Dynamic gadolinium-enhanced MRI evaluation of porcine femoral head ischemia and reperfusion

OBJECTIVE: To examine the potential of gadolinium (Gd)-enhanced dynamic MRI in the detection of early femoral head ischemia. Furthermore, to apply a three-compartment model to achieve a clinically applicable MR index for femoral head perfusion during the steady state and arterial hip joint tamponade. DESIGN AND MATERIALS: In a porcine model femoral head perfusion was measured by radioactive tracer microspheres and by using a dynamic Gd-enhanced MRI protocol. Femoral head perfusion measurements and MRI tests were performed unilaterally before, during and after the experimentally induced ischemia of one of the hip joints. Ischemia was induced by increasing intra-articular pressure to 250 mmHg. RESULTS: All pigs showed ischemia of the femoral head epiphysis under hip joint tamponade followed by reperfusion to the same level as before joint tamponade. In two cases perfusion after removal of tamponade continued to be low. In dynamic MRI measurements increases in signal intensity were seen after intravenous infusion of Gd-DTPA, followed by a slow decrease in signal intensity. The signal-intensity curve during femoral head ischemia had a minor increase. Also the coefficient determined was a helpful indicator of femoral head ischemia. CONCLUSIONS: Femoral head blood flow as measured by microspheres fell significantly under joint tamponade. Early detection of this disturbed regional blood flow was possible using a dynamic MRI procedure. A biomathematical model resulted from the evaluation of the intervals of signal intensity over time which allows detection of bone blood flow changes at a very early stage. Using this new method earlier detection of femoral head necrosis may be possible.     

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.     

K(ATP) channels and pancreatic islet blood flow in anesthetized rats: increased blood flow induced by potassium channel openers

K(ATP) channels are important for insulin secretion and depolarization of vascular smooth muscle. In view of the importance of drugs affecting K(ATP) channels in the treatment of diabetes, we investigated the effects of these channels on splanchnic blood perfusion in general and pancreatic islet blood flow in particular. We treated anesthetized Sprague-Dawley rats with the K(ATP) channel openers diazoxide or NNC 55-0118 or the K(ATP) channel closer glipizide. Both diazoxide and NNC 55-0118 dose-dependently increased total pancreatic and islet blood flow in the presence of moderate hyperglycemia, but had no effects on the blood perfusion of other splanchnic organs. Diazoxide markedly lowered the mean arterial blood pressure and thus increased vascular conductance in all organs studied. NNC 55-0118 had much smaller effects on the blood pressure. Glipizide did not affect total pancreatic blood flow, but decreased islet blood flow by 50% in the presence of hypoglycemia. We conclude that K(ATP) channels actively participate in the blood flow regulation of the pancreatic islets and that substances affecting such channels may also influence islet blood flow.     

Improved iodine radiolabels for monoclonal antibody therapy

A major disadvantage of (131)iodine (I)-labeled monoclonal antibodies (MAbs) for radioimmunotherapy has been the rapid diffusion of iodotyrosine from target cells after internalization and catabolism of the radioiodinated MAbs. We recently reported that a radioiodinated, diethylenetriaminepentaacetic acid-appended peptide, designated immunomedics' residualizing peptide 1 (IMP-R1), was a residualizing iodine label that overcame many of the limitations that had impeded the development of residualizing iodine for clinical use. To determine the factors governing the therapeutic index of the labeled MAb, as well as the factors required for production of radioiodinated MAb in high yield and with high specific activity, variations in the peptide structure of IMP-R1 were evaluated. A series of radioiodinated, diethylenetriaminepentaacetic acid-appended peptide moieties (IMP-R1 through IMP-R8) that differed in overall hydrophilicity and charge were compared. Radioiodinations of the peptides followed by conjugations to disulfide-reduced RS7 (an anti-epithelial glycoprotein-1 MAb) furnished radioimmunoconjugates in good overall incorporations, with immunoreactivities comparable to that of directly radioiodinated RS7. Specific activities of up to 8 mCi/mg and yields > 80% have been achieved. In vitro processing experiments showed marked increases in radioiodine retention with all of the adducts; radioiodine retention at 45 h was up to 86% greater in cells than with directly iodinated RS7. Each of the (125)I-peptide-RS7 conjugates was compared with (131)I-RS7 (labeled by the chloramine-T method) in paired-label biodistribution studies in nude mice bearing human lung tumor xenografts. All of the residualizing substrates exhibited significantly enhanced retention in tumor in comparison to directly radioiodinated RS7, but the nontarget uptakes differed significantly among the residualizing labels. The best labels were IMP-R4 and IMP-R8, showing superior tumor-to-non-tumor ratios by virtue of high tumor uptake and retention and low normal organ uptake, as well as superior radiochemical properties. The therapeutic efficacy of (131)I-IMP-R4-RS7 was compared with that of conventionally (131)I-labeled RS7 and (90)yttrium-RS7 in the nude mice lung cancer model. The therapeutic efficacy of (131)I-IMP-R4-RS7 and (90)yttrium-RS7 were equivalent, and both agents yielded significantly improved control of tumor growth compared with conventional (131)I-labeled RS7.     

Determination of a minimal region of loss of heterozygosity on chromosome 18q21.33 in osteosarcoma

Previous analysis of tumor-specific constitutional LOH had identified a putative tumor-suppressor gene (LOH18CR) active in osteosarcoma tumorigenesis, which mapped to a subregion of chromosome 18q linked to both familial Paget's disease and FEO. Using 9 new polymorphic loci within the previous minimal region of LOH, we have reduced the minimal region of LOH in osteosarcoma tumors to localize the LOH18CR locus to the distal end of chromosome 18q21.33. This new region is approximately 500 kb and contains at least 7 known genes; however, it excludes 2 previous candidate genes: TNFRSF11A (RANK) and BCL2.     

Patient-focused research: using patient outcome data to enhance treatment effects

A program of research aimed at improving the quality of psychological interventions is described. Data from over 10,000 patients were analyzed to understand the association between number of treatment sessions and clinically significant improvement. In addition to a potential dose-response relationship, typical recovery curves were generated for patients at varying levels of disturbance and were used to identify patients whose progress was less than expected ("signal" cases). The consequences of passing this information along to therapists were reported. Analyses of dose-response data showed that 50% of patients required 21 sessions of treatment before they met criteria for clinically significant improvement. Seventy-five percent of patients were predicted to improve only after receiving more than 40 treatment sessions in conjunction with other routine contacts, including medication in some cases. Identification of signal cases (potential treatment failures) shows promise as a decision support tool, although further research is needed to elucidate the nature of helpful feedback. Outgrowths of this research include its possible contribution to social policy decisions, reductions in the need for case management, use in supervision, and possible effects on theories of change.