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63


Intraarticular alpha 2-macroglobulin complexes and proteolytic activity in children with juvenile rheumatoid arthritis

Levine, J J; Sherry, D D; Strickland, D K; Ilowite, N T
In juvenile rheumatoid arthritis (JRA), it is likely that the release of proteolytic enzymes from activated synovial fluid neutrophils overwhelms the major protease inhibitor, alpha 2-macroglobulin (alpha 2-MG), and leads to cartilage destruction. Due to the unique nature of the alpha 2-MG-protease complex, proteolytic function is maintained until the complex is cleared. In this study, we sought to determine the concentration of alpha 2-MG-protease complexes in synovial fluid of patients with JRA, the proteolytic activity found in their synovial fluid, and whether the alpha 2-MG complexes are associated with increased proteolytic activity. The JRA patients' synovial fluids had complex levels of 217.0 +/- 192.2 nmol/L--significantly elevated compared with plasma values (p < 0.001) and with control synovial fluid (p < 0.05). Elastase activity (almost entirely neutrophil elastase) was detected in all JRA synovial fluid samples (mean 2.9 +/- 2.6 mg/L) and significantly correlated with alpha 2-MG-complex values (r = 0.67, p < 0.01). Synovial fluid tryptic activity was detectable in all JRA patients but did not significantly correlate with alpha 2-MG complexes (r = 0.53, p > 0.05). Seventy-four percent of total elastase activity and 41% of total tryptic activity were contained in the alpha 2-MG-complex fractions. We suggest that the increased concentration of synovial fluid alpha 2-MG complexes with retained elastase activity contributes to continued proteolysis and joint destruction and may affect the subsequent disease course through its role as a modulator of IL-6.
PMID: 7694228
ISSN: 0031-3998
CID: 587472

Essential fatty acid deficiency associated with the use of a medium-chain-triglyceride infant formula in pediatric hepatobiliary disease [Case Report]

Pettei, M J; Daftary, S; Levine, J J
Serum phospholipid fatty acid patterns were determined by gas chromatography in four infants with hepatobiliary disease receiving a formula with a high content of medium-chain-triglyceride (MCT) oil. All four infants demonstrated signs of essential fatty acid deficiency, characterized by decreased arachidonic acid and increased palmitoleic and oleic acids. All had substantial concentrations of the pathologic triene 5,8,11-eicosatrienoic acid. Three of four had decreased linoleic acid concentrations and abnormal ratios of triene to tetraene (5,8,11-eicosatrienoic acid: arachidonic acid), greater than 0.38. One patient may have experienced growth failure due to abnormal essential fatty acid status. Infants with the potential for fat malabsorption should only receive MCT-oil feedings with well above the generally recommended requirements for linoleic acid (3% of total caloric intake).
PMID: 2021130
ISSN: 0002-9165
CID: 587482

Liver uptake of trypsin-inhibitor complexes; differences between suckling and adult rats

Levine, J J; Pettei, M J
Previous studies have demonstrated increased intestinal trypsin uptake in newborn rats compared to adults. The mechanisms that protect tissues against proteolytic damage by trypsin include trypsin-inhibitor binding and subsequent liver uptake. In order to examine these mechanisms, bovine trypsin (1.25 mg/100 g body weight) plus trace 125I-trypsin were injected into the portal vein of 2-week-old and adult rats. Liver, kidney and plasma 125I activity were assessed at 1, 5 or 15 min following infusion and the different trypsin inhibitor fractions were separated and examined for 125I activity. Newborn rats had significantly increased plasma levels of 125I-trypsin and significantly decreased liver 125I levels 1 min after infusion compared to adults. In addition, the slow decline in liver 125I activity seen in the adult rats did not occur in the newborns. The pattern of trypsin-inhibitor binding was not significantly different at 1, 5 and 15 min and there were no differences at these time intervals between newborns and adults. We suggest that the newborn liver is less effective in clearing infused trypsin leading to increased plasma levels, and this increased plasma trypsin concentration subsequently leads to increased liver levels of 125I-trypsin. The increased trypsin levels in the liver may predispose newborns to protease-induced liver damage.
PMID: 1724607
ISSN: 0006-3126
CID: 587492

Manometric variations following spiral myotomy for long-gap esophageal atresia

Levine, J J; Shoshany, G; Davidson, M; Kimura, K
We have previously demonstrated that a spiral myotomy and delayed definitive procedure is a viable alternative for esophageal reconstruction in long-gap esophageal atresia. In this study we sought to determine whether this procedure leads to esophageal motility disturbances and to compare the manometric findings with controls as well as with those seen in children with esophageal atresia and primary anastomosis. Six beagles had esophageal transection and a spiral myotomy, one had esophageal transection without a myotomy, and two served as normal controls. Following esophageal reconstruction, esophageal manometry was studied in all dogs using a standard pull-through technique. We found that the three control dogs all had similar manometric findings with normal peristalsis. In contrast, the dogs with a spiral myotomy all had propagation of waves in the myotomized segment but termination of waves at the anastomotic site. There was delayed velocity through the myotomized segment and retrograde peristalsis distally. Finally, upper esophageal sphincter pressure was elevated, while lower esophageal sphincter pressure was similar to that in the normal dogs. These findings are similar to those described in children with primary anastomosis and suggest that (a) spinal myotomy is a good alternative to other esophageal replacement options in patients with long-gap esophageal atresia and that (b) the motility dysfunction observed in children with esophageal atresia following primary anastomosis may be secondary to the disruption of the vagus nerve and that may be part of the congenital abnormality or secondary to surgical trauma.
PMID: 2324900
ISSN: 0277-2116
CID: 587502

The role of alpha-macroglobulin in experimental intestinal ischemia

Levine, J J; Dietzek, A; Davidson, M; Pillari, G; Cohen, J R
Intestinal ischemia can lead to mucosal damage and presumably increased intestinal permeability. alpha-Macroglobulin (alpha-MG) is a plasma protein responsible for the inhibition and clearance of systemic proteases, including those derived from the intestinal lumen. In this study, we sought to determine the relationship between intestinal ischemia and alpha-MG in dogs using a nonsurgical model of ischemia. In addition, we sought to detect plasma alpha-MG complexes after ischemic injury. We found that alpha-MG levels were significantly reduced 24 h after induction of occlusion compared with those values obtained immediately after vascular occlusion. The onset of the decline in alpha-MG coincided with the onset of full-thickness intestinal damage, alpha-MG levels in the control animals were unchanged. However, alpha-MG complexes were not elevated in the experimental dogs after ischemia. We suggest that the decline in alpha-MG levels reflects a response to excessive protease uptake across a damaged intestine, leading to increase formation of alpha-MG-protease complexes, which are then rapidly cleared. The absence of detectable systemic complexes suggests that in ischemia, clearance is effective in removing the complexes from the bloodstream, alpha-MG appears to play an important role in protecting against proteolytic damage in prolonged intestinal ischemia.
PMID: 2482881
ISSN: 0277-2116
CID: 587512

The relationship between biochemical adrenarche and decreasing alpha-2-macroglobulin levels in children

Levine, J J; Chasalow, F I; Udall, J N; Blethen, S L
Alpha-2-macroglobulin (alpha 2-MG) is one of the major serum protease inhibitors in adults and appears to be even more important in children. Previous studies have suggested that alpha 2-MG levels are dependent upon age and sex. In order to evaluate the influence of biochemical adrenarche on alpha 2-MG, we compared alpha 2-MG concentrations in normal children and children with premature adrenarche (PA) with levels of dehydroepiandrosterone sulfate (D-S), the marker for biochemical adrenarche. We found that alpha 2-MG was inversely correlated with age and with log10 [D-S] in the normal children. In the children with PA, the alpha 2-MG levels were significantly lower than predicted based on age alone and were similar to the predicted values based on log10 [D-S] levels. We suggest that adrenarche is the process that causes the age-related changes in alpha 2-MG.
PMID: 2475921
ISSN: 0039-128x
CID: 587532

Trypsin uptake and trypsin-inhibitor complexes. Differences between suckling and adult rats

Levine, J J; Udall, J N; Pettei, M J; Davidson, M
Previous studies have suggested that both newborn animals and humans absorb intact proteases from the intestine in greater amounts than do adults. Absorbed proteases are rapidly complexed in plasma by several inhibitors which inactivate free proteases. In order to confirm increased intestinal uptake in newborns, we evaluated the plasma trypsin activity in both 2-week-old and adult rats following a trypsin feed. In addition, we studied the interaction between absorbed trypsin and rat trypsin inhibitors (alpha-macroglobulin, alpha 1-inhibitor 3, and alpha 1-protease inhibitor) by determining the concentration of alpha-macroglobulin complexes both in vivo and in vitro following trypsin feeding and by evaluating the amount of trypsin activity complexed with the different inhibitors. In vivo experiments demonstrated that trypsin uptake was significantly increased in newborns compared to adult rats and that 50-70% of plasma trypsin activity was associated with alpha 1-inhibitor 3. Increased uptake was not accompanied by increased alpha-macroglobulin complexes. In vitro trypsin incubation did not lead to increased alpha-macroglobulin complexes until the other inhibitors were removed. These findings suggest that newborns have increased trypsin uptake, and the trypsin initially binds to alpha 1-inhibitor 3 before being transferred to alpha-macroglobulin for clearance. Further studies are needed in order to understand the interaction between intestinal uptake and plasma inhibition of absorbed proteases.
PMID: 2474336
ISSN: 0006-3126
CID: 587522

Plasma immunoreactive-trypsin(ogen) levels during development

Levine, J J; Udall, J N Jr; Bloch, K J; Hanson, D G; James, B C; Walker, W A
We previously showed that the uptake of intact trypsin from the intestine of suckling animals was greater than that of weaned animals. To extend these studies, we measured plasma cationic immunoreactive-trypsin(ogen) in human subjects aged 3 days to 43 years. In agreement with the observation of other investigators, we found that the concentration of cationic immunoreactive-trypsin(ogen) was significantly increased in 3-day-old infants compared with other age groups. None of the cationic immunoreactive-trypsin in adult samples was bound to alpha 1-antitrypsin, whereas 28% of cationic immunoreactive-trypsin in infant samples was bound to alpha 1-anti-trypsin.
PMID: 3260281
ISSN: 0277-2116
CID: 587542

Chronic nonspecific diarrhea

Levine, J J
PMID: 3317234
ISSN: 0090-4481
CID: 587552

Screening tests for enteropathy in children

Levine, J J; Seidman, E; Walker, W A
Three widely used screening tests for enteropathy in childhood are the lactose breath hydrogen test, the one-hour serum D-xylose absorption test, and the 72-hour fecal fat determination. To our knowledge, no study has compared these three tests and jejunal biopsy results. A retrospective survey of all jejunal biopsy results at Children's Hospital, Boston, from July 1983 to July 1984 was undertaken to evaluate which test best predicted a normal biopsy result. None of the screening tests was ideal. The lactose breath test had low sensitivity and specificity and did not correlate significantly with biopsy results. The D-xylose and fecal fat tests were each significantly correlated with biopsy results; a normal result of either test was highly predictive of a normal biopsy result. Combining the results of two or more screening tests did not improve predictive value. The xylose test is preferable on the basis of greater sensitivity and ease of patient compliance.
PMID: 3565331
ISSN: 0002-922x
CID: 587562