Limited effect of erythrocyte and plasma infusions in adenosine deaminase deficiency.

A 10-month-old child with a profound deficiency of adenosine deaminase and severe combined immunodeficiency was treated for a period of 17 months with red cell and plasma transfusions containing normal amounts of the deficient enzyme. Following each transfusion, the plasma adenosine, red cell and lymphocyte ATP, urinary adenine, and urinary deoxyadenosine decreased transiently. During this period, the absolute blood lymphocyte count rose and a limited increased in the response of the lymphocytes to PHA-P was observed. Delayed hypersensitivity skin tests remained negative during the transfusion periods. A quantitative elevation of serum immunoglobulins occurred, but specific antibody formation was not elicited. In contrast to a previous report of successful therapy of ADA deficiency with red cell and plasma infusions, this patient responded poorly to enzyme replacement therapy. The difference may be related to a more profound enzyme deficiency in our patient.     

Monokine-induced lung injury in rats: similarities to monocrotaline-induced pneumotoxicity

Previous studies have shown that abnormal alveolar macrophages and biological activity resembling the macrophage-derived mediator interleukin-1 (IL-1) can be detected in bronchoalveolar lavage fluid from rats with monocrotaline-induced lung injury and pulmonary hypertension. To determine if monokines might play a pathogenic role in this model, the present study evaluated the effects of a murine monokine preparation enriched in IL-1 bioactivity on selected events characterizing the early pneumotoxic response to monocrotaline, including pulmonary edema and protein extravasation, pulmonary vascular hyperreactivity, and enhanced lung tissue activity of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). Intravenous injection of the monokine preparation containing 200 units/kg IL-1 (quantified by lymphocyte activating factor assay) into intact rats produced pulmonary edema within 3 hr manifested by increases in the lung wet-to-dry weight ratio and in the extent of pulmonary albumin extravasation. The edema had resolved within 24 hr of monokine administration as indicated by a return to control levels of the wet-to-dry weight ratio and albumin extravasation index. The monokine preparation also increased the transfer of albumin across monolayers of cultured porcine pulmonary vascular endothelial cells. While salt solution-perfused rat lungs isolated from animals treated 3 hr previously with the monokine preparation were hyporesponsive to angiotensin II, preparations derived from animals treated 24 hr previously were markedly hyperresponsive to the vasoconstrictor actions of the peptide. Pressor responses to potassium chloride and prostaglandin F2a were unaffected by exposure to the monokine preparation. Lung ODC activity in monokine-exposed animals did not differ from control at 3, 6, or 24 hr after treatment. In contrast, a 24-hr exposure of cultured pulmonary vascular endothelial cells to the monokine preparation increased ODC activity approximately 100-fold. These observations indicate that a monokine preparation containing IL-1 bioactivity causes transient pulmonary edema and pulmonary vascular hyperreactivity and increases ODC activity in pulmonary vascular endothelial cells. Because the monokine preparation mimics certain aspects of monocrotaline-induced pneumotoxicity in the rat, it is reasonable to postulate that monokines could play a pathogenic role in this and similar animal models of lung injury and pulmonary hypertension.     

Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles

Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein     

Helicobacter pylori infection, not gastroesophageal reflux, is the major cause of inflammation and intestinal metaplasia of gastric cardiac mucosa

OBJECTIVE: The etiology of inflammation below the normal Z-line is an area of intense debate. Some suggest this is the earliest change of chronic gastroesophageal reflux disease (GERD), whereas others indict Helicobacter pylori (H. pylori) as the main cause. The aim of this study was to evaluate the relationship among inflammation of gastric cardiac mucosa (carditis), H. pylori infection, and intestinal metaplasia in patients with GERD and Barrett's esophagus compared with age-matched controls. METHODS: Patients with GERD and Barrett's esophagus were compared with controls undergoing endoscopy for a variety of other conditions. Endoscopic biopsy specimens from the gastric cardia (obtained on retroflexed view), fundus, and antrum were evaluated for inflammation, H. pylori infection, and intestinal metaplasia. RESULTS: The prevalence of H. pylori infection did not significantly differ among the study populations: controls (42%), GERD (33%), and Barrett's esophagus (27%) (p = 0.20). However, the prevalence of carditis significantly decreased from the control group (30%) to those with GERD (23%) and Barrett's esophagus (11%) (p = 0.03). Overall, 42 of 51 (82%) patients with carditis had H. pylori; all had pangastritis. The prevalence of cardia intestinal metaplasia also significantly decreased from the control group (15%) to those with GERD (4%) and Barrett's esophagus (0%) (p = 0.003). Of 13 patients with cardia intestinal metaplasia, 12 had carditis, 10 had H. pylori infection, and seven had intestinal metaplasia elsewhere in the stomach. CONCLUSIONS: Inflammation of gastric cardiac mucosa decreases in prevalence from controls to patients with GERD and Barrett's esophagus and correlates strongly with H. pylori infection. Cardia intestinal metaplasia is associated with H. pylori-related cardiac inflammation and intestinal metaplasia elsewhere in the stomach.