TO DECREASED PHOSPHATE IN

218
00:09:00,753 --> 00:09:02,555
THE URINE. INCREASED PHOSPHATE

219
00:09:02,555 --> 00:09:06,125
IN THE URINE AND DECREASED BLOOD

220
00:09:06,125 --> 00:09:09,896
PHOSPHATE. ONE OF THE

221
00:09:09,896 --> 00:09:10,897
HYDROXYLASES IS IMPORTANT

222
00:09:10,897 --> 00:09:15,034
BECAUSE IT HYDROXYLATES 25

223
00:09:15,034 --> 00:09:15,902
HYDROXY VITAMIN D, ACTIVE FORM

224
00:09:15,902 --> 00:09:19,973
OF VITAMIN D, 125 DIHYDROXY

225
00:09:19,973 --> 00:09:22,508
VITAMIN D. IT INCREASES CALCIUM

226
00:09:22,508 --> 00:09:23,643
AND PHOSPHATE ABSORPTION FROM

227
00:09:23,643 --> 00:09:27,614
THE INTESTINE. SO FGF 23 ACTS IN

228
00:09:27,614 --> 00:09:29,315
TOTAL TO DECREASE SERUM

229
00:09:29,315 --> 00:09:30,717
PHOSPHATE AND DECREASE ACTIVE

230
00:09:30,717 --> 00:09:35,521
VITAMIN D. SO AS I SAID FGF 23

231
00:09:35,521 --> 00:09:37,490
IS MADE IN BONE CELLS WHERE

232
00:09:37,490 --> 00:09:39,158
UNDERGOES POST TRANSLATIONAL

233
00:09:39,158 --> 00:09:43,329
REGULATION. FGF 23 IS

234
00:09:43,329 --> 00:09:47,200
GLYCOSYLATED BY GALLIN T 3 AND

235
00:09:47,200 --> 00:09:50,637
UPON GLYCOSYLATION FGF 23 IS

236
00:09:50,637 --> 00:09:53,406
STABILIZED AND SECRETED AND

237
00:09:53,406 --> 00:09:54,874
ACTED IN INTACT FORM. IN THE

238
00:09:54,874 --> 00:09:59,379
ABSENCE OF GALNT 3 FGF 23 CAN BE

239
00:09:59,379 --> 00:10:02,915
CLEAVED BY A CONVERTASE CALLED

240
00:10:02,915 --> 00:10:07,954
FERINNIN. INACTIVE C AND END

241
00:10:07,954 --> 00:10:09,322
TERMINAL FRAGMENTS HERE AND NO

242
00:10:09,322 --> 00:10:11,190
BINDING AND INCREASE IN SERUM

243
00:10:11,190 --> 00:10:13,860
PHOSPHATE AND ACTIVE VITAMIN D. 

244
00:10:13,860 --> 00:10:16,496
SO IN THE CASE OF FGF 23

245
00:10:16,496 --> 00:10:22,635
DEFICIENCY NAPI 2A AND ONE ALPHA

246
00:10:22,635 --> 00:10:23,603
HYDROXY ALREADY EXPRESSED WITH

247
00:10:23,603 --> 00:10:25,638
INCREASE IN SERUM PHOSPHATE AND

248
00:10:25,638 --> 00:10:26,939
ACTIVE VITAMIN D. THE CALCIUM

249
00:10:26,939 --> 00:10:28,775
TENDS TO BE IN THE HIGH NORMAL

250
00:10:28,775 --> 00:10:30,977
RANGE AND THE CALCIUM PHOSPHATE

251
00:10:30,977 --> 00:10:33,513
PRODUCT TENDS TO BE QUITE

252
00:10:33,513 --> 00:10:36,182
ELEVATED YOU CAN SEE HERE. IN

253
00:10:36,182 --> 00:10:37,750
MANY OF OUR PATIENTS THE PATTERN

254
00:10:37,750 --> 00:10:39,886
OF FGF 23 FOLLOWS WHAT YOU CAN

255
00:10:39,886 --> 00:10:42,422
SEE IN THIS GRAPH HERE, WITH THE

256
00:10:42,422 --> 00:10:45,525
INTACT ACTIVE FGF 23 BEING QUITE

257
00:10:45,525 --> 00:10:48,261
LOW BUT THE TOTAL FGF 23 WHICH

258
00:10:48,261 --> 00:10:49,762
INCLUDES THE INACTIVE BREAK DOWN

259
00:10:49,762 --> 00:10:53,633
PRODUCTS IS QUITE HIGH. SO THE

260
00:10:53,633 --> 00:10:56,302
LOSS OF FGF 23 ACTION IS MOST

261
00:10:56,302 --> 00:10:58,271
COMMONLY CAUSED BY PATHOGENIC

262
00:10:58,271 --> 00:11:01,507
VARIANTS IN GALNT 3, THIS LEADS

263
00:11:01,507 --> 00:11:03,142
TO LACK OF GLYCOSYLATION AND A

264
00:11:03,142 --> 00:11:05,978
BREAKDOWN OF FGF 23 INTO ITS

265
00:11:05,978 --> 00:11:08,014
INACTIVE FRAGMENTS. THIS CAN BE

266
00:11:08,014 --> 00:11:11,250
DO YOU KNOW TO PATHOGEN -- DUE

267
00:11:11,250 --> 00:11:12,985
TO PATHOGENIC VARIANTS ITSELF.

268
00:11:12,985 --> 00:11:15,221
THIS LEADS TO LOW INTACT FGF 23

269
00:11:15,221 --> 00:11:18,157
AND ELEVATED C TERMINAL FGF 23

270
00:11:18,157 --> 00:11:19,926
THE PATTERN I DESCRIBED IN MOST

271
00:11:19,926 --> 00:11:22,862
PATIENTS. ADDITIONALLY, THERE'S

272
00:11:22,862 --> 00:11:24,997
BEEN ONE CASE DESCRIBED OF A

273
00:11:24,997 --> 00:11:26,833
PATHOGENIC VARIANT IN THE

274
00:11:26,833 --> 00:11:29,902
CORECEPTOR CLOCO AND ONE

275
00:11:29,902 --> 00:11:33,239
PATHOGENIC VARIANT IN THE FGF 1

276
00:11:33,239 --> 00:11:34,674
RECEPTOR ITSELF. IN THESE

277
00:11:34,674 --> 00:11:37,343
PATIENTS IT LEADS TO PATTERN OF

278
00:11:37,343 --> 00:11:40,213
HIGH INTACT FGF 23 BE HIGH C

279
00:11:40,213 --> 00:11:42,448
TERMINAL FGF 23 BREAKDOWN

280
00:11:42,448 --> 00:11:44,584
PRODUCTS.  WE HAVE DESCRIBED ONE

281
00:11:44,584 --> 00:11:47,120
CASE OF AUTOANTIBODIES TO FGF 23

282
00:11:47,120 --> 00:11:49,355
WHICH LEAD TO THAT SAME PATTERN

283
00:11:49,355 --> 00:11:52,658
WITH HIGH INTACT FGF 23. SO OUR

284
00:11:52,658 --> 00:11:55,094
TEAM AT THE NIH HERE INCLUDES

285
00:11:55,094 --> 00:11:57,330
DR. RACHEL AND DR. IRIS HEARTLY,

286
00:11:57,330 --> 00:11:59,098
WE HAVE SEEN A TOTAL OF 21

287
00:11:59,098 --> 00:12:00,433
PATIENTS IN OUR COHORT. SO THE

288
00:12:00,433 --> 00:12:02,368
WORK THAT I'M GOING TO TELL YOU

289
00:12:02,368 --> 00:12:04,937
ABOUT REPRESENTS AN ANALYSIS OF

290
00:12:04,937 --> 00:12:07,707
17 PATIENTS, THE MAJORITY HAD

291
00:12:07,707 --> 00:12:10,276
PATHOGENIC VARIANTS IN GANT 3.

292
00:12:10,276 --> 00:12:11,944
WE ALSO HAVE SINGLE PATIENTS

293
00:12:11,944 --> 00:12:14,814
WITH VARIANTS IN FGF 23 ITSELF,

294
00:12:14,814 --> 00:12:20,186
ONE PATIENT WITH A CLOTHO

295
00:12:20,186 --> 00:12:23,122
TRIPLICATION AND ONE FGF 23

296
00:12:23,122 --> 00:12:24,090
AUTOANTIBODIES AND ONE WITH

297
00:12:24,090 --> 00:12:26,325
UNKNOWN GENETICS. SO DENTAL

298
00:12:26,325 --> 00:12:27,560
CALCIFICATION AND SHORT ROOTS IN

299
00:12:27,560 --> 00:12:29,595
THE TEETH WERE PRESENT IN 92% OF

300
00:12:29,595 --> 00:12:32,532
OUR PATIENTS. THAT MAKES THIS

301
00:12:32,532 --> 00:12:34,133
THE MOST PENETRANT PHENOTYPE OF

302
00:12:34,133 --> 00:12:36,903
THIS DISORDER. WE SAW SOFT

303
00:12:36,903 --> 00:12:38,638
TISSUE CALCIFICATION IN 82% OF

304
00:12:38,638 --> 00:12:40,907
THE PATIENTS, 59% OF THE

305
00:12:40,907 --> 00:12:45,411
PATIENTS WERE FOUND TO HAVE

306
00:12:45,411 --> 00:12:48,114
VASCULAR CALCIFICATION, 44% HAD

307
00:12:48,114 --> 00:12:49,248
INFLAMMATION, YOU WILL HEAR MORE

308
00:12:49,248 --> 00:12:50,783
FROM DR. KLEINER WHO LOGO OVER

309
00:12:50,783 --> 00:12:53,586
THE PATHOLOGY. IDEAS SO WE HAVE

310
00:12:53,586 --> 00:12:56,022
BEEN CHARACTERIZING LOCATION OF

311
00:12:56,022 --> 00:12:58,024
THESE SOFT TISSUE CALCIFICATIONS

312
00:12:58,024 --> 00:12:59,192
WITH THE MOST COMMON BEING AT

313
00:12:59,192 --> 00:13:01,127
THE HIPS, FOLLOWED BY THE

314
00:13:01,127 --> 00:13:04,197
SHOULDERS AND THEN THE ELBOWS.

315
00:13:04,197 --> 00:13:05,731
SO INTERESTINGLY ONE OF OUR

316
00:13:05,731 --> 00:13:07,300
PATIENTS DEVELOPED THESE VERY

317
00:13:07,300 --> 00:13:09,302
PRONOUNCED CALCIFICATIONS OF THE

318
00:13:09,302 --> 00:13:10,970
THUMB AND THEN WE FOUND OUT THAT

319
00:13:10,970 --> 00:13:15,408
SHE WAS AN AVID BOWELLER. THUS

320
00:13:15,408 --> 00:13:17,143
THE CURRENT HYPOTHESIS IS THE

321
00:13:17,143 --> 00:13:18,611
CALCIFICATIONS OCCUR IN AREAS OF

322
00:13:18,611 --> 00:13:20,813
PRESSURE OR REPEATED TRAUMA. AND

323
00:13:20,813 --> 00:13:23,216
WE THINK INFLAMMATION AND

324
00:13:23,216 --> 00:13:24,784
HYPOXIA MIGHT BE A MAJOR FACTOR

325
00:13:24,784 --> 00:13:26,319
IN THIS. SO WE ARE CURRENTLY

326
00:13:26,319 --> 00:13:27,653
WORKING WITH OUR MOUSE MODEL TO

327
00:13:27,653 --> 00:13:29,822
TRY TO ELUCIDATE THE MECHANISM

328
00:13:29,822 --> 00:13:34,293
OF CALCIFICATION FORMATION. SO

329
00:13:34,293 --> 00:13:35,528
THROUGH OUR OBSERVATIONS WITH

330
00:13:35,528 --> 00:13:37,063
THE PATIENT COHORT, WE HAVE

331
00:13:37,063 --> 00:13:39,232
DEVISED THIS WORKING MECHANISTIC

332
00:13:39,232 --> 00:13:40,433
HYPOTHESIS. SO WE BELIEVE THAT

333
00:13:40,433 --> 00:13:43,736
AN ELEVATED CALCIUM PHOSPHATE

334
00:13:43,736 --> 00:13:45,137
PRODUCT IS NECESSARY BUT NOT

335
00:13:45,137 --> 00:13:46,772
SUFFICIENT TO CAUSE THOSE

336
00:13:46,772 --> 00:13:48,007
CALCIFICATIONS. IN THE SETTING

337
00:13:48,007 --> 00:13:49,775
OF THIS ELEVATED CALCIUM

338
00:13:49,775 --> 00:13:50,643
PHOSPHATE PRODUCT WE BELIEVE

339
00:13:50,643 --> 00:13:52,712
THERE ARE OTHER FACTORS SUCH AS

340
00:13:52,712 --> 00:13:54,480
PRESSURE, HYPOXIA, AND

341
00:13:54,480 --> 00:13:56,816
INFLAMMATION THAT ARE THE

342
00:13:56,816 --> 00:13:58,150
TRIGGERS FOR CALCIFICATION.  WE

343
00:13:58,150 --> 00:14:00,152
ALSO HYPOTHESIZED THAT THERE ARE

344
00:14:00,152 --> 00:14:02,288
INSUFFICIENT INHIBITORS OF

345
00:14:02,288 --> 00:14:04,590
MINERALIZATION SUCH AS

346
00:14:04,590 --> 00:14:06,225
PYELOPHOSPHATE, THAT PERMIT THIS

347
00:14:06,225 --> 00:14:07,727
CALCIFICATION TO FORM. THEN

348
00:14:07,727 --> 00:14:09,629
AFTER CALCIFICATION IS TRIGGERED

349
00:14:09,629 --> 00:14:11,330
WE BELIEVE THERE IS A VICIOUS

350
00:14:11,330 --> 00:14:12,832
CYCLE WHERE CALCIFICATION

351
00:14:12,832 --> 00:14:14,333
TRIGGER ES INFLAMMATION AND

352
00:14:14,333 --> 00:14:16,802
INFLAMMATION TRIGGERS FURTHER

353
00:14:16,802 --> 00:14:17,803
CALCIFICATION. THAT CAN BE SHOWN

354
00:14:17,803 --> 00:14:22,808
HERE. SO NOW I WOULD LIKE TO

355
00:14:22,808 --> 00:14:25,311
INTRODUCE DR. SABOURY, A

356
00:14:25,311 --> 00:14:26,479
DIAGNOSTIC RADIOLOGIST AND

357
00:14:26,479 --> 00:14:27,947
NUCLEAR MEDICINE PHYSICIAN, A

358
00:14:27,947 --> 00:14:29,615
SPECIAL VOLUNTEER IN SKELETAL

359
00:14:29,615 --> 00:14:32,585
DISORDERS IN MINERAL HOMEOSTASIS

360
00:14:32,585 --> 00:14:41,294
SECTION IN THE NIDCR. 

361
00:14:41,294 --> 00:14:45,731
>> HELLO, EVERYBODY. AFTER
THESE

362
00:14:45,731 --> 00:14:47,366
TWO GREAT PRESENTATIONS I ONLY

363
00:14:47,366 --> 00:14:50,603
NEED TO REPEAT WHATEVER YOU

364
00:14:50,603 --> 00:14:53,072
HEARD. BUT THAT IS EXACTLY MY

365
00:14:53,072 --> 00:14:56,175
JOB. AND I START WITH THE PLAIN

366
00:14:56,175 --> 00:14:59,345
RAID YES GRAPH AND CALCIUM AND

367
00:14:59,345 --> 00:15:00,713
CALCIFICATION IN GENERAL IS THE

368
00:15:00,713 --> 00:15:03,149
FRIEND OF THE RADIOLOGIST

369
00:15:03,149 --> 00:15:04,583
BECAUSE OF THE ELECTRON DENSITY

370
00:15:04,583 --> 00:15:07,553
OF CALCIUM SO IT IS NOT VERY

371
00:15:07,553 --> 00:15:11,057
SURPRISING TO YOU TO SEE THESE

372
00:15:11,057 --> 00:15:15,728
PLAIN RADIOGRAPHS IN THE LEFT

373
00:15:15,728 --> 00:15:17,830
SIDE, YOU SEE FRONTAL X-RAY OF

374
00:15:17,830 --> 00:15:21,867
THE RIGHT SHOULDER AND ALSO

375
00:15:21,867 --> 00:15:24,770
ELBOW. I WANT TO BRING YOUR

376
00:15:24,770 --> 00:15:27,340
ATTENTION TO TWO DIFFERENT TYPE

377
00:15:27,340 --> 00:15:31,143
OF CALCIFICATION PATTERN. ONE IS

378
00:15:31,143 --> 00:15:33,479
COURSE, DENSE, WITH SOME LUCENT

379
00:15:33,479 --> 00:15:36,415
LINES BETWEEN THEM. AND THE

380
00:15:36,415 --> 00:15:38,985
OTHER IS VERY FINE. IT IS JUST

381
00:15:38,985 --> 00:15:43,356
LIKE A LINEAR AS IF MOVE THROUGH

382
00:15:43,356 --> 00:15:48,327
THE FASCIA. IN ADDITION, IN THIS

383
00:15:48,327 --> 00:15:51,764
IMAGE ON THE RIGHT SIDE YOU SEE

384
00:15:51,764 --> 00:15:58,170
TUBULAR AND CALCIFICATION THAT

385
00:15:58,170 --> 00:16:01,107
MOVES BEHIND THECALCA INHIUS AND

386
00:16:01,107 --> 00:16:02,875
SUBSEQUENTLY YOU WILL SEE THIS

387
00:16:02,875 --> 00:16:07,613
IS CORRESPOND TO THE POSTERIOR

388
00:16:07,613 --> 00:16:09,949
TIBIAL ARTERY. ONE OTHER POINT

389
00:16:09,949 --> 00:16:11,517
TO MENTION IS LOCATIONS THAT WE

390
00:16:11,517 --> 00:16:15,721
SEE THE CALCIFICATION.  SO

391
00:16:15,721 --> 00:16:18,057
SURROUNDING THE JOINTS AS WE

392
00:16:18,057 --> 00:16:20,693
DISCUSSED BEFORE, SUBCUTANEOUS

393
00:16:20,693 --> 00:16:28,834
DEEP MUSCULAR AND ALSO VASCU VA.

394
00:16:28,834 --> 00:16:31,804
GOING TO MORE THREE DIMENSIONAL

395
00:16:31,804 --> 00:16:34,774
IMAGING, ON THE LEFT SIDE YOU

396
00:16:34,774 --> 00:16:36,475
SEE MAXIMUM INTENSITY PROJECTION

397
00:16:36,475 --> 00:16:39,879
OF THE CT. BY THAT YOU MAY HAVE

398
00:16:39,879 --> 00:16:42,214
A VERY GOOD GRASP OF DIFFERENT

399
00:16:42,214 --> 00:16:45,618
TYPE OF CALCIFICATIONS. THE

400
00:16:45,618 --> 00:16:48,387
COURSE CALCIFICATIONS THAT WE

401
00:16:48,387 --> 00:16:53,325
TALKED ABOUT AROUND THE

402
00:16:53,325 --> 00:16:55,494
SHOULDERS, THIS THICK SHAPE

403
00:16:55,494 --> 00:16:57,596
HYPERDENSE LESION THAT DR.

404
00:16:57,596 --> 00:17:00,266
KLEINER LATER TALK ABOUT IT, AND

405
00:17:00,266 --> 00:17:05,838
IN ADDITION TO THAT, THESE BOWEL

406
00:17:05,838 --> 00:17:07,540
RELATED HYPERDENSE MATERIAL AND

407
00:17:07,540 --> 00:17:10,176
OF COURSE THE SURROUNDING THE

408
00:17:10,176 --> 00:17:11,944
HIP JOINT ON THE LEFT SIDE. BUT

409
00:17:11,944 --> 00:17:14,613
THE THING THAT I WANT TO BRING

410
00:17:14,613 --> 00:17:19,618
OUR ATTENTION TO IS THE IMAGE ON

411
00:17:19,618 --> 00:17:23,322
THE RIGHT SIDE. BONE HAS CORTEX

412
00:17:23,322 --> 00:17:28,561
AND MEDULLA.ND USUALLY WHEN WE

413
00:17:28,561 --> 00:17:30,863
HAVE NORMAL CORTEX WE HAVE A

414
00:17:30,863 --> 00:17:32,398
CONTINUE MITY OF THESE DENSE

415
00:17:32,398 --> 00:17:36,168
LINE. AS WE SEE HERE WE HAVE THE

416
00:17:36,168 --> 00:17:38,170
CORTICAL EROSION. WHEN WE HAVE

417
00:17:38,170 --> 00:17:41,173
CORTICAL EROSION WITHOUT A DOUBT

418
00:17:41,173 --> 00:17:42,208
THERE SHOULD BE SOME

419
00:17:42,208 --> 00:17:44,410
INFLAMMATORY PROCESS IN THE

420
00:17:44,410 --> 00:17:46,512
REGION. AND THIS IS ONE OF THE

421
00:17:46,512 --> 00:17:51,917
HALLMARKS THAT WE LATER SEE, HOW

422
00:17:51,917 --> 00:17:55,654
PLAY THE ROLE HERE. BUT THE NAME

423
00:17:55,654 --> 00:17:58,791
OF THE GAME IS QUANTIFICATION OF

424
00:17:58,791 --> 00:18:00,726
THESE DISEASE BURDEN AS A

425
00:18:00,726 --> 00:18:05,064
HOLISTIC ASPECT OF THE PATIENT

426
00:18:05,064 --> 00:18:07,633
IN GENERAL. EARLY EFFORTS WERE

427
00:18:07,633 --> 00:18:13,272
BASED ON EITHER DUAL X RAY

428
00:18:13,272 --> 00:18:17,109
ABSORBOMETRY OR DEXA WHICH SHOWS

429
00:18:17,109 --> 00:18:19,011
THE GROWTH IN THE GLOBAL BURDEN

430
00:18:19,011 --> 00:18:23,182
OF DISEASE FOR THAT MATTER OR

431
00:18:23,182 --> 00:18:30,856
USING MVP MY THEY WILL DIPHOS 

432
00:18:30,856 --> 00:18:32,091
DIPHOSPHANATE SINGLE PHOTON

433
00:18:32,091 --> 00:18:36,495
IMAGING. THESE ARE DECENT FIRST

434
00:18:36,495 --> 00:18:39,465
LEVEL OF QUANTIFICATION BUT AS

435
00:18:39,465 --> 00:18:43,969
YOU CAN IMAGINE THEY LACK THE

436
00:18:43,969 --> 00:18:46,639
ACCURACY AND PRECISION WE NEED.

437
00:18:46,639 --> 00:18:51,677
SO HOW WE CAN DO A BETTER JOB? 

438
00:18:51,677 --> 00:18:53,579
GOING BACK TO THE MOLECULAR

439
00:18:53,579 --> 00:18:57,383
MECHANISM OF THESE

440
00:18:57,383 --> 00:18:58,784
CALCIFICATIONS YOU SEE THE

441
00:18:58,784 --> 00:19:01,587
DEPOSITED MOLECULES ARE A

442
00:19:01,587 --> 00:19:03,756
COMBINATION OF CALCIUM YOU SEE

443
00:19:03,756 --> 00:19:06,392
IN THIS ORANGE SCHEMATIC DRAWING

444
00:19:06,392 --> 00:19:09,495
AND THE PHOSPHATE. AND HYDROXYL

445
00:19:09,495 --> 00:19:11,497
GROUPS OVER THERE. THE IMAGE

446
00:19:11,497 --> 00:19:14,533
THAT I SHOWED YOU BEFORE MVP,

447
00:19:14,533 --> 00:19:18,204
THAT MOLECULE IS A BIPHOSPHANATE

448
00:19:18,204 --> 00:19:19,638
THAT EXCHANGE WITH PHOSPHATE.

449
00:19:19,638 --> 00:19:22,708
WHAT IF WE CAN HAVE A MOLECULE

450
00:19:22,708 --> 00:19:25,311
THAT OR ATOM THAT CAN EXCHANGE

451
00:19:25,311 --> 00:19:27,413
WITH THE DIHYDROXY GROUP AND

452
00:19:27,413 --> 00:19:29,949
THEN WE CAN IMAGE IT? AND WE

453
00:19:29,949 --> 00:19:32,518
HAVE THAT P. FLOOR RENNE 18 IS

454
00:19:32,518 --> 00:19:34,987
ONE RADIO TRACERS. ONE OF THE

455
00:19:34,987 --> 00:19:37,523
FIRST RADIO TRAITSERS BEFORE ANY

456
00:19:37,523 --> 00:19:38,991
OTHER PET TRACER COMES OUT THAT

457
00:19:38,991 --> 00:19:42,494
CAN DO THAT. IF WE DO THAT WE

458
00:19:42,494 --> 00:19:45,297
HAVE A SODIUM FLUORIDE PATH THAT

459
00:19:45,297 --> 00:19:47,333
CAN DEMONSTRATE THE POSITION OF

460
00:19:47,333 --> 00:19:51,604
THESE EXPOSED HYDROXYAPATITE

461
00:19:51,604 --> 00:19:53,672
MOLECULES. NOT ONLY CAN WE SEE

462
00:19:53,672 --> 00:19:57,309
THE AREAS OF ACTIVE AND MACRO

463
00:19:57,309 --> 00:19:59,345
CALCIFICATION BUT ALSO YOU CAN

464
00:19:59,345 --> 00:20:03,048
POTENTIALLY FIND THE LOCATIONS

465
00:20:03,048 --> 00:20:04,617
THAT MICROCALCIFICATION HAPPEN

466
00:20:04,617 --> 00:20:05,951
SINCE THE SENSITIVITY OF THE

467
00:20:05,951 --> 00:20:09,054
PATH IS IN THE ORDER OF

468
00:20:09,054 --> 00:20:11,290
NANOMOLAR IN COMPARISON TO THE

469
00:20:11,290 --> 00:20:13,192
CT WHICH IS MILLIMOLAR FOR

470
00:20:13,192 --> 00:20:17,663
DETECTION. SO GOING THERE YOU

471
00:20:17,663 --> 00:20:21,333
SEE THE DEVICES OF THIS KIT IS

472
00:20:21,333 --> 00:20:22,835
ALSO ACTIVE, A NORMAL ACTIVITY.

473
00:20:22,835 --> 00:20:24,236
YOU SEE SOME ACTIVITY IN THE

474
00:20:24,236 --> 00:20:27,139
KIDNEYS AND ALSO BLADDER. BUT

475
00:20:27,139 --> 00:20:30,843
THING THAT I WANT TO BRING OUR

476
00:20:30,843 --> 00:20:33,078
ATTENTION TO IS THE VASCULAR

477
00:20:33,078 --> 00:20:34,880
CALCIFICATION. THE REASON FOR

478
00:20:34,880 --> 00:20:40,486
THAT, AS YOU HEARD, BY MY

479
00:20:40,486 --> 00:20:41,720
COLLEAGUES, THIS DISEASE IS

480
00:20:41,720 --> 00:20:45,024
SPATIALLY HETEROGENOUS. WHEN YOU

481
00:20:45,024 --> 00:20:47,059
ARE DEALING WITH THE SPATIALLY

482
00:20:47,059 --> 00:20:48,427
HETEROGENOUS PROCESS YOU SHOULD

483
00:20:48,427 --> 00:20:49,895
THINK HOW YOU CAN QUANTIFY

484
00:20:49,895 --> 00:20:51,997
BURDEN OF DISEASE TO CAPTURE

485
00:20:51,997 --> 00:20:53,699
THIS HETEROGENEITY IN ONE HAND

486
00:20:53,699 --> 00:20:55,167
AND GLOBAL BURDEN OF DISEASE ON

487
00:20:55,167 --> 00:20:59,138
THE OTHER HAND. THAT IS THE

488
00:20:59,138 --> 00:21:01,940
DILEMMA WE WANTED TO SOLVE. FOR

489
00:21:01,940 --> 00:21:06,845
THAT WE WANTED TO QUANTIFY THE

490
00:21:06,845 --> 00:21:08,147
CALCIFICATION MICROSCOPY

491
00:21:08,147 --> 00:21:09,648
CALCIFICATION IN EACH LOCATION

492
00:21:09,648 --> 00:21:11,750
OF THE AORTA. BUT AT THE SAME

493
00:21:11,750 --> 00:21:14,453
TIME WE WANTED TO BRING ALL THE

494
00:21:14,453 --> 00:21:17,189
DATA IN A COMMON SPACE THAT WE

495
00:21:17,189 --> 00:21:19,525
CAN DO STATISTICAL ANALYSIS ON.

496
00:21:19,525 --> 00:21:20,859
OTHERWISE WE COULDN'T COMPARE

497
00:21:20,859 --> 00:21:23,295
THE PATTERNS WITH EACH OTHER. TO

498
00:21:23,295 --> 00:21:29,501
DO THAT WE HAD -- CREATED THESE

499
00:21:29,501 --> 00:21:32,838
VASCULAR ATLAS METHOD. THAT IS

500
00:21:32,838 --> 00:21:35,574
WITH GREAT COLLABORATION BETWEEN

501
00:21:35,574 --> 00:21:38,277
THE CLINICIANS AND RADIOLOGY AND

502
00:21:38,277 --> 00:21:39,845
BASIC SCIENTISTS, ONE OF THE

503
00:21:39,845 --> 00:21:42,881
HALLMARK OF THIS PROJECT IS THAT

504
00:21:42,881 --> 00:21:44,883
HOW DISCLOSE -- THIS CLOSE

505
00:21:44,883 --> 00:21:46,452
COLLABORATION RESULTED IN THE

506
00:21:46,452 --> 00:21:47,820
DEVELOPMENT OF THIS METHOD. FOR

507
00:21:47,820 --> 00:21:50,522
THAT WE CREATE A LINE THAT GOES

508
00:21:50,522 --> 00:21:51,957
THROUGH THE CENTER OF THE

509
00:21:51,957 --> 00:21:53,792
VESSELS AND EACH LOCATION WE

510
00:21:53,792 --> 00:21:55,527
HAVE A PLATE THAT IS

511
00:21:55,527 --> 00:21:58,430
PERPENDICULAR TO THE AXIS OF THE

512
00:21:58,430 --> 00:22:00,532
VESSEL AND WE MEASURED THE

513
00:22:00,532 --> 00:22:03,068
AMOUNT OF ACTIVITY IN EACH

514
00:22:03,068 --> 00:22:05,003
LOCATION. IMAGINE THIS LOCATION

515
00:22:05,003 --> 00:22:08,841
IS THE POINT OF ZERO AND IT GOES

516
00:22:08,841 --> 00:22:10,876
ON TO LET'S SAY THIS LOCATION.

517
00:22:10,876 --> 00:22:12,644
SO THE DISTANCE OF ZERO AND

518
00:22:12,644 --> 00:22:14,246
HUNDRED FOR EXAMPLE. AND THEN

519
00:22:14,246 --> 00:22:17,015
YOU MAP IT FROM HERE TO HERE. 

520
00:22:17,015 --> 00:22:19,718
THEN IN EACH LOCATION FOR EACH

521
00:22:19,718 --> 00:22:21,653
PARENT YOU SEE HOW MUCH ACTIVITY

522
00:22:21,653 --> 00:22:25,724
WAS THERE AND YOU DEPICT THAT

523
00:22:25,724 --> 00:22:27,226
OVER THERE. BY THAT YOU BRING IN

524
00:22:27,226 --> 00:22:29,795
ALL THE DATA IN A COMMON SPACE

525
00:22:29,795 --> 00:22:31,430
WHICH WE CALL THE VASCULAR

526
00:22:31,430 --> 00:22:33,599
ATLAS.  THAT GIVES YOU A

527
00:22:33,599 --> 00:22:36,802
CAPACITY TO COMPARE DIFFERENT

528
00:22:36,802 --> 00:22:39,438
PATTERNS WITH EACH OTHER.

529
00:22:39,438 --> 00:22:41,039
TESTING YOUR HYPOTHESIS

530
00:22:41,039 --> 00:22:44,376
MECHANISTIC HYPOTHESIS THAT HOW

531
00:22:44,376 --> 00:22:46,845
DIFFERENT HYDRO DYNAMIC IN

532
00:22:46,845 --> 00:22:50,949
ADDITION TO THE BACKGROUND COULD

533
00:22:50,949 --> 00:22:54,052
RESULT IN DIFFERENT -- I JUST

534
00:22:54,052 --> 00:22:58,223
WANT TO SHOW YOU A COUPLE OF

535
00:22:58,223 --> 00:23:02,027
EXAMPLES TO EMPHASIZE THAT MACRO

536
00:23:02,027 --> 00:23:03,829
CALCIFY QUAILINGS AS WE SEE ON

537
00:23:03,829 --> 00:23:06,165
CT AND MICROCALCIFICATION AS WE

538
00:23:06,165 --> 00:23:08,667
SEE ON SODIUM FLUORIDE PET, THEY

539
00:23:08,667 --> 00:23:11,437
ARE NOT SHOWING THE SAME

540
00:23:11,437 --> 00:23:13,939
INFORMATION. THERE IS SOME

541
00:23:13,939 --> 00:23:14,773
DISCREPANCY BETWEEN INFORMATION

542
00:23:14,773 --> 00:23:17,810
BECAUSE THEY ARE TALKING ABOUT

543
00:23:17,810 --> 00:23:19,478
DIFFERENT SCALE OF THE

544
00:23:19,478 --> 00:23:21,180
PATHOGENESIS. ONE IS AT THE

545
00:23:21,180 --> 00:23:22,614
MICROSCALE AND THE OTHER IS AT

546
00:23:22,614 --> 00:23:25,517
THE MACRO SCALE. AND GOING FROM

547
00:23:25,517 --> 00:23:26,752
ONE TO THE OTHER IS EXTREMELY

548
00:23:26,752 --> 00:23:32,191
IMPORTANT.  SOMETIMES YOU HAVE A

549
00:23:32,191 --> 00:23:33,225
CALCIFICATION AND CORRESPONDING

550
00:23:33,225 --> 00:23:35,127
HIGH ACTIVITY. SOMETIMES YOU

551
00:23:35,127 --> 00:23:37,596
HAVE MICROSCOPY CALCIFICATION

552
00:23:37,596 --> 00:23:39,398
WITHOUT VERY HIGH MICROSCOPY

553
00:23:39,398 --> 00:23:42,401
ACTIVITY. AND THE OTHER

554
00:23:42,401 --> 00:23:45,103
LOCATIONS YOU MAY SEE

555
00:23:45,103 --> 00:23:48,440
HYPERACTIVITY IN A MICROSCOPY

556
00:23:48,440 --> 00:23:49,274
MICROCALCIFICATION, WHILE YOU

557
00:23:49,274 --> 00:23:53,011
HAVE NOT SEEN YET THE MICROSCOPY

558
00:23:53,011 --> 00:23:56,215
CALCIFICATION. THAT IS THE POINT

559
00:23:56,215 --> 00:24:01,887
THAT CAN BE USED AS A BIOMARKER

560
00:24:01,887 --> 00:24:05,824
FOR SHOWING EFFICACY OF THE

561
00:24:05,824 --> 00:24:06,859
TREATMENT BEFORE YOU WAIT FOR

562
00:24:06,859 --> 00:24:10,829
LONG PERIOD OF TIME TO SEE

563
00:24:10,829 --> 00:24:14,900
MICROSCOPY CHANGES. BY THIS I

564
00:24:14,900 --> 00:24:16,902
WANT TO CONCLUDES AND ASK THE

565
00:24:16,902 --> 00:24:19,137
DISTINGUISHED PATHOLOGISTS AND

566
00:24:19,137 --> 00:24:21,039
SENIOR RESEARCH CLINICIAN DR.

567
00:24:21,039 --> 00:24:23,575
DAVID KLEINER TO TEACH US HOW

568
00:24:23,575 --> 00:24:32,618
THE LOOK AT THE SLIDES. 

569
00:24:32,618 --> 00:24:34,953
>> IT IS MY JOB TO SHOW
YOU

570
00:24:34,953 --> 00:24:37,756
PATHOLOGY OF THESE PATIENTS

571
00:24:37,756 --> 00:24:40,926
WHICH IS IN SOME WAYS MORE

572
00:24:40,926 --> 00:24:42,828
COLORFUL AND SOME WAYS LESS

573
00:24:42,828 --> 00:24:46,298
COLORFUL THAN WHAT YOU HAVE

574
00:24:46,298 --> 00:24:52,004
ALREADY SEEN. SO THIS PATIENT

575
00:24:52,004 --> 00:24:54,039
HAD MULTIPLE PROCEDURES OVER THE

576
00:24:54,039 --> 00:24:57,709
TIME THAT HE SPENT AT THE NIH.

577
00:24:57,709 --> 00:25:01,780
FOUR SEPARATE PROCEDURES IN 2011

578
00:25:01,780 --> 00:25:05,050
ALONE THREE WHICH TOOK PLACE IN

579
00:25:05,050 --> 00:25:07,419
ONE MONTH. THEN TWO PROCEDURES

580
00:25:07,419 --> 00:25:09,388
LATER ON, YOU CAN SEE THAT SOME

581
00:25:09,388 --> 00:25:12,591
OF THESE REPEATED PROCEDURES AT

582
00:25:12,591 --> 00:25:14,393
SAME LOCATION. SO TWO RESECTIONS

583
00:25:14,393 --> 00:25:18,730
OF THE RIGHT SHOULDER MASS, AND

584
00:25:18,730 --> 00:25:23,735
OTHER MASSES THAT RECURRED AND

585
00:25:23,735 --> 00:25:26,171
REQUIRED RETREATMENT. HERE IS

586
00:25:26,171 --> 00:25:33,445
THIS FIG SHAPED MASS THAT YOU

587
00:25:33,445 --> 00:25:34,746
PRESENT, ONCE IT WAS REMOVEDDED

588
00:25:34,746 --> 00:25:36,114
IN THIS PARTICULAR INSTANCE IT

589
00:25:36,114 --> 00:25:38,417
WAS QUITE WELL CIRCUMSCRIBED SO

590
00:25:38,417 --> 00:25:43,689
YOU CAN SEE THE WHOLE THING

591
00:25:43,689 --> 00:25:45,924
COULD BE REMOVED, BIG TEAR

592
00:25:45,924 --> 00:25:47,426
DROPPED SHAPE THING, YOU CAN SEE

593
00:25:47,426 --> 00:25:48,760
THE EXTERNAL SURFACE BUT WHEN WE

594
00:25:48,760 --> 00:25:54,199
CUT INTO IT WHAT WE SAW WAS NOT

595
00:25:54,199 --> 00:25:56,868
NORMAL TISSUE SO THE NORMAL

596
00:25:56,868 --> 00:25:58,337
TISSUE IN THIS AREA LOOK THE

597
00:25:58,337 --> 00:26:00,939
SAME AS EXTERNAL SURFACE.  BUT

598
00:26:00,939 --> 00:26:05,243
WHAT WE SAW INSIDE WAS THIS

599
00:26:05,243 --> 00:26:08,680
CHALKY MATERIAL VERY THICK AND

600
00:26:08,680 --> 00:26:13,919
GRANULAR IN CONSISTENCY TO LOOK

601
00:26:13,919 --> 00:26:15,621
AT SOME OF THESE LESIONS YOU CAN

602
00:26:15,621 --> 00:26:18,957
SEE THE X-RAYS OF THESE COURSE

603
00:26:18,957 --> 00:26:20,959
DEPOSITS. THIS IS WHAT THEY

604
00:26:20,959 --> 00:26:23,862
LOOKED LIKE MICROSCOPEICALLY SO

605
00:26:23,862 --> 00:26:26,098
THIS WAS TAKEN IN THE PRE-SINGLE

606
00:26:26,098 --> 00:26:28,233
MASS, YOU CAN SEE SURFACE HERE,

607
00:26:28,233 --> 00:26:30,402
THE EPIDERMIS, DERMIS, AND THIS

608
00:26:30,402 --> 00:26:33,572
LESION WHICH IS REALLY NOT A

609
00:26:33,572 --> 00:26:36,241
SINGLE LESION BUT MULTIPLE

610
00:26:36,241 --> 00:26:39,411
CYSTIC SPACES EACH IRREGULAR IN

611
00:26:39,411 --> 00:26:43,315
SHAPE AND PROBABLY WITH SOME

612
00:26:43,315 --> 00:26:44,883
COMMUNICATION BETWEEN BUT YOU

613
00:26:44,883 --> 00:26:46,585
CAN SEE THIS IS NOT SOMETHING TO

614
00:26:46,585 --> 00:26:49,521
DRAIN VERY EASILY. WHEN WE STAIN

615
00:26:49,521 --> 00:26:52,391
THIS TISSUE SECTION FOR CALCIUM

616
00:26:52,391 --> 00:26:55,794
USING A STAIN, THE CALCIUM WILL

617
00:26:55,794 --> 00:26:57,829
STAIN BLACK. SO CONFIRMING THE

618
00:26:57,829 --> 00:27:01,266
APPEARANCE OR THE CALCIFICATION

619
00:27:01,266 --> 00:27:03,802
OF THIS LESION. IT DOES ERODE

620
00:27:03,802 --> 00:27:06,605
THROUGH THE SURFACE WHICH I WILL

621
00:27:06,605 --> 00:27:09,808
SHOW YOU THE NEXT SLIDE. SO HERE

622
00:27:09,808 --> 00:27:13,912
AGAIN IS THE EPIDERMIS UP HERE,

623
00:27:13,912 --> 00:27:17,282
COMING DOWN INTO THIS ALLS

624
00:27:17,282 --> 00:27:18,750
SOREATION WHERE IT DISAPPEARS

625
00:27:18,750 --> 00:27:23,121
AND THE DERMIS DISAPPEARING INTO

626
00:27:23,121 --> 00:27:27,459
THIS MASS. YOU CAN SEE THE

627
00:27:27,459 --> 00:27:29,895
INDIVIDUAL CYSTIC SPACES

628
00:27:29,895 --> 00:27:31,463
SEPARATED BY FIBER INFLAMMATORY

629
00:27:31,463 --> 00:27:33,598
TISSUE AND THIS ULCERATED

630
00:27:33,598 --> 00:27:36,134
SURFACE. YOU CAN IMAGINE THE

631
00:27:36,134 --> 00:27:38,737
CAUSE SEEMIC DEBRIS FLOWS OUT OF

632
00:27:38,737 --> 00:27:47,679
LEAGUES UNDER THE SKIN SURFA SU 

633
00:27:47,679 --> 00:27:49,681
SO WE LOOK CLOSELY AT THE

634
00:27:49,681 --> 00:27:51,783
INDIVIDUAL CYSTIC SPACES THE

635
00:27:51,783 --> 00:27:55,120
DEBRIS IS GRANULAR AND

636
00:27:55,120 --> 00:27:56,588
ACELLULAR, NO CELLS WITHIN HERE

637
00:27:56,588 --> 00:28:00,459
BUT YOU HAVE INFLAMMATORY EDGE

638
00:28:00,459 --> 00:28:02,060
TO ALL THESE SPACES, THIS IS

639
00:28:02,060 --> 00:28:03,395
SOMETHING THE BODY TRIES TO DO

640
00:28:03,395 --> 00:28:05,063
WHEN IT ENCOUNTERS A FOREIGN

641
00:28:05,063 --> 00:28:11,636
SUBSTANCE CREATES A GRAIN LOMA

642
00:28:11,636 --> 00:28:15,207
THUS THERE'S FEW SITES IN THIS

643
00:28:15,207 --> 00:28:16,308
INFLAMMATORY INFILTRATE, THEY

644
00:28:16,308 --> 00:28:20,345
ARE ALL ACTIVATED SO

645
00:28:20,345 --> 00:28:22,781
EOSINOPHILIC CYTOPLASM, THEY ARE

646
00:28:22,781 --> 00:28:25,117
ENLARGED AND THEY ALSO FORM

647
00:28:25,117 --> 00:28:27,018
GIANT CELLS WHICH YOU CAN SEE ON

648
00:28:27,018 --> 00:28:28,587
THIS VERY HIGH MAGNIFICATION

649
00:28:28,587 --> 00:28:31,456
PICTURE YOU CAN SEE THE

650
00:28:31,456 --> 00:28:32,591
MULTI-NUCLEATED GIANT CELLS,

651
00:28:32,591 --> 00:28:36,995
VEINLY TRYING TO ENGULF THIS

652
00:28:36,995 --> 00:28:38,063
CALCIFIC DEBRIS AT THE EDGE OF

653
00:28:38,063 --> 00:28:42,501
THE LESION. HERE IS ANOTHER

654
00:28:42,501 --> 00:28:44,069
IMAGE TAKEN FROM A DIFFERENT

655
00:28:44,069 --> 00:28:45,337
PART WHERE YOU CAN SEE THEM

656
00:28:45,337 --> 00:28:49,107
TRYING TO ENGULF THIS DEBRIS.

657
00:28:49,107 --> 00:28:52,344
THEY JUST CAN'T KEEP UP, AS YOU

658
00:28:52,344 --> 00:28:54,513
SAW BEFORE FEEDS INTO THIS LOOP

659
00:28:54,513 --> 00:28:57,916
OF INFLAMMATION, AND REPEATED

660
00:28:57,916 --> 00:28:59,718
CALCIFICATION. IT GOES ON AND ON

661
00:28:59,718 --> 00:29:04,456
AND NEVER ACTUALLY HEALS.  ONE

662
00:29:04,456 --> 00:29:05,891
OF THE OTHER THINGS YOU SEE IN

663
00:29:05,891 --> 00:29:08,727
THESE DEPOSITS IS NEW BONE

664
00:29:08,727 --> 00:29:10,395
FORMATION, SO WHENEVER YOU GET

665
00:29:10,395 --> 00:29:12,731
CALCIUM DEPOSITED IN THE BODY NO

666
00:29:12,731 --> 00:29:13,899
MATTER WHERE IT MIGHT BE THERE

667
00:29:13,899 --> 00:29:16,434
IS A CHANCE THAT IT WILL BECOME

668
00:29:16,434 --> 00:29:20,572
BONE. . YOU CAN SEE BONEY

669
00:29:20,572 --> 00:29:22,808
TRABECULAE IN A MARROW SPACE

670
00:29:22,808 --> 00:29:25,043
HERE NOT FILLED WITH

671
00:29:25,043 --> 00:29:26,244
HEMATOPOIETIC STEM CELLS BUT

672
00:29:26,244 --> 00:29:29,447
FIBROUS TISSUE IN HISTIOCYTES.

673
00:29:29,447 --> 00:29:33,852
THAT IS SHOWN AT HIGHER

674
00:29:33,852 --> 00:29:36,087
MAGNIFICATION HERE. I HAVE TAKEN

675
00:29:36,087 --> 00:29:39,424
ONE OUT ONE OF THE TREABECULAE

676
00:29:39,424 --> 00:29:41,626
AND YOU CAN SEE OSTEOBLASTS

677
00:29:41,626 --> 00:29:44,162
LINING THIS AND A OSTEOCLAST UP

678
00:29:44,162 --> 00:29:47,299
THERE AND MATURE OSTEO SITES IN

679
00:29:47,299 --> 00:29:50,268
THE TRABECULAE. THE MARROW SPACE

680
00:29:50,268 --> 00:29:51,937
ITSELF IS NOT CELLULAR IN THIS

681
00:29:51,937 --> 00:29:55,740
PARTICULAR EXAMPLE,S BUT CAN BE

682
00:29:55,740 --> 00:29:58,176
FILLED WITH FIBROBLASTS AND

683
00:29:58,176 --> 00:29:59,711
HISTIOCYTES.  ONE THING WE DID

684
00:29:59,711 --> 00:30:00,946
WITH ONE OF THESE SPECIMENS WAS

685
00:30:00,946 --> 00:30:02,414
TO TAKE A SMALL PIECE OF TISSUE

686
00:30:02,414 --> 00:30:05,517
AND LOOK AT IT UNDER ELECTRON

687
00:30:05,517 --> 00:30:08,286
MICROSCOPY. SO YOU CAN SEE THE

688
00:30:08,286 --> 00:30:10,488
MACROPHAGES HERE, THESE ARE

689
00:30:10,488 --> 00:30:15,026
THREE MACROPHAGES SOME OF THEM

690
00:30:15,026 --> 00:30:19,064
ARE VACULATED BUT WITHIN THESE

691
00:30:19,064 --> 00:30:22,934
MACROPHAGES YOU CAN SEE THE DARK

692
00:30:22,934 --> 00:30:25,503
SPICULATED MASSES THAT ARE THESE

693
00:30:25,503 --> 00:30:26,972
CALCIUM DEPOSITS THAT HAVE BEEN

694
00:30:26,972 --> 00:30:30,842
ENGULFED BY THE MACROPHAGES. NOW

695
00:30:30,842 --> 00:30:34,913
I WILL TURN THIS OVER TO DR.

696
00:30:34,913 --> 00:30:37,249
GOUHR WHO WILL CONTINUE THE

697
00:30:37,249 --> 00:30:41,253
ADVENTURE.

698
00:30:41,253 --> 00:30:47,025
>> THANK YOU, DR. KLEINER.
SO AS

699
00:30:47,025 --> 00:30:48,593
WE ALL HEARD ONE OF THE MAJOR

700
00:30:48,593 --> 00:30:51,663
PROBLEMS IN THESE PATIENTS BE

701
00:30:51,663 --> 00:30:52,964
FAMILIAR TUMORAL CALCINOSIS HAS

702
00:30:52,964 --> 00:30:55,267
BEEN HYDROXYAPATITE CHRISALS. 

703
00:30:55,267 --> 00:30:58,470
DR. KLEINER NICELY SHOWED

704
00:30:58,470 --> 00:31:00,438
MACROPHAGES ENGULFING THEM.

705
00:31:00,438 --> 00:31:03,208
WHERE I GOT INVOLVED AS A

706
00:31:03,208 --> 00:31:04,409
RHEUMATOLOGIST, WE HAVE VERY

707
00:31:04,409 --> 00:31:05,577
MANY SCRIESAL ASSOCIATED

708
00:31:05,577 --> 00:31:08,747
DISEASES INCLUDING -- MANY

709
00:31:08,747 --> 00:31:12,851
CRYSTAL, BUT HYDROXYAPATITE

710
00:31:12,851 --> 00:31:13,752
ASSOCIATED AIRLOPOTHYS ARE KNOWN

711
00:31:13,752 --> 00:31:17,622
IN RHEUMATOLOGY. MORE COMMONLY A

712
00:31:17,622 --> 00:31:19,624
DISEASE CALLED OSTEOARTHRITIS,

713
00:31:19,624 --> 00:31:22,360
MOST OF US KNOW WEAR AND TEAR

714
00:31:22,360 --> 00:31:23,495
ARTHRITIS IS SHOWN WITH

715
00:31:23,495 --> 00:31:25,263
DEPOSITION OF HYDROXYAPATITE

716
00:31:25,263 --> 00:31:28,233
CRYSTALS AROUND THE JOINT. THEY

717
00:31:28,233 --> 00:31:33,071
CAN SOMETHING CALLED CALCIFIC

718
00:31:33,071 --> 00:31:35,307
OSTEOARTHRITIS ALONG THE TENDONS

719
00:31:35,307 --> 00:31:36,942
AND TUMORAL CALCINOSIS,

720
00:31:36,942 --> 00:31:41,212
SOMETHING I STUDY CLOSE, THE

721
00:31:41,212 --> 00:31:44,149
CALCIUM DEPOSITS ALSO MORE SO

722
00:31:44,149 --> 00:31:46,251
UNDER THE SENSE OF -- UNDER THE

723
00:31:46,251 --> 00:31:48,486
SKIN SUBCUTANEOUS LEAGUES

724
00:31:48,486 --> 00:31:50,088
PRIMARILY HYDROXYAPATITE

725
00:31:50,088 --> 00:31:51,323
CRYSTALS AS WELL. SO WHAT DO WE

726
00:31:51,323 --> 00:31:54,659
KNOW ABOUT THIS? SO THE SOME

727
00:31:54,659 --> 00:31:55,794
STUDIES HAVE BEEN DONE IN THE

728
00:31:55,794 --> 00:31:57,529
PAST COUPLE OF DECADES THAT HAVE

729
00:31:57,529 --> 00:31:59,230
SUGGESTED THESE HYDROXYAPATITE

730
00:31:59,230 --> 00:32:01,333
CRYSTALS THAT ARE HERE CAN BE

731
00:32:01,333 --> 00:32:04,069
ENGULFED BY THE THE MACROPHAGES

732
00:32:04,069 --> 00:32:06,604
AS WE HAVE SHOWN ELECTRON

733
00:32:06,604 --> 00:32:09,474
MICROSCOPY AND BEING ENGULFED

734
00:32:09,474 --> 00:32:12,043
ACTIVATE THE NLRP 3 INFLAMMASOME

735
00:32:12,043 --> 00:32:16,614
WHICH IS COMPOSED OF THE NLRP 3,

736
00:32:16,614 --> 00:32:19,484
C COMPLEX AN PRO CASPASE 1. WHEN

737
00:32:19,484 --> 00:32:22,487
THIS COMES TOGETHER IT FORMS NLR

738
00:32:22,487 --> 00:32:24,622
BETWEEN INFLAMMASOME, RELEASES

739
00:32:24,622 --> 00:32:26,825
ACTIVE CASPASE ON ENZYME, THIS

740
00:32:26,825 --> 00:32:28,626
CLEAVES THIS PRO INTERLEUKIN 1

741
00:32:28,626 --> 00:32:30,128
BETA MOLECULE TO THE ACTIVE FORM

742
00:32:30,128 --> 00:32:32,063
OF THE INTERLEUKIN 1 BETA. THIS

743
00:32:32,063 --> 00:32:34,199
IS A PRO-INFLAMMATORY CYTOKINE.

744
00:32:34,199 --> 00:32:37,736
SO THIS IS THE IDEA THAT THESE

745
00:32:37,736 --> 00:32:38,937
CRYSTALS WHEN PRESENT IN TISSUE

746
00:32:38,937 --> 00:32:40,705
CAN LEAD TO ACTIVATION AND

747
00:32:40,705 --> 00:32:41,606
RELEASE OF INFLAMMATORY

748
00:32:41,606 --> 00:32:46,811
MOLECULE. ALMOST I THINK 11

749
00:32:46,811 --> 00:32:49,347
YEARS AGO STUDY PUBLISHED IN

750
00:32:49,347 --> 00:32:51,349
PNAS WHERE THEY LOOK AT A MOUSE

751
00:32:51,349 --> 00:32:54,352
MODEL AND IN THIS STUDY IT WAS

752
00:32:54,352 --> 00:32:56,621
THEY INJECTED MICE WITH PBS, OR

753
00:32:56,621 --> 00:32:58,556
THEY INJECTED THE MICE WITH

754
00:32:58,556 --> 00:33:00,992
HYDROXYAPATITE CRYSTALS. AND

755
00:33:00,992 --> 00:33:02,727
THEN THEY WERE INJECTING MICE

756
00:33:02,727 --> 00:33:04,829
WITH HYDROXYAPATITE CRYSTALS

757
00:33:04,829 --> 00:33:06,631
THERE WAS A NEUTROPHILIC

758
00:33:06,631 --> 00:33:08,199
INFILTRATE OBSERVED AND NOT SEEN

759
00:33:08,199 --> 00:33:10,835
WITH PBS INJECTION. NOW THEY

760
00:33:10,835 --> 00:33:12,504
ALSO USE GENETICALLY MODIFIED

761
00:33:12,504 --> 00:33:14,839
MICE WHERE THEY KNOCKED DOWN

762
00:33:14,839 --> 00:33:17,275
NLRP 3 OR THE ASC COMPLEX OR

763
00:33:17,275 --> 00:33:18,843
CASPASE 1. THESE ARE THE THREE

764
00:33:18,843 --> 00:33:21,813
DIFFERENT COMPONENTS OF THE

765
00:33:21,813 --> 00:33:22,814
INFLAMMASOME AND KNOCKING THEM

766
00:33:22,814 --> 00:33:25,950
OUT AND STIMULATING WITH

767
00:33:25,950 --> 00:33:27,285
HYDROXYAPATITE CRYSTALS NO

768
00:33:27,285 --> 00:33:29,020
TISSUE INFLAMMATION WAS OBSERVED

769
00:33:29,020 --> 00:33:30,355
AT THIS POINT AND THESE MICE

770
00:33:30,355 --> 00:33:32,290
DEVELOPED JOINT ARTHRITIS AND

771
00:33:32,290 --> 00:33:33,525
THEY HAD HYDROXYAPATITE

772
00:33:33,525 --> 00:33:39,297
CRYSTALS.  THUS THE IDEA WAS THE

773
00:33:39,297 --> 00:33:42,100
HYDROXYAPATITE CHRISALS LEAD TO

774
00:33:42,100 --> 00:33:44,302
INFLAMMASOME IN THE MACROPHAGES

775
00:33:44,302 --> 00:33:46,604
AND SECRETION OF ACTIVE

776
00:33:46,604 --> 00:33:48,373
INTERLEUKIN 1 BETA MOLECULE.

777
00:33:48,373 --> 00:33:52,911
THIS IS A PRO CYTOKINE AND LEADS

778
00:33:52,911 --> 00:33:54,446
TO C REACTIVE PROTEIN AS WE CAN

779
00:33:54,446 --> 00:33:58,750
MEASURE IN A PATIENT. SO WITH

780
00:33:58,750 --> 00:33:59,984
THAT KNOWLEDGE, WE THOUGHT ABOUT

781
00:33:59,984 --> 00:34:02,454
THIS AND THIS IS ALMOST A DECADE

782
00:34:02,454 --> 00:34:04,489
AGO WHEN WE FIRST STARTED, IS

783
00:34:04,489 --> 00:34:06,491
COULD WE USE IL 1 INHIBITORS IN

784
00:34:06,491 --> 00:34:09,160
THIS PATIENT OR THESE PATIENTS? 

785
00:34:09,160 --> 00:34:11,062
SO THE IL 1B MOLECULE BINDS TO

786
00:34:11,062 --> 00:34:14,065
THE IL 1 RECEPTOR AND CAUSES

787
00:34:14,065 --> 00:34:15,333
SIGNAL TRANSDUCTION AND

788
00:34:15,333 --> 00:34:17,068
ACTIVATION OF A FEW INFLAMMATORY

789
00:34:17,068 --> 00:34:18,736
PATHWAYS.  AT THAT TIME THREE

790
00:34:18,736 --> 00:34:21,072
DRUGS WERE AVAILABLE TO BLOCK

791
00:34:21,072 --> 00:34:23,775
THIS PATHWAY IN THREE WAYS. ONE

792
00:34:23,775 --> 00:34:25,376
COMMONLY KNOWN AS ANNA KIN DR.

793
00:34:25,376 --> 00:34:28,046
IS A RECOMBINANT PROTEIN OF

794
00:34:28,046 --> 00:34:29,514
INTERLEUKIN 1 REACCEPT TOKER

795
00:34:29,514 --> 00:34:31,616
ANTAGONIST SHOWN HERE. IT BLOCKS

796
00:34:31,616 --> 00:34:33,418
THE INTERLEUKIN ONE RECEPTOR SO

797
00:34:33,418 --> 00:34:35,487
THE ALPHA OR BETA MOLECULES BIND

798
00:34:35,487 --> 00:34:37,956
TO RECEPTOR THUS INHIBITING THE

799
00:34:37,956 --> 00:34:40,725
SIGNIFICANT DOWNSTREAM. ANOTHER

800
00:34:40,725 --> 00:34:45,130
ONE CALLED RELONACEPT IS A DECOY

801
00:34:45,130 --> 00:34:47,499
RECEPTOR WHICH CAPTURES IL 1

802
00:34:47,499 --> 00:34:49,033
ALPHA OR BETA IN CIRCULATION.

803
00:34:49,033 --> 00:34:51,169
ONCE YOU REMOVE THE IL 1 ALPHA

804
00:34:51,169 --> 00:34:53,304
AND BETA INFLAMMATORY CYTOKINES

805
00:34:53,304 --> 00:34:54,873
NOTHING REMAINS TO BIND TO

806
00:34:54,873 --> 00:34:57,041
RECEPTOR AND THUS THERE'S NO

807
00:34:57,041 --> 00:34:58,143
SIGNIFICANT INFLAMMATION

808
00:34:58,143 --> 00:35:03,348
DOWNSTREAM. ANOTHER THIRD ONE IS

809
00:35:03,348 --> 00:35:06,017
KANAKINAMAD, A MONOCLONAL

810
00:35:06,017 --> 00:35:07,051
INTERLEUKIN 1 ANTIBODIES THIS

811
00:35:07,051 --> 00:35:09,220
BINDS TO THE INTERLEUKIN 1 BETA

812
00:35:09,220 --> 00:35:12,290
IN CIRCULATION AND THUS NO

813
00:35:12,290 --> 00:35:13,758
INTERLEUKIN 1 REMAINING TO BIND

814
00:35:13,758 --> 00:35:14,759
RECEPTORS AND PREVENTS

815
00:35:14,759 --> 00:35:16,694
DOWNSTREAM SIGNALING. SO LEE

816
00:35:16,694 --> 00:35:18,029
WAYS OF -- AT THAT TIME THREE

817
00:35:18,029 --> 00:35:20,398
DIFFERENT WAYS OF BLOCKING

818
00:35:20,398 --> 00:35:21,733
INTERLEUKIN 1 SIGNALING. WE

819
00:35:21,733 --> 00:35:25,503
DECIDED TO PURSUE WITH ANAKINRA

820
00:35:25,503 --> 00:35:27,238
FOR A COUPLE OF REASONS.  ONE

821
00:35:27,238 --> 00:35:29,340
HAD A SHORT LAUGH LIFE OF FIVER

822
00:35:29,340 --> 00:35:30,708
HOURS SO YOU CAN SEE RESPONSE

823
00:35:30,708 --> 00:35:32,944
QUICKLY BUT IN CASE OF CONCERNS

824
00:35:32,944 --> 00:35:34,345
OF SIDE EFFECTS WE CAN STOP IT

825
00:35:34,345 --> 00:35:38,116
ALSO.  SECONDLY IT WAS AT THAT

826
00:35:38,116 --> 00:35:39,250
TIME AVAILABLE IN THE CLINICAL

827
00:35:39,250 --> 00:35:43,221
CENTER AS WELL. SO COMES UNDER

828
00:35:43,221 --> 00:35:45,657
THE BRAND NAME KINARED AND

829
00:35:45,657 --> 00:35:47,926
PATIENT STARTED AT 100

830
00:35:47,926 --> 00:35:48,893
MILLIGRAMS SUBCUTANEOUS

831
00:35:48,893 --> 00:35:50,562
INJECTIONS DAILY. BESIDES HAVING

832
00:35:50,562 --> 00:35:53,431
THE LOCALIZED INJECTION SITE

833
00:35:53,431 --> 00:35:55,667
ERYTHEMA THE PATIENT TOLERATED

834
00:35:55,667 --> 00:35:57,368
THE DRUG WELL. AND THE C

835
00:35:57,368 --> 00:35:58,636
REACTIVE PROTEIN LEVELS OF

836
00:35:58,636 --> 00:36:00,171
PATIENTS WERE MONITORED DURING

837
00:36:00,171 --> 00:36:04,375
THE DURATION OF THE THERAPY. SO

838
00:36:04,375 --> 00:36:05,777
HERE WE HAVE A PLOT SHOWING THE

839
00:36:05,777 --> 00:36:07,812
C REACTIVE PROTEIN LEVELS AS

840
00:36:07,812 --> 00:36:09,781
MEASURED IN MILLIGRAMS PER

841
00:36:09,781 --> 00:36:11,249
LITTERS AND Y AXIS IN OUR

842
00:36:11,249 --> 00:36:12,784
PATIENT AND YOU CAN SEE A HIGH

843
00:36:12,784 --> 00:36:15,420
LEVELS OF THE C REACTIVE PROTEIN

844
00:36:15,420 --> 00:36:17,455
BETWEEN 200 TO 300 MILLIGRAMS

845
00:36:17,455 --> 00:36:19,624
PER LITTER AND ON THE X AXIS IS

846
00:36:19,624 --> 00:36:22,527
THE TIME DURATION OF THERAPY. SO

847
00:36:22,527 --> 00:36:25,863
HERE THE POINT ANAKINRA WAS

848
00:36:25,863 --> 00:36:26,965
INITIATED, THERE WAS DRAMATIC

849
00:36:26,965 --> 00:36:28,132
DECLINE IN THE C REACTIVE

850
00:36:28,132 --> 00:36:30,068
PROTEIN AND THIS PERSISTED

851
00:36:30,068 --> 00:36:33,605
DURING THE DURATION OF THERAPY. 

852
00:36:33,605 --> 00:36:35,306
THE PATIENT MISSED ONE DOSE AND

853
00:36:35,306 --> 00:36:36,574
YOU SAW THAT THERE WAS A

854
00:36:36,574 --> 00:36:38,543
DRAMATIC INCREASE THE NEXT DAY

855
00:36:38,543 --> 00:36:41,145
IN THE C REACTIVE PROTEIN LEVEL

856
00:36:41,145 --> 00:36:42,947
BUT ON RESTARTING THERAPY, C

857
00:36:42,947 --> 00:36:44,649
REACTIVE PROTEIN LEVELS DECLINED

858
00:36:44,649 --> 00:36:46,751
FURTHER AGAIN. SO WHAT WE

859
00:36:46,751 --> 00:36:47,785
OBSERVED IN THIS PATIENT WAS

860
00:36:47,785 --> 00:36:50,255
THAT USING ANAKINRA WE WERE ABLE

861
00:36:50,255 --> 00:36:53,191
TO REDUCE THE C REACTIVE PROTEIN

862
00:36:53,191 --> 00:36:55,093
LEVELS, THIS LED TO INCREASE IN

863
00:36:55,093 --> 00:36:56,694
THE ENERGY LEVEL THE PATIENT

864
00:36:56,694 --> 00:36:59,030
COULD EASILY TELL US ABOUT. 

865
00:36:59,030 --> 00:37:00,732
THERE WAS AN INCREASE IN

866
00:37:00,732 --> 00:37:02,767
APPETITE AND THIS INCREASED

867
00:37:02,767 --> 00:37:04,802
APPETITE OVER PERIOD OF TIME LED

868
00:37:04,802 --> 00:37:06,404
TO THE PATIENT GAINING WEIGHT

869
00:37:06,404 --> 00:37:07,672
WHICH WAS AN ISSUE. AND THERE

870
00:37:07,672 --> 00:37:10,008
WAS A GENERAL FEELING OF WELL

871
00:37:10,008 --> 00:37:11,509
BEING. ALONG WITH AN IMPROVEMENT

872
00:37:11,509 --> 00:37:14,445
IN ANEMIA, NOW THERE ARE CERTAIN

873
00:37:14,445 --> 00:37:16,347
ANEMIAS ASSOCIATED WITH HAVING

874
00:37:16,347 --> 00:37:18,383
PERSISTENT OR CHRONIC SYSTEMIC

875
00:37:18,383 --> 00:37:21,185
INFLAMMATION THAT GOES WITH THE

876
00:37:21,185 --> 00:37:22,120
PATHWAY AND PERHAPS IT WAS

877
00:37:22,120 --> 00:37:24,889
BECAUSE OF THAT AS WELL. I WOULD

878
00:37:24,889 --> 00:37:27,659
ALSO LIKE TO PRESENT ANOTHER

879
00:37:27,659 --> 00:37:30,428
PATIENT WITH THE SAME PHENOTYPE,

880
00:37:30,428 --> 00:37:33,131
BUT PEDIATRIC CASE WHERE WE USED

881
00:37:33,131 --> 00:37:35,500
ANOTHER FORM OF IL 1 INHIBITOR,

882
00:37:35,500 --> 00:37:39,203
THE KANAKINAMAB, AUTOANTIBODY.

883
00:37:39,203 --> 00:37:40,638
THE C REACTIVE PROTEIN SHOWN

884
00:37:40,638 --> 00:37:45,343
HERE IN MILLIGRAMS PER LITTER LR

885
00:37:45,343 --> 00:37:47,845
AND THE PATIENT HAD 80

886
00:37:47,845 --> 00:37:50,114
MILLIGRAMS HIGHEST LEVEL OF CRP.

887
00:37:50,114 --> 00:37:54,752
HERE IS WHEN KANA CAN,INAMAB

888
00:37:54,752 --> 00:37:56,688
STARTED, SUN CUTANEOUS INJECTION

889
00:37:56,688 --> 00:37:58,623
ONCE A MONTH EVERY 28 DAYS. YOU

890
00:37:58,623 --> 00:38:00,391
CAN SEE DECLINE IN THE C

891
00:38:00,391 --> 00:38:02,427
REACTIVE PROTEIN TO

892
00:38:02,427 --> 00:38:03,895
NORMALIZATION OF CRP IN THIS

893
00:38:03,895 --> 00:38:07,298
PATIENT. BUT WHAT WAS REALLY

894
00:38:07,298 --> 00:38:08,733
DRAMATIC AND REMARKABLE, BEFORE

895
00:38:08,733 --> 00:38:12,770
THE CANAKINUMAB ON THE HUMOROUS

896
00:38:12,770 --> 00:38:13,838
YOU CAN SEE THE LESION HERE

897
00:38:13,838 --> 00:38:15,406
THERE WAS CALCIUM DEPOSIT THAT

898
00:38:15,406 --> 00:38:16,874
WAS THERE AND ALSO THE LEVEL

899
00:38:16,874 --> 00:38:17,875
LEFT SIDE OF THE NECK OF THE

900
00:38:17,875 --> 00:38:19,644
PATIENT YOU CAN SEE THIS

901
00:38:19,644 --> 00:38:23,281
CUTANEOUS LESION. AFTER A YEAR

902
00:38:23,281 --> 00:38:27,685
OF THERAPY ON CANAKINUMAB THIS

903
00:38:27,685 --> 00:38:28,853
LESION COMPLETELY RESOLVED AND

904
00:38:28,853 --> 00:38:29,954
DISAPPEARED.  ALONG WITH THAT

905
00:38:29,954 --> 00:38:32,323
THERE WAS ALSO A DRAMATIC

906
00:38:32,323 --> 00:38:34,258
RESOLUTION OF THIS CALCIFICATION

907
00:38:34,258 --> 00:38:37,028
THAT IS SEEN ON THE NECK. NOW,

908
00:38:37,028 --> 00:38:38,763
THIS -- WE HAVE TO KEEP IN MIND

909
00:38:38,763 --> 00:38:41,499
THE PATIENTS ARE ON AGGRESSIVE

910
00:38:41,499 --> 00:38:42,900
PHOSPHATE LOWERING THERAPY AT

911
00:38:42,900 --> 00:38:44,569
THIS TIME BUT BEFORE THE

912
00:38:44,569 --> 00:38:46,471
PATIENTS WERE ON THESE THERAPIES

913
00:38:46,471 --> 00:38:47,605
THEY DIDN'T HAVE THIS KIND OF

914
00:38:47,605 --> 00:38:49,073
RESOLUTION SO IT IS A COPY

915
00:38:49,073 --> 00:38:50,875
NATION OF THIS INTERRUPTION OF

916
00:38:50,875 --> 00:38:53,111
THE INFLAMMATORY SIGNAL ALONG

917
00:38:53,111 --> 00:39:00,618
WITH THE AGGRESSIVE PHOSP

918
00:39:00,618 --> 00:39:01,986
PHOSPHOLOWERRING THERAPY. WITH

919
00:39:01,986 --> 00:39:04,255
THAT I WILL HAND IT OVER TO DR.

920
00:39:04,255 --> 00:39:08,259
ROSZKO.

921
00:39:08,259 --> 00:39:11,829
>> THANK YOU. SO IN OUR
ONGOING

922
00:39:11,829 --> 00:39:13,197
WORK WE ARE CONTINUING TO

923
00:39:13,197 --> 00:39:14,665
CHARACTERIZE THE NATURAL HISTORY

924
00:39:14,665 --> 00:39:17,468
OF HFTC. AND WHILE WE DOING THIS

925
00:39:17,468 --> 00:39:19,137
WE ARE PLACING A SPECIAL

926
00:39:19,137 --> 00:39:21,172
EMPHASIS ON UNCOVERING POTENTIAL

927
00:39:21,172 --> 00:39:23,241
END POINTS FOR FUTURE CLINICAL

928
00:39:23,241 --> 00:39:25,476
TRIAL. SO THIS IS AN EXCITING

929
00:39:25,476 --> 00:39:27,612
PROJECT, THIS IS A COLLABORATION

930
00:39:27,612 --> 00:39:29,714
WITH DR. SABOURY WHO YOU JUST

931
00:39:29,714 --> 00:39:32,083
HEARD FROM AND OUR SKILLS

932
00:39:32,083 --> 00:39:35,153
MEDICAL MRST STUDENT AARON

933
00:39:35,153 --> 00:39:36,621
SHEPHERD LED THIS PROJECT AND

934
00:39:36,621 --> 00:39:39,090
DID MUCH OF THIS WORK. SO WE ARE

935
00:39:39,090 --> 00:39:42,994
USING SODIUM FLUORIDE PET SCANS

936
00:39:42,994 --> 00:39:44,295
TO QUANTIFY CALCIFICATION

937
00:39:44,295 --> 00:39:49,133
BURDEN. YOU CAN SEE HERE OUR TWO

938
00:39:49,133 --> 00:39:50,968
SODIUM FLUORIDE PET SCANS OF

939
00:39:50,968 --> 00:39:53,237
THIS PATIENT ONE AT AGE 11 AND

940
00:39:53,237 --> 00:39:56,507
TWO YEARS LATER AT AGE 13. YOU

941
00:39:56,507 --> 00:39:58,142
CAN SO E THIS LARGE DEBILITATING

942
00:39:58,142 --> 00:39:58,810
SHOULDER LESION THAT SHE HAD

943
00:39:58,810 --> 00:40:03,014
HERE. WHAT WE DID WAS WE GRAPHED

944
00:40:03,014 --> 00:40:06,818
THE SUB, METABOLIC ACTIVITY OF

945
00:40:06,818 --> 00:40:09,954
THE LESION, VERSUS HANS FIELD

946
00:40:09,954 --> 00:40:11,322
UNITS THE DENSITY OF THAT LESION

947
00:40:11,322 --> 00:40:14,091
ON CT PORTION. AND YOU CAN SEE

948
00:40:14,091 --> 00:40:17,328
THAT AT THE ORIGINAL TIME POINT

949
00:40:17,328 --> 00:40:19,230
5.2% OF THE LESION WAS SHOWING A

950
00:40:19,230 --> 00:40:21,566
HIGHER METABOLIC ACTIVITY AND

951
00:40:21,566 --> 00:40:23,234
LESS OF THE LESION WAS SHOWING

952
00:40:23,234 --> 00:40:25,803
AN INCREASE DENSITY HERE. YOU

953
00:40:25,803 --> 00:40:28,406
CAN SEE TWO YEARS LATER LESS OF

954
00:40:28,406 --> 00:40:30,675
THE LESION WAS HIGHLY METABOLIC

955
00:40:30,675 --> 00:40:32,910
ACTIVE BUT MUCH MORE OF LESION

956
00:40:32,910 --> 00:40:35,780
HERE HAD CALCIFIED AND WAS MORE

957
00:40:35,780 --> 00:40:38,015
DENSE. SO WE THINK HERE THAT WE

958
00:40:38,015 --> 00:40:41,786
ARE ACTUALLY SEEING A VERSUS

959
00:40:41,786 --> 00:40:43,120
SELL BY VOX SELL ANALYSIS

960
00:40:43,120 --> 00:40:44,989
SHOWING THE LESION PROGRESSION

961
00:40:44,989 --> 00:40:47,024
OVER TIME. WE ARE GOING TO USE

962
00:40:47,024 --> 00:40:48,059
THIS TO LEARN MORE ABOUT THE

963
00:40:48,059 --> 00:40:51,095
NATURAL HISTORY OF THIS DISEASE

964
00:40:51,095 --> 00:40:52,563
BUT ALSO TO DEVELOP END POINTS

965
00:40:52,563 --> 00:40:54,999
THAT CAN POSSIBLY BE USED IN A

966
00:40:54,999 --> 00:40:56,734
CLINICAL TRIAL TO LOOK FOR

967
00:40:56,734 --> 00:40:57,969
IMPROVEMENT WHEN PATIENTS ARE

968
00:40:57,969 --> 00:41:00,505
TREATED WITH MEDICATION.  SO WE

969
00:41:00,505 --> 00:41:02,106
HAVE ALSO WORKED TOGETHER WITH

970
00:41:02,106 --> 00:41:04,342
DR. SABOURY TO EVALUATE THIS

971
00:41:04,342 --> 00:41:05,943
VASCULAR CALCIFICATION IN

972
00:41:05,943 --> 00:41:08,279
PATIENTS WITH HFTC AND AS YOU

973
00:41:08,279 --> 00:41:09,647
HEARD FROM HIS PRESENTATION HE

974
00:41:09,647 --> 00:41:11,749
GAVE YOU A LOT OF THE TECHNIQUE

975
00:41:11,749 --> 00:41:14,018
THAT WE HAVE USED. WE HAVE USED

976
00:41:14,018 --> 00:41:15,920
SODIUM FLUORIDE PET SCANS TO GET

977
00:41:15,920 --> 00:41:17,622
A MICROCALCIFICATION SCORE

978
00:41:17,622 --> 00:41:19,924
LISTED HERE ON THE Y AXIS. AND

979
00:41:19,924 --> 00:41:22,193
THEN ON THE X AXIS WE HAVE A

980
00:41:22,193 --> 00:41:24,829
VASCULAR ATLAS WHICH IS THE

981
00:41:24,829 --> 00:41:28,099
STANDARD ACCESS WHERE WE MAP THE

982
00:41:28,099 --> 00:41:30,868
PATIENT GOING FROM THE AORTA,

983
00:41:30,868 --> 00:41:33,404
HERE IS THE ARCH OF THE AORTA TO

984
00:41:33,404 --> 00:41:36,173
THE DISTAL EXTREMITIES AS IF THE

985
00:41:36,173 --> 00:41:38,109
PATIENT WERE LYING DOWN HERE ON

986
00:41:38,109 --> 00:41:39,510
THE GRAPH. EACH DOTTED LINE

987
00:41:39,510 --> 00:41:41,078
REPRESENTS A TRANSITION BETWEEN

988
00:41:41,078 --> 00:41:45,783
DIFFERENT VASCULAR SEGMENTS. YOU

989
00:41:45,783 --> 00:41:47,418
CAN SEE THAT WE WERE SURPRISED

990
00:41:47,418 --> 00:41:50,821
TO SEE MANY OF OUR FTC PATIENTS

991
00:41:50,821 --> 00:41:52,957
HAD VASCULAR CALCIFICATION OVER

992
00:41:52,957 --> 00:41:54,492
THAT OF THE CONTROL. SO WE HAVE

993
00:41:54,492 --> 00:41:56,494
SIX PATIENTS MAPPED HERE AND THE

994
00:41:56,494 --> 00:41:59,263
CONTROL IS THIS DOTTED LINE

995
00:41:59,263 --> 00:42:01,766
BELOW. WE WERE VERY SURPRISED TO

996
00:42:01,766 --> 00:42:03,367
SEE THAT EVEN OUR YOUNGER

997
00:42:03,367 --> 00:42:05,736
PATIENTS YOU CAN SEE AGE 11

998
00:42:05,736 --> 00:42:08,339
THROUGH 20 ON THIS GRAPH HAD

999
00:42:08,339 --> 00:42:10,808
GREATER VASCULAR CALCIFICATION.

1000
00:42:10,808 --> 00:42:12,677
THAT WAS SURPRISING TO US AND

1001
00:42:12,677 --> 00:42:14,812
HAS LED US TO SCREEN THESE

1002
00:42:14,812 --> 00:42:17,248
PATIENTS MORE AND WATCH THEM

1003
00:42:17,248 --> 00:42:19,016
CAREFULLY. ADDITIONALLY I WILL

1004
00:42:19,016 --> 00:42:20,051
DRAW YOUR ATTENTION TO THE

1005
00:42:20,051 --> 00:42:22,186
YELLOW LINE, THE 11-YEAR-OLD

1006
00:42:22,186 --> 00:42:24,055
PATIENT, SEEMS TO BE AROUND THE

1007
00:42:24,055 --> 00:42:26,023
AREA OF THE CONTROL, BUT THAT

1008
00:42:26,023 --> 00:42:27,091
MEANS THAT THAT 1 # 1-YEAR-OLD

1009
00:42:27,091 --> 00:42:29,226
HAS THE SAME AMOUNT OF

1010
00:42:29,226 --> 00:42:30,995
MICROCALCIFICATION AS A

1011
00:42:30,995 --> 00:42:32,029
46-YEAR-OLD WHO IS THE CONTROL

1012
00:42:32,029 --> 00:42:34,432
HERE.  SO AS WE ASSESS MORE

1013
00:42:34,432 --> 00:42:35,533
PATIENTS WE ARE GOING TO

1014
00:42:35,533 --> 00:42:37,568
CONTINUE TO LOOK FOR PATTERNS,

1015
00:42:37,568 --> 00:42:38,703
IN WHICH CERTAIN SEGMENTS MIGHT

1016
00:42:38,703 --> 00:42:41,472
HAVE A GREATER TENDENCY TO

1017
00:42:41,472 --> 00:42:43,374
DEVELOP VASCULAR CALCIFICATION

1018
00:42:43,374 --> 00:42:46,143
IN HFTC AND ALSO WE WILL STUDY

1019
00:42:46,143 --> 00:42:47,678
THESE PATIENTS PROSPECTIVELY TO

1020
00:42:47,678 --> 00:42:50,014
DETERMINE THE TENDENCY OF

1021
00:42:50,014 --> 00:42:51,182
VASCULAR CALCIFICATION TO CHANGE

1022
00:42:51,182 --> 00:42:54,018
OVER TIME. BUT WE WERE VERY

1023
00:42:54,018 --> 00:42:55,620
EXCITED TO SEE THAT WE CAN

1024
00:42:55,620 --> 00:42:58,589
ACTUALLY INDEED USE SODIUM

1025
00:42:58,589 --> 00:43:00,157
FLUORIDE PET SCANNING TECHNOLOGY

1026
00:43:00,157 --> 00:43:01,859
TO MONITOR AND QUANTIFY THE

1027
00:43:01,859 --> 00:43:03,427
RESPONSE TREATMENT IN BUN OF OUR

1028
00:43:03,427 --> 00:43:06,430
PATIENTS. . . SO THIS IS A

1029
00:43:06,430 --> 00:43:10,334
53-YEAR-OLD WOMAN WITH HFTC WITH

1030
00:43:10,334 --> 00:43:11,769
EXTENSIVE VASCULAR AND SOFT

1031
00:43:11,769 --> 00:43:13,137
TISSUE CALCIFICATION AND

1032
00:43:13,137 --> 00:43:14,472
INFLAMMATION AS YOU JUST HEARD

1033
00:43:14,472 --> 00:43:17,575
ABOUT FROM DR. GOUHR. HER CRP

1034
00:43:17,575 --> 00:43:21,145
WAS EXTREMELY ELEVATED AT 44. SO

1035
00:43:21,145 --> 00:43:23,914
SHE WAS TREATED WITH ANAKINRA

1036
00:43:23,914 --> 00:43:26,150
FOR A TOTAL OF 15 MONTHS. AND

1037
00:43:26,150 --> 00:43:29,020
HER CRP DECREASED DURING THAT

1038
00:43:29,020 --> 00:43:32,023
TIME 44 TO 5.9. PHOSPHATE

1039
00:43:32,023 --> 00:43:35,693
REMAINED UNCHANGED AT 5.8 AND

1040
00:43:35,693 --> 00:43:37,328
6.7 PRE AND POST TREATMENT. SO

1041
00:43:37,328 --> 00:43:39,563
HER BASELINE SODIUM FLUORIDE PET

1042
00:43:39,563 --> 00:43:41,666
SCAN IS THE RED LINE HERE. WHICH

1043
00:43:41,666 --> 00:43:43,868
IS THE UPPER GRAPH. AND YOU CAN

1044
00:43:43,868 --> 00:43:45,770
SEE THERE IS A MARKED ELEVATION

1045
00:43:45,770 --> 00:43:48,339
IN THE MICROCALCIFICATION SCORE.

1046
00:43:48,339 --> 00:43:51,142
THIS BLUE LINE HERE REPRESENTS

1047
00:43:51,142 --> 00:43:53,144
HER POST TREATMENT SCAN WHICH

1048
00:43:53,144 --> 00:43:55,413
YOU CAN SEE HERE BELOW ACTUALLY

1049
00:43:55,413 --> 00:43:57,281
DOES LOOK IMPROVEMENT --

1050
00:43:57,281 --> 00:43:59,950
IMPROVED. SO THE FINDING THAT

1051
00:43:59,950 --> 00:44:00,951
MICROCALCIFICATION COULD RESPOND

1052
00:44:00,951 --> 00:44:03,554
TO TREATMENT IN THIS PATIENT IS

1053
00:44:03,554 --> 00:44:04,989
PROMISING. AND AGAIN WE ARE

1054
00:44:04,989 --> 00:44:07,625
LOOKING TO DEFINE THESE FUTURE

1055
00:44:07,625 --> 00:44:08,759
POTENTIAL END POINTS FOR

1056
00:44:08,759 --> 00:44:10,528
CLINICAL TRIAL THAT COULD CHANGE

1057
00:44:10,528 --> 00:44:12,630
WITH INTERVENTION. SO WE ARE

1058
00:44:12,630 --> 00:44:14,365
VERY EXCITED OF THESE RESULTS

1059
00:44:14,365 --> 00:44:17,168
GOING FORWARD. ONE OF THE MAJOR

1060
00:44:17,168 --> 00:44:18,803
UNANSWERED QUESTIONS ABOUT HFTC

1061
00:44:18,803 --> 00:44:21,672
IS WHAT CAUSES THE HUGE DEGREE

1062
00:44:21,672 --> 00:44:23,340
OF PHENOTYPIC VARIATION BETWEEN

1063
00:44:23,340 --> 00:44:27,411
PATIENTSS. AS I MENTIONED WEED T

1064
00:44:27,411 --> 00:44:28,746
LOCATION OF CALCIFICATION IN OUR

1065
00:44:28,746 --> 00:44:30,748
PATIENTS AND WE CALCULATED THE

1066
00:44:30,748 --> 00:44:33,517
TOTAL LESION VOLUME PER LESION

1067
00:44:33,517 --> 00:44:35,886
AT EACH LOCATION AND TOTAL

1068
00:44:35,886 --> 00:44:36,887
LESION VOLUME OF CALCIFICATION

1069
00:44:36,887 --> 00:44:38,556
PER PATIENT. AS YOU CAN SEE

1070
00:44:38,556 --> 00:44:42,860
HERE, THERE IS HUGE VARIATIONS

1071
00:44:42,860 --> 00:44:44,595
OF LESION VOLUME BOTH BETWEEN

1072
00:44:44,595 --> 00:44:46,864
LESIONS AND ACROSS PATIENTS. 

1073
00:44:46,864 --> 00:44:48,199
THESE ARE EACH INDIVIDUAL

1074
00:44:48,199 --> 00:44:49,867
PATIENTS AND SOME HAVE A PRETTY

1075
00:44:49,867 --> 00:44:51,335
LOW BURDEN OF DISEASE WHILE

1076
00:44:51,335 --> 00:44:52,803
OTHERS HAVE EXTREME AMOUNTS OF

1077
00:44:52,803 --> 00:44:55,239
CALCIFICATION.  SO A MAJOR

1078
00:44:55,239 --> 00:44:56,373
QUESTION IN THIS FIELD IS WHY

1079
00:44:56,373 --> 00:44:58,576
SOME OF THESE PATIENTS DEVELOPED

1080
00:44:58,576 --> 00:45:00,544
THOSE DEBILITATING CALCIFY CASES

1081
00:45:00,544 --> 00:45:01,746
WHILE OTHERS ARE ALMOST

1082
00:45:01,746 --> 00:45:05,416
ASYMPTOMATIC. THIS IS FURTHER

1083
00:45:05,416 --> 00:45:06,884
EXEMPLIFIED BY THE BROTHER OF

1084
00:45:06,884 --> 00:45:08,586
THE PATIENT WHO WE HAVE JUST

1085
00:45:08,586 --> 00:45:10,588
DISCUSSED IN THIS CASE. SO THE

1086
00:45:10,588 --> 00:45:12,256
PATIENT'S BROTHER WAS

1087
00:45:12,256 --> 00:45:13,724
ASYMPTOMATIC. WE ENROLLED HIM TO

1088
00:45:13,724 --> 00:45:15,426
OUR PROTOCOL AND WE MEASURED HIS

1089
00:45:15,426 --> 00:45:16,660
PHOSPHATE.  AND WE FOUND THAT IT

1090
00:45:16,660 --> 00:45:19,563
WAS ELEVATED. ON GENETIC TESTING

1091
00:45:19,563 --> 00:45:22,066
HE HAD THE SAME GENETIC VARIANT

1092
00:45:22,066 --> 00:45:24,869
IN GALNT 3 AS HIS SEVERELY

1093
00:45:24,869 --> 00:45:27,238
AFFECTED BROTHER. IN FACT, THE

1094
00:45:27,238 --> 00:45:29,707
ASYMPTOMATIC BROTHER HAD HIGHER

1095
00:45:29,707 --> 00:45:31,709
ELEVATION IN PHOSPHATE AND

1096
00:45:31,709 --> 00:45:33,110
CALCIUM PHOSPHATE PRODUCT. YOU

1097
00:45:33,110 --> 00:45:38,449
CAN SEE HERE AT 6.3 AND 62. 

1098
00:45:38,449 --> 00:45:39,750
HOWEVER, AS I SAID OUR PATIENT

1099
00:45:39,750 --> 00:45:42,319
YOU SAW HAD THESE MASSIVE

1100
00:45:42,319 --> 00:45:43,654
CALCIFICATIONS AND THIS PATIENT,

1101
00:45:43,654 --> 00:45:44,989
THE ONLY THING WE COULD FIND HE

1102
00:45:44,989 --> 00:45:47,024
WAS ASYMPTOMATIC BUT ON DENTAL

1103
00:45:47,024 --> 00:45:49,193
X-RAYS WE WERE ABLE TO FIND THE

1104
00:45:49,193 --> 00:45:51,095
DENTAL FINDINGS OF DENTAL

1105
00:45:51,095 --> 00:45:53,297
CALCIFICATION AN SHORT BULBUS

1106
00:45:53,297 --> 00:45:56,500
ROOTS. SO HE HAS HIGHER WANT FGF

1107
00:45:56,500 --> 00:45:58,202
23 WHICH MAYBE PROTECTIVE BUT

1108
00:45:58,202 --> 00:46:00,204
SURPRISING BECAUSE THE PHOSPHATE

1109
00:46:00,204 --> 00:46:02,673
LEVEL ARE ACTUALLY HIGHER.

1110
00:46:02,673 --> 00:46:04,441
THEREFORE WE KNOW THE ELEVATED

1111
00:46:04,441 --> 00:46:06,644
CALCIUM PHOSPHATE PRODUCT IS

1112
00:46:06,644 --> 00:46:08,712
NECESSARY FOR CALCIFICATION BUT

1113
00:46:08,712 --> 00:46:10,381
NOT SUFFICIENT TO CAUSE

1114
00:46:10,381 --> 00:46:11,882
CALCIFICATCALCIFICATION. SO A LT

1115
00:46:11,882 --> 00:46:13,317
OF THE FUTURE WORK IN OUR

1116
00:46:13,317 --> 00:46:14,251
LABORATORY WILL BE AIMED AT

1117
00:46:14,251 --> 00:46:17,021
UNDERSTANDING THE MECHANISM OF

1118
00:46:17,021 --> 00:46:19,356
CALCIFICATIONS AND THE REASONING

1119
00:46:19,356 --> 00:46:22,593
FOR THIS VARIABILITY. TO FURTHER

1120
00:46:22,593 --> 00:46:24,628
EXPLORE THE PATHOMECHANISM OF

1121
00:46:24,628 --> 00:46:25,996
OUR DISEASE, IN CONJUNCTION WITH

1122
00:46:25,996 --> 00:46:27,364
OUR WORK ON THE PATIENTS WE HAVE

1123
00:46:27,364 --> 00:46:30,167
BEEN WORKING WITH THE GALNT 3

1124
00:46:30,167 --> 00:46:31,468
KNOCK-OUT MICE.  HERE YOU CAN

1125
00:46:31,468 --> 00:46:34,038
SEE THE BIOCHEMICAL PROFILE OF

1126
00:46:34,038 --> 00:46:36,240
THESE MICE. WE HAVE WILD TYPE

1127
00:46:36,240 --> 00:46:39,143
MICE AND HOMOZYGOUS MICE.  AT

1128
00:46:39,143 --> 00:46:40,845
TWO DIFFERENT AGE POINTS, 12 TO

1129
00:46:40,845 --> 00:46:43,781
13 WEEKS. AND AT 19 TO 20 WEEKS.

1130
00:46:43,781 --> 00:46:46,016
YOU CAN SEE THAT IN THE

1131
00:46:46,016 --> 00:46:47,251
HOMOZYGOUS MICE THERE IS

1132
00:46:47,251 --> 00:46:48,919
SIGNIFICANT ELEVATIONS IN

1133
00:46:48,919 --> 00:46:52,256
PHOSPHATE, THERE'S LOWER INTACT

1134
00:46:52,256 --> 00:46:54,258
FGF 23 LEVELS AND REALLY

1135
00:46:54,258 --> 00:46:57,561
STRIKING ELEVATIONS IN C

1136
00:46:57,561 --> 00:47:00,097
TERMINAL FGF 23 LEVELS.  THIS

1137
00:47:00,097 --> 00:47:02,433
MOUSE WORK IS CARRIED OUT BY

1138
00:47:02,433 --> 00:47:04,335
SKILLED LABORATORY MANAGER

1139
00:47:04,335 --> 00:47:07,738
REBECCA GALISTEO. TO FURTHER

1140
00:47:07,738 --> 00:47:09,306
EXPLORE THE CALCIFICATIONS WE

1141
00:47:09,306 --> 00:47:11,742
ESTABLISHED A COLLABORATION WITH

1142
00:47:11,742 --> 00:47:16,347
DR. (INDISCERNIBLE) IN THE NIBIB

1143
00:47:16,347 --> 00:47:18,749
TO IMAGE THE MICE WITH PET

1144
00:47:18,749 --> 00:47:20,484
SCANS.  FOR THIS I WILL FOCUS ON

1145
00:47:20,484 --> 00:47:22,820
THIS LESION WHICH APPEARS TO BE

1146
00:47:22,820 --> 00:47:24,021
A LARGE TONGUE LESION. SO WE

1147
00:47:24,021 --> 00:47:26,457
WERE ABLE TO SEE THE LESION ON

1148
00:47:26,457 --> 00:47:28,559
SODIUM FLUORIDE PET SCANS AND

1149
00:47:28,559 --> 00:47:30,461
ALSO ABLE TO SEE THE LESION HERE

1150
00:47:30,461 --> 00:47:33,130
ON X-RAY. AND FINALLY WE ARE

1151
00:47:33,130 --> 00:47:36,000
ABLE TO LOOK ON HISTOLOGY AND

1152
00:47:36,000 --> 00:47:40,871
SEE THIS LARGE CALCIFICATION IN

1153
00:47:40,871 --> 00:47:43,040
THE TONGUE OF THAT MOUSE. SO WE

1154
00:47:43,040 --> 00:47:45,175
HAVE ALSO FOUND THAT WE CAN

1155
00:47:45,175 --> 00:47:48,145
DETECT MUCH SMALLER LESIONS WHEN

1156
00:47:48,145 --> 00:47:50,147
LOOKING THROUGH MICRO-CT

1157
00:47:50,147 --> 00:47:51,715
ANALYSIS.  THIS WORK IS DONE

1158
00:47:51,715 --> 00:47:52,750
WITH THE HELP OF THE MOUSE

1159
00:47:52,750 --> 00:47:53,884
IMAGING FACILITY WHERE WE HAVE

1160
00:47:53,884 --> 00:47:57,354
BEEN ABLE TO DO IN VIVO MICRO-CT

1161
00:47:57,354 --> 00:47:59,356
ON OUR MICE. SO ON THE LEFT YOU

1162
00:47:59,356 --> 00:48:01,558
CAN SEE THIS MOUSE, IT HAS

1163
00:48:01,558 --> 00:48:03,827
SEVERAL CALCIFICATIONS AND THESE

1164
00:48:03,827 --> 00:48:06,897
HAVE BEEN SEGMENTED WITH MIM

1165
00:48:06,897 --> 00:48:07,765
SOFTWARE TO DETERMINE THE SIZE

1166
00:48:07,765 --> 00:48:10,100
OF THE CALCIFICATIONS. AND THEN

1167
00:48:10,100 --> 00:48:12,336
THE GRAPHS ON THE RIGHT HERE

1168
00:48:12,336 --> 00:48:15,339
SHOW THE TOTAL CALCIUM VOLUME

1169
00:48:15,339 --> 00:48:17,875
PER CALCIFICATION. AND THE

1170
00:48:17,875 --> 00:48:22,046
INTEGRAL DENSITY HERE. YOU CAN

1171
00:48:22,046 --> 00:48:25,983
SEE THAT -- SORRY THIS IS NOT

1172
00:48:25,983 --> 00:48:29,520
WORKING. ANYWAYS YOU CAN SEE

1173
00:48:29,520 --> 00:48:30,754
CALCIFICATION BURDEN IS INDEED

1174
00:48:30,754 --> 00:48:33,857
HIGHER IN THE HOMOZYGOUS MICE

1175
00:48:33,857 --> 00:48:35,559
AND INTEGRAL DENSITY OF THESE

1176
00:48:35,559 --> 00:48:37,394
LESIONS IS HIGHER IN THE

1177
00:48:37,394 --> 00:48:40,564
HOMOZYGOUS MICE.  SO WE WERE

1178
00:48:40,564 --> 00:48:41,632
ALSO HAPPY TO SEE WE WERE ABLE

1179
00:48:41,632 --> 00:48:44,535
TO TRACK THE CALCIFICATION

1180
00:48:44,535 --> 00:48:46,603
CHANGES OVER TIME USING THE

1181
00:48:46,603 --> 00:48:47,338
MOUSE MODEL. ON THE LEFT HERE

1182
00:48:47,338 --> 00:48:50,007
YOU CAN SEE THE LESION, THIS IS

1183
00:48:50,007 --> 00:48:52,476
WHEN THE MOUSE IS 11 WEEKS OLD

1184
00:48:52,476 --> 00:48:55,612
AND HOW IT CHANGED AND DEVELOPED

1185
00:48:55,612 --> 00:48:57,381
AT AGE 16 WEEKS SO OVER THE FIVE

1186
00:48:57,381 --> 00:49:00,384
WEEKS. WE WERE ALSO ABLE TO

1187
00:49:00,384 --> 00:49:02,619
GRAPH EACH LESION AND SHOW

1188
00:49:02,619 --> 00:49:04,088
INCREASE IN MAXIMUM HANS FIELD

1189
00:49:04,088 --> 00:49:05,489
UNITS OVER FIVE WEEKS ON THIS

1190
00:49:05,489 --> 00:49:07,291
GRAPH AND THIS IS SIX CALCIFY

1191
00:49:07,291 --> 00:49:08,692
CASES IN ONE SINGLE MOUSE AND

1192
00:49:08,692 --> 00:49:10,561
YOU CAN SEE EACH LINE

1193
00:49:10,561 --> 00:49:12,363
REPRESENTING CALCIFICATION HAS

1194
00:49:12,363 --> 00:49:14,098
HAD A BIT OF INCREASE OVER THAT

1195
00:49:14,098 --> 00:49:18,168
TIME PERIOD.  FINALLY HERE YOU

1196
00:49:18,168 --> 00:49:20,637
CAN SEE A 3-D SURFACE MODEL OF

1197
00:49:20,637 --> 00:49:23,073
ONE CALCIFICATIONS AT TWO TIME

1198
00:49:23,073 --> 00:49:25,409
POINTS. THE TIME POINT 1 IS IN

1199
00:49:25,409 --> 00:49:28,178
BLUE AND TIME POINT 2 IN RED RE 

1200
00:49:28,178 --> 00:49:29,446
YOU ARE SEEING A SPATIAL GROWTH

1201
00:49:29,446 --> 00:49:32,916
OF CALCIFICATION OVER THOSE FIVE

1202
00:49:32,916 --> 00:49:34,051
WEEKS. SO WE HAVE A MOUSE MODEL

1203
00:49:34,051 --> 00:49:36,186
WHICH SHOWS CALCIFICATION AND WE

1204
00:49:36,186 --> 00:49:37,788
ARE CHARACTERIZING HOW THESE

1205
00:49:37,788 --> 00:49:38,956
LESIONS GROW AND HOW THEY CHANGE

1206
00:49:38,956 --> 00:49:41,025
OVER TIME. WE ARE GOING TO BE

1207
00:49:41,025 --> 00:49:42,693
USING THIS MOUSE MODEL IN

1208
00:49:42,693 --> 00:49:44,361
PRE-CLINICAL STUDIES WITH THE

1209
00:49:44,361 --> 00:49:45,596
GOAL OF FINDING A TREATMENT THAT

1210
00:49:45,596 --> 00:49:47,664
CAN ACTUALLY DECREASE

1211
00:49:47,664 --> 00:49:49,666
CALCIFICATION THAT THEN WE CAN

1212
00:49:49,666 --> 00:49:54,805
APPLY TO OUR PATIENTS. A BRIEF

1213
00:49:54,805 --> 00:49:56,974
NOTE ON THE TREATMENT OF HFTC.

1214
00:49:56,974 --> 00:49:58,308
UNFORTUNATELY THERE'S NO

1215
00:49:58,308 --> 00:50:00,010
DEDICATED THERAPY FOR THIS

1216
00:50:00,010 --> 00:50:03,480
DISEASE. AS YOU SAW IN THE CASE

1217
00:50:03,480 --> 00:50:05,082
WE HAVE TRIED NUMEROUS AGENTS

1218
00:50:05,082 --> 00:50:06,316
WITH GOAL OF DECREASING

1219
00:50:06,316 --> 00:50:08,452
PHOSPHATE AND INFLAMMATION BUT

1220
00:50:08,452 --> 00:50:10,587
THE SUCCESS HAS BEEN VARIED AND

1221
00:50:10,587 --> 00:50:12,923
IN GENERAL PRETTY LIMITED. SO

1222
00:50:12,923 --> 00:50:14,958
HERE I'M MENTIONING ONE PATIENT

1223
00:50:14,958 --> 00:50:18,262
YOU SAW FROM DR. GOUHR WHERE THE

1224
00:50:18,262 --> 00:50:23,100
CRP WAS LOWERED WITH ANAKINRA

1225
00:50:23,100 --> 00:50:24,768
ASSOCIATED WITH RESOLUTION OF

1226
00:50:24,768 --> 00:50:28,872
HER SKIN AND ELBOW LESIONS.

1227
00:50:28,872 --> 00:50:29,973
HOWEVER, THIS IS GRAPH ON THE

1228
00:50:29,973 --> 00:50:31,909
PATIENT IN THE CASE WE DESCRIBED

1229
00:50:31,909 --> 00:50:33,110
TODAY.  YOU CAN SO E THE

1230
00:50:33,110 --> 00:50:34,278
TREATMENT THE PHOSPHATE LEVELS

1231
00:50:34,278 --> 00:50:36,413
WHICH ARE THOSE BLUE DIAMONDS

1232
00:50:36,413 --> 00:50:39,550
ACTUALLY GO UP OVER TIME AND

1233
00:50:39,550 --> 00:50:41,452
CONTINUED ADDITION OF THERAPIES

1234
00:50:41,452 --> 00:50:45,556
GOING ACROSS THE GRAPH HERE AS

1235
00:50:45,556 --> 00:50:46,323
IS HOSPITAL STAY PROGRESSES. 

1236
00:50:46,323 --> 00:50:49,793
YOU CAN ALSO SEE THE RED SQUARES

1237
00:50:49,793 --> 00:50:51,361
WHICH ARE TUBULAR REABSORPTION

1238
00:50:51,361 --> 00:50:53,730
OF PHOSPHATE DON'T CHANGE

1239
00:50:53,730 --> 00:50:55,099
SHOWING THAT WE ARE REALLY NOT

1240
00:50:55,099 --> 00:50:59,303
MAKING MUCH PROGRESS WITH HIM.

1241
00:50:59,303 --> 00:51:00,571
ANOTHER QUESTION HAS ALWAYS BEEN

1242
00:51:00,571 --> 00:51:02,372
WHETHER THESE LESIONS SHOULD BE

1243
00:51:02,372 --> 00:51:04,408
SURGICALLY RESECTED. WE ALSO

1244
00:51:04,408 --> 00:51:07,211
PLAN TO USE OUR MOUSE MODEL TO

1245
00:51:07,211 --> 00:51:09,113
DETERMINE THE AFFECTS OF SURGERY

1246
00:51:09,113 --> 00:51:11,148
ON THESE LESIONS. SO THIS IS

1247
00:51:11,148 --> 00:51:12,716
GRAPH OF THE PATIENT WE

1248
00:51:12,716 --> 00:51:14,685
DESCRIBED HERE SHOWING THE

1249
00:51:14,685 --> 00:51:16,453
LESION VOLUME OVER SEVEN YEARS

1250
00:51:16,453 --> 00:51:18,255
TIME WE HAVE BEEN FOLLOWING HIM.

1251
00:51:18,255 --> 00:51:20,057
THE ASTERISK HERE SHOW TWO

1252
00:51:20,057 --> 00:51:22,426
POINTS HE HAD SURGERY ON THESE

1253
00:51:22,426 --> 00:51:25,028
LESIONS. AS YOU CAN SEE, THE

1254
00:51:25,028 --> 00:51:27,331
LESION VOLUME INCREASES

1255
00:51:27,331 --> 00:51:29,266
EXPONENTIALLY AFTER SURGICAL

1256
00:51:29,266 --> 00:51:30,701
INTERVENTION. SO THEREFORE FOR

1257
00:51:30,701 --> 00:51:33,170
THIS REASON OUR CURRENT

1258
00:51:33,170 --> 00:51:34,171
RECOMMENDATION HAS BEEN TO

1259
00:51:34,171 --> 00:51:35,539
PATIENTS THAT WE SHOULD HOLD

1260
00:51:35,539 --> 00:51:37,174
SURGICAL INTERVENTION UNLESS

1261
00:51:37,174 --> 00:51:38,742
CALCIFICATION IS LOCATED IN A

1262
00:51:38,742 --> 00:51:40,911
PLACE THAT REALLY REQUIRES

1263
00:51:40,911 --> 00:51:43,714
DEBULKING TO PREVENT LOSS OF

1264
00:51:43,714 --> 00:51:47,217
FUNCTION FOR THESE PATIENTS.  SO

1265
00:51:47,217 --> 00:51:49,353
WE ARE OPTIMISTIC THAT THERE ARE

1266
00:51:49,353 --> 00:51:51,288
FUTURE POTENTIAL THERAPIES, THAT

1267
00:51:51,288 --> 00:51:53,457
CAN BE EXPLORED, THAT CAN HELP

1268
00:51:53,457 --> 00:51:55,058
CORRECT THE BIOCHEMICAL

1269
00:51:55,058 --> 00:51:56,226
ABNORMALITIES IN THIS DISORDER

1270
00:51:56,226 --> 00:51:59,429
AND TO IDEALLY DECREASE

1271
00:51:59,429 --> 00:52:03,100
CALCIFICATION. SO NHE 3

1272
00:52:03,100 --> 00:52:03,800
INHIBITORS COULD FURTHER

1273
00:52:03,800 --> 00:52:05,903
DECREASE ABSORPTION OF CALCIUM

1274
00:52:05,903 --> 00:52:09,139
FROM THE INTESTINE. NAPI 2A

1275
00:52:09,139 --> 00:52:11,241
INHIBITORS HAVE POTENTIAL TO

1276
00:52:11,241 --> 00:52:12,943
INCREASE RENAL PHOSPHATE

1277
00:52:12,943 --> 00:52:15,245
EXCRETION. AND FGF 23

1278
00:52:15,245 --> 00:52:17,181
REPLACEMENT THERAPY WOULD BE A

1279
00:52:17,181 --> 00:52:21,752
PROMISING FUTURE TREATMENT. SO

1280
00:52:21,752 --> 00:52:24,054
TO END I WILL GIVE BRIEF

1281
00:52:24,054 --> 00:52:26,490
FOLLOW-UP ABOUT OUR PATIENT.

1282
00:52:26,490 --> 00:52:28,392
UNFORTUNATELY THE PATIENT WAS

1283
00:52:28,392 --> 00:52:30,894
USING CHRONIC NSAIDS BECAUSE OF

1284
00:52:30,894 --> 00:52:32,462
ALL PAIN HE WAS EXPERIENCING AND

1285
00:52:32,462 --> 00:52:34,731
HE ENDED UP DEVELOPING CHRONIC

1286
00:52:34,731 --> 00:52:38,135
RENAL FAILURE DUE TO NSAID USE

1287
00:52:38,135 --> 00:52:39,036
HIS DISEASE CONTINUED TO

1288
00:52:39,036 --> 00:52:40,837
PROGRESS AND HIS CALCIFICATIONS

1289
00:52:40,837 --> 00:52:44,508
CONTINUED TO GROW AND FORM. YOU

1290
00:52:44,508 --> 00:52:46,843
CAN SEE HERE ON CT THIS IS A

1291
00:52:46,843 --> 00:52:48,979
SHOULDER PROGRESSION -- SHOULDER

1292
00:52:48,979 --> 00:52:50,781
LESION PROGRESSING OVER SIX

1293
00:52:50,781 --> 00:52:55,485
YEARS TIME HERE ON CT. IT WAS

1294
00:52:55,485 --> 00:52:56,386
INCREASINGLY DIFFICULT TO GET

1295
00:52:56,386 --> 00:52:58,188
HIM ACCESS TO THESE MEDICATIONS,

1296
00:52:58,188 --> 00:52:59,690
AS HE LIVED OUTSIDE THE U.S. AND

1297
00:52:59,690 --> 00:53:02,559
DID NOT HAVE INSURANCE ACCESS.

1298
00:53:02,559 --> 00:53:04,761
SO UNFORTUNATELY A DIFFICULT

1299
00:53:04,761 --> 00:53:06,964
CASE FROM THE STANDPOINT OF OUR

1300
00:53:06,964 --> 00:53:09,299
PATIENT. BUT WE DO REMAIN

1301
00:53:09,299 --> 00:53:10,500
OPTIMISTIC AS I SAID, WE HAVE

1302
00:53:10,500 --> 00:53:12,502
NEW MEDICATIONS ON THE HORIZON

1303
00:53:12,502 --> 00:53:13,737
AND WE ARE HOPING THROUGH THE

1304
00:53:13,737 --> 00:53:15,405
PROGRAM HERE THAT WE WILL BE

1305
00:53:15,405 --> 00:53:17,074
ABLE TO TEST THESE AND IDEALLY

1306
00:53:17,074 --> 00:53:18,875
BRING A NEW TREATMENT TO THESE

1307
00:53:18,875 --> 00:53:21,111
PATIENTS. THANK YOU ALL ALL FORR

1308
00:53:21,111 --> 00:53:26,083
TIME.

1309
00:53:26,083 --> 00:53:28,785
[APPLAUSE]

1310
00:53:28,785 --> 00:53:31,221
>> THANK YOU FOR THIS
PHENOMENAL

1311
00:53:31,221 --> 00:53:32,356
PRESENTATIONS. SO FIRST TO

1312
00:53:32,356 --> 00:53:34,558
REMIND THOSE WHO ARE VIRTUALLY,

1313
00:53:34,558 --> 00:53:36,026
THAT YOU CAN CLICK THE BUTTON

1314
00:53:36,026 --> 00:53:38,495
AND ASK A QUESTION VIRTUALLY AND

1315
00:53:38,495 --> 00:53:41,231
ALSO FOR EVERYBODY WHO IS HERE

1316
00:53:41,231 --> 00:53:42,933
IN THE ROOM TO COME TO THE

1317
00:53:42,933 --> 00:53:44,368
MICROPHONE. WHILE WE ARE WAITING

1318
00:53:44,368 --> 00:53:46,703
FOR OTHER QUESTIONS, I WAS

1319
00:53:46,703 --> 00:53:49,006
WONDERING ABOUT THE IL 1 BETA

1320
00:53:49,006 --> 00:53:53,677
ASPECT. I THINK THE CRYSTALS

1321
00:53:53,677 --> 00:53:57,247
PROMOTING IL 1 BETA IS AS YOU

1322
00:53:57,247 --> 00:53:59,082
DESCRIBED KNOWN AND EXPECTED THE

1323
00:53:59,082 --> 00:54:00,751
CRP WILL COME DOWN BUT IT IS

1324
00:54:00,751 --> 00:54:04,688
VERY IMPRESSIVE THAT YOU COVER

1325
00:54:04,688 --> 00:54:06,223
REVERSAL OF INFLAMMATION THAT

1326
00:54:06,223 --> 00:54:07,891
THEN LEADS TO REVERSAL OF

1327
00:54:07,891 --> 00:54:11,361
CALCIUM. MY QUESTION, IS THAT AN

1328
00:54:11,361 --> 00:54:12,896
OUTLIER OF THE PATIENT OR IS

1329
00:54:12,896 --> 00:54:15,365
THAT GENERALIZABLE FINDING? IF

1330
00:54:15,365 --> 00:54:18,669
THE LATTER, IT SOUNDS LIKE IT,

1331
00:54:18,669 --> 00:54:21,605
IS THIS THEN CONSISTENT WITH THE

1332
00:54:21,605 --> 00:54:23,140
MODAL BY WHICHEVER TIME YOU HAVE

1333
00:54:23,140 --> 00:54:26,076
SOME INFLAMMATORY INSULT THAT

1334
00:54:26,076 --> 00:54:28,979
THEN IS REALLY ONE OF THE

1335
00:54:28,979 --> 00:54:30,514
REASONS IL 1 BETA DRIVEN THAT

1336
00:54:30,514 --> 00:54:32,616
YOU HAVE MORE CALCIUM. SO WHAT

1337
00:54:32,616 --> 00:54:34,351
ARE THE SPECULATIONS OF THE

1338
00:54:34,351 --> 00:54:35,352
MECHANISM? SECOND WHEN THE

1339
00:54:35,352 --> 00:54:36,653
PATIENTS GO FOR SURGE ARE I

1340
00:54:36,653 --> 00:54:39,523
SHOULD THEY BE ON ANAKINRA TO

1341
00:54:39,523 --> 00:54:42,426
PREVENT THE WORSENING?

1342
00:54:42,426 --> 00:54:45,696
>> GREAT QUESTION.
DEFINITELY

1343
00:54:45,696 --> 00:54:47,030
NOT ONE PATIENT ALONE, THERE'S

1344
00:54:47,030 --> 00:54:48,932
MULTIPLE PATIENTS WITH THIS

1345
00:54:48,932 --> 00:54:50,400
DISORDER THAT HAVE BEEN TREATED

1346
00:54:50,400 --> 00:54:55,539
WITH EITHER ANAKINRA OR

1347
00:54:55,539 --> 00:54:56,907
CANAFINAMAB MONOCLONAL ANTIBODY

1348
00:54:56,907 --> 00:54:58,008
AND RESPONDED WELL. THESE ARE

1349
00:54:58,008 --> 00:55:00,010
PATIENTS WITH ELEVATED CRP

1350
00:55:00,010 --> 00:55:02,379
LEVELS.  I THINK DR. ROSZKO IN

1351
00:55:02,379 --> 00:55:04,848
INITIATE SLIDE SHOWED THAT THERE

1352
00:55:04,848 --> 00:55:06,950
WERE I THINK ABOUT 47% OF THE

1353
00:55:06,950 --> 00:55:09,720
PATIENTS IN THE COHORT OF 21

1354
00:55:09,720 --> 00:55:11,922
PATIENTS WHO HAVE ELEVATED CRP

1355
00:55:11,922 --> 00:55:13,256
LEVELS SO WE DON'T KNOW WHAT

1356
00:55:13,256 --> 00:55:14,391
WOULD HAPPEN IN PATIENTS WHO

1357
00:55:14,391 --> 00:55:18,795
DON'T HAVE ELEVATED CRP LEVEL. I

1358
00:55:18,795 --> 00:55:20,297
DON'T THINK IT IS -- JUST

1359
00:55:20,297 --> 00:55:21,732
REDUCTION OF INFLAMMATION

1360
00:55:21,732 --> 00:55:23,667
OBVIOUSLY THERE IS PRIMARY

1361
00:55:23,667 --> 00:55:25,001
PATHOLOGY THAT IS PERSISTING AND

1362
00:55:25,001 --> 00:55:26,603
STILL THERE BUT I THINK IT

1363
00:55:26,603 --> 00:55:28,271
CREATES A FEET FORWARD MECHANISM

1364
00:55:28,271 --> 00:55:31,241
THIS INFLAMMATION LEADS TO

1365
00:55:31,241 --> 00:55:34,044
TISSUE INJURY AND THE HEALING

1366
00:55:34,044 --> 00:55:35,946
MECHANISM OF BODY FORMING A

1367
00:55:35,946 --> 00:55:37,147
SCAR, FIBROSIS OR CALCIFICATION

1368
00:55:37,147 --> 00:55:38,749
THEY HAVE. SINCE THEY HAVE A

1369
00:55:38,749 --> 00:55:40,684
PROPENSITY TO HAVE A HIGHER

1370
00:55:40,684 --> 00:55:42,152
CALCIUM PHOSPHATE PRODUCT MORE

1371
00:55:42,152 --> 00:55:43,787
LIKELY THEY END OF DEPOSITING AT

1372
00:55:43,787 --> 00:55:45,722
SITE OF INJURY AND PERPETUATES

1373
00:55:45,722 --> 00:55:47,591
THE CYCLE, INTERRUPTING THAT

1374
00:55:47,591 --> 00:55:50,327
WITH IL 1 PERHAPS LEADS TO

1375
00:55:50,327 --> 00:55:51,628
IMPROVEMENT IN THIS PATHOLOGY

1376
00:55:51,628 --> 00:55:53,930
AND CAN LEAD TO NORMAL HEALING. 

1377
00:55:53,930 --> 00:55:55,332
I HAVE TRIED THIS IN OTHER

1378
00:55:55,332 --> 00:55:57,734
PATIENTS WITH SYSTEMIC SCLEROSIS

1379
00:55:57,734 --> 00:56:03,006
AS WELL. LARGE CALCINOSIS AND

1380
00:56:03,006 --> 00:56:05,575
ELEVATED CRP LEVELS AND WE HAVE

1381
00:56:05,575 --> 00:56:07,644
HAD GOOD RESULTS OF THAT. WHERE

1382
00:56:07,644 --> 00:56:09,246
WE HAVE BEEN ABLE TO REDUCE THE

1383
00:56:09,246 --> 00:56:10,747
CRP LEVELS AS EXPECTED BUT ALSO

1384
00:56:10,747 --> 00:56:13,083
THERE IS SOME REDUCTION IN THE

1385
00:56:13,083 --> 00:56:14,317
CALCIUM, IT IS NOT DRAMATIC

1386
00:56:14,317 --> 00:56:15,652
RESULTS LIKE YOU SAW IN THIS

1387
00:56:15,652 --> 00:56:17,087
PATIENT HERE THE NUMBER 2. BUT

1388
00:56:17,087 --> 00:56:18,655
WE DO SEE THAT IMPROVEMENT IN

1389
00:56:18,655 --> 00:56:21,992
OTHER DISEASES AS WELL. 

1390
00:56:21,992 --> 00:56:24,127
>> WE HAVE A QUESTION FROM

1391
00:56:24,127 --> 00:56:25,662
ONLINE. WHAT IS THE STATUS OF

1392
00:56:25,662 --> 00:56:28,565
THE FGF 23 AS A THERAPEUTIC

1393
00:56:28,565 --> 00:56:29,466
AGENT, HOW LONG BEFORE IT WILL

1394
00:56:29,466 --> 00:56:36,506
BE AVAILABLE TO TRY?

1395
00:56:36,506 --> 00:56:41,812
THAT IS A GOOD
QUESTION.

1396
00:56:41,812 --> 00:56:47,250
THERE IS -- THERE ARE SEVERAL

1397
00:56:47,250 --> 00:56:48,552
GROUPS WITHIN A COMPANY WORKING

1398
00:56:48,552 --> 00:56:50,587
TO DEVELOP THAT, IT IS IN THE

1399
00:56:50,587 --> 00:56:52,456
PIPELINE, IT IS NOT IN HUMAN

1400
00:56:52,456 --> 00:56:56,059
STUDIES YET BUT TO GIVE IT A

1401
00:56:56,059 --> 00:56:57,727
TIME LINE COUPLE OF YEARS MAYBE,

1402
00:56:57,727 --> 00:57:02,098
I WOULD SAY. 

1403
00:57:02,098 --> 00:57:04,568
>> LET ME REPEAT THE CME
CODE

1404
00:57:04,568 --> 00:57:05,735
BECAUSE I THINK THERE MIGHT BE

1405
00:57:05,735 --> 00:57:06,970
AN ERROR ON THE SCREEN THERE SO

1406
00:57:06,970 --> 00:57:10,307
THE CORRECT ONE IS 50533. I

1407
00:57:10,307 --> 00:57:11,541
WOULD LIKE TO THANK ALL OF YOU

1408
00:57:11,541 --> 00:57:12,976
FOR BEING HERE AND VIRTUALLY.

1409
00:57:12,976 --> 00:57:15,679
THANK YOU FOR THIS GREAT

1410
00:57:15,679 --> 00:57:17,781
PRESENTATION. WELCOME TO THE NIH

1411
00:57:17,781 --> 00:57:18,148
CLINICAL CENTER.

1412
00:57:18,148 --> 00:57:28,325
[APPLAUSE]