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Increased serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolytic activity (IGFBP-3-PA) has been demonstrated in a number of clinical states of insulin resistance, including severe illness, after surgery, and in noninsulin-dependent diabetes mellitus. In the present study we assessed the role of insulin sensitivity in expression of IGFBP-3-PA in serum. In 18 patients studied, a significant increase in IGFBP-3-PA (P < 0.005) was demonstrated after colo-rectal surgery. Eight patients receiving an oral glucose load before surgery demonstrated a significant greater relative increase in IGFBP-3-PA compared with 10 patients not receiving glucose (32.9 +/- 7.1% vs. 8.6 +/- 6.7%, respectively; P < 0.05). Both groups had reduced insulin sensitivity after surgery (-58 +/- 4%; P < 0.0001; n = 18), as determined by hyperinsulinemic, normoglycemic clamps; however, the group not receiving glucose displayed 18% less insulin sensitivity than the oral glucose load group (P < 0.05). Multiple regression analysis demonstrated that the relative changes in IGFBP-3-PA and C peptide levels were inversely correlated (P < 0.05), suggesting that increased IGFBP-3-PA, presumably increasing IGF bioavailability, may be associated with decreased insulin demands. Interestingly, insulin infusion during the 4-h hyperinsulinemic, normoglycemic clamp performed 24 h after surgery (post-op) resulted in a further increase in IGFBP-3-PA in both groups (P < 0.005), whereas no significant responses could be demonstrated during the pre-op clamp. The expression of increased IGFBP-3-PA was accompanied by conversion of endogenous intact 39/42-kDa IGFBP-3 into its 30-kDa fragmented form as determined by Western immunoblotting, and this conversion was virtually complete after the 4-h post-op clamp in patients displaying marked increases in IGFBP-3-PA. Characterization of the IGFBP-3-PA demonstrated that it was specific for IGFBP-3, as no degradation of IGFBP-1 and -2 was detected, and the use of various protease inhibitors demonstrated that serine proteases and possibly matrix metalloproteinases contribute to the increased IGFBP-3-PA level after surgery. We propose that IGF bioavailability may be increased by the induction of IGFBP-3-PA in insulin-resistant subjects, and that insulin regulates IGFBP-3-PA in this state.  相似文献   
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Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.  相似文献   
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In early-onset familial Alzheimer's disease (AD) pathogenic mutations have been found in the amyloid precursor protein (APP) gene and in the presenilin (PS)-1 and PS-2 genes. We screened for mutations in these genes in 20 patients with familial AD from the Finnish population. In addition, we sampled 41 sporadic AD patients and 59 controls to test for mutations identified in our familial AD cases. We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients. The Glu318Gly mutation has previously been reported to cause AD. We also found the Glu318Gly mutation in 4 healthy aged controls (range, 74-87 years). We thus conclude that the mutation is most likely a rare polymorphism not related to AD.  相似文献   
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In order to understand the mechanisms of cellular immune injury in hypersensitivity pneumonitis, the effect of type of antigen on cell-mediated immunity in guinea-pigs receiving respiratory immunization was studied. Lymphocytes obtained by pulmonary lavage were compared with those from peritoneal exudate following immunization with either a soluble protein, human serum albumin, or a particulate suspension of Thermoactinomyces vulgaris. Assays were obtained without mixing cells from these two sources. Statistically significant increases (13-22%) in the number of alveolar rosette-forming cells (RFC) were found in the animals immunized with either antigen, but only the particulate T. vulgaris was also capable of inducing a systemic increase of such cells. That this increase in RFC could be due to specifically reactive lymphocytes was demonstrated by the production of antigen-stimulated macrophage migration inhibition. Some evidence was obtained that indicated that T. vulgaris could act both as a non-specific B-cell stimulant and a specific T-cell activator. The concept of a hypothetical pulmonary 'barrier' is discussed which must be overcome to induce systemic immune responses following respiratory immunization. T. vulgaris must be added to the list of known agents or means for overcoming this 'barrier'.  相似文献   
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The records were reviewed of 97 episodes of unsuspected pneumococcemia in children not initially admitted to the hospital. Antimicrobial agents were prescribed at the first visit for 46 children; at the second visit 37 of them were improved and nine were not. No antimicrobial agents were prescribed at the first visit for 51; at the second visit 16 of these patients were improved and 35 were not. Pneumococcemia persisted in two treated children and in 13 untreated children. Meningitis was identified later in four children (two treated and two untreated). Although pneumococcemia in children may be a transient event, it may also persist or result in meningitis or other localized infections.  相似文献   
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