Lymphotactin: a key regulator of lymphocyte trafficking during acute graft rejection

One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems with suitable transport proteins. Thus, four maleimide derivatives of doxorubicin were bound to thiolated human serum albumin which differed in the stability of the chemical link between drug and spacer. In the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive albumin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable with that of the free drug (using the BrdU-(5-bromo-2'-deoxyuridine)-incorporation assay and tritiated thymidine incorporation assay respectively, IC50 approximately 0.1-1 microM) whereas conjugates with the amide derivatives showed no or only marginal activity. These results demonstrate that antiproliferative activity depends on the nature of the chemical bond between doxorubicin and carrier protein. Acid-sensitive albumin conjugates are suitable candidates for further in vitro and in vivo assessment.     

Diagnosing ovarian torsion with computed tomography. A case report

BACKGROUND: The diagnosis of adnexal torsion is difficult to make on the basis of symptoms, physical findings or radiologic techniques. Unfortunately, delayed intervention can lead to irreversible damage and loss of the adnexa. This report describes a finding seen on computed tomography (CT) that may increase suspicion of the diagnosis of ovarian torsion. CASE: A 21-year-old woman was admitted with constant abdominal pain and a tender retrouterine mass. Ultrasound failed to provide a definitive diagnosis. CT showed a central, hypodense area consistent with fat and surrounded by a shell of intermediate density. At laparotomy the patient was found to have a necrotic left adnexa due to torsion. Bisection of the adnexal mass confirmed a dermoid cyst with overlying edematous ovarian cortex. CONCLUSION: The observation of a round, hypodense central lesion (dermoid cyst) surrounded by thickened, edematous ovarian cortex on CT is a finding that may aid in the diagnosis of adnexal torsion. The finding is a thickened shell of ovarian cortex surrounding a central mass that has caused the torsion; in this case it was a dermoid cyst.     

Prevention of colon cancer by pre- and probiotics: evidence from laboratory studies

Oligofructose and inulin, selective fermentable chicory fructans, have been shown to stimulate the growth of bifidobacteria which are regarded as beneficial strains in the colon. Studies were designed to evaluate inulin (Raftiline) and oligofructose (Raftilose), for their potential inhibitory properties against aberrant crypt foci (ACF) formation in the colon of rats. ACF are putative preneoplastic lesions from which adenomas and carcinomas may develop. The results of this study demonstrate that dietary administration of oligofructose and inulin inhibits the formation of preneoplastic lesions in the colon suggesting the potential colon tumour inhibitory properties of chicory fructans. Since these prebiotics selectively stimulate the growth of bifidobacteria, tumour inhibitory activity of lyophilized cultures of Bifidobacterium longum (BL) against azoxymethane (AOM)-induced colon carcinogenesis in rats and modulating effect of these cultures on colonic tumour cell proliferation, ornithine decarboxylase (ODC) activity, and ras-p21 oncoprotein expression were investigated. Dietary administration of lyophilized cultures of BL strongly suppressed AOM-induced colon tumour development. Inhibition of colon carcinogenesis was associated with a decrease in colonic mucosal cell proliferation and colonic mucosal and tumour ODC and ras-p21 activities.     

The relation between personality and anxiety: findings from a 3-year prospective study

The authors tested the extent to which the personality dimensions of neuroticism, extraversion, and psychoticism (H. J. Eysenck & S. B. G. Eysenck, 1975) prospectively predicted global anxiety (assessed by items from the Brief Symptom Inventory: L. R. Derogatis & M. S. Spencer, 1982). The authors also examined prospective relations among these personality dimensions and depression to evaluate the specificity of findings. Participants were 466 young adults, primarily undergraduate students, assessed twice over a 3-year interval. An interaction between neuroticism and extraversion predicted both global anxiety and depression 3 years later. Findings indicated that personality, in particular the combination of high neuroticism and low extraversion, may play an important predisposing, etiological role in anxiety. Interpretations and implications of the predictive importance of the Neuroticism x Extraversion interaction in anxiety are discussed, and further speculations about the relation between anxiety and depression are put forth.     

Identification of Asp95 as the site of succinimide formation in recombinant human glial cell line-derived neurotrophic factor

PURPOSE: To compare gadolinium-enhanced inversion-recovery magnetic resonance (MR) imaging with renal cortical scintigraphy in the diagnosis of childhood pyelonephritis. MATERIALS AND METHODS: Thirty-seven patients with fever-producing urinary tract infection underwent gadolinium-enhanced inversion-recovery MR imaging and technetium-99m renal cortical scintigraphy. Each study was read in double-blind fashion by two radiologists. The kidney was divided into three zones, and each was graded as positive, equivocal, or negative for pyelonephritis. RESULTS: Seventy kidneys (210 zones) were imaged. Twenty-six kidneys (54 zones) had evidence of pyelonephritis at both MR imaging and scintigraphy. Twenty-four kidneys (100 zones) were negative on both studies. Twelve kidneys (42 zones) were positive at MR imaging but negative at scintigraphy, and four kidneys (seven zones) were negative at MR imaging but positive at scintigraphy. The results of MR imaging for pyelonephritis were not equivalent to the results of scintigraphy (P = .001 for renal zones). The proportion of positive agreement between readers for the presence of pyelonephritis was 0.85 and 0.57 for MR imaging and scintigraphy, respectively. The proportion of negative agreement was 0.88 and 0.80 for MR imaging and scintigraphy, respectively. CONCLUSION: Gadolinium-enhanced inversion-recovery MR imaging enabled detection of more pyelonephritic lesions than did renal cortical scintigraphy and had superior interobserver agreement.     

Characterization of the effects of retinoic acid on vasoactive intestinal polypeptide gene expression in neuroblastoma cells

The neuropeptide vasoactive intestinal polypeptide (VIP) has a broad range of functions, and its expression has been correlated with neuronal differentiation. Here we present data on the effects of retinoic acid (RA), a known modulator of neuronal differentiation, on VIP gene expression in the human neuroblastoma cell line NB-1. Morphological data, surprisingly, indicate that these cells are not differentiated concomitant with the increase in VIP gene expression. RA was found to exert a concentration-dependent induction of peptides derived from the VIP precursor molecule, prepro-VIP. The effect at both the messenger RNA (mRNA) level, evaluated by Northern blots, and the peptide level, measured by RIAs, was found to be slow and long lasting. No changes in the processing of prepro-VIP were observed using gel chromatography and RIAs specific for various prepro-VIP sequences. Also, the expression of mRNA for the prohormone-processing enzyme PC2, present in these cells, was not altered by RA. The lag period preceding the increase in VIP mRNA led to experiments with the translational inhibitor cycloheximide showing an indirect effect of RA on VIP mRNA expression. Northern blots revealed that at least three mRNAs encoding RA receptor were expressed and rapidly induced by RA in the cells, thus making them possible candidates for the intermediate protein(s) required from the induction of VIP gene expression.     

The pathogenesis and treatment of hemolytic uremic syndrome

BACKGROUND: This study evaluated the cost-effectiveness of posttreatment surveillance after radiation therapy for early stage seminoma. METHODS: From 1988-1995, 47 patients with Stage I, and 11 patients with Stage II seminoma (based on the Royal Marsden staging system) received paraaortic and pelvic lymph node radiation after radical orchiectomy. Patient records were reviewed and patients surveyed to determine the tests ordered for posttreatment surveillance. RESULTS: With a median follow-up of 55 months, there were 2 recurrences among the 58 patients. Eight-year actuarial disease free survival was 93%, with 100% overall survival. Information concerning follow-up screening was available for 56 patients. The follow-up tests ordered included 842 physical examinations, 815 chest X-rays, 839 serum markers, 250 computerized tomography scans, and 112 abdominal plain films. The total cost of these examinations according to 1996 private sector charges and 1996 Medicare reimbursement rates, respectively, was $602,673.01 (average $10,762.02 per patient) and $282,746.52 (average $5049.05 per patient). The two patients who experienced recurrence were diagnosed independently of their posttreatment screening program. One patient recurred 7.5 months after his original diagnosis with an isolated spinal cord compression. The second patient had a mediastinum recurrence > 6 years after treatment. At last follow-up, both patients were disease free after salvage treatment. CONCLUSIONS: Patients with early stage seminoma treated with orchiectomy and radiation have excellent disease free survival rates. The cost of the surveillance program studied does not appear to be justifiable.     

Metoprolol metabolism via cytochrome P4502D6 in ethnic populations

OBJECTIVE: The objective of this study was to determine whether metabolism via cytochrome P4502D6 (CYP2D6) was higher in Black subjects than White subjects. METHODS: Ten Black and 10 White healthy male volunteers who were phenotyped CYP2D6 extensive metabolizer phenotypes participated in this randomized, cross-over study in which metoprolol was used as a model CYP2D6 substrate. In both study phases, subjects received oral rac-metoprolol tartrate (200 mg); during one phase, subjects also took quinidine sulfate (100 mg) daily beginning 3 days before the dose of metoprolol. Plasma samples were collected for 12 and 24 hr after the dose in the metoprolol and metoprolol plus quinidine phases, respectively. Metoprolol enantiomer concentrations were determined by chiral HPLC with fluorescence detection. RESULTS: S-metoprolol areas under the concentration vs. time curves during the metoprolol phase were 879 +/- 600 ng/ml*hr in White subjects vs. 984 +/- 653 ng/ml*hr in Black subjects. During inhibition of CYP2D6-mediated metabolism with quinidine, S-metoprolol areas under the concentration vs. time curves were 2515 +/- 749 and 2719 +/- 742 in White and Black subjects, respectively. Metoprolol elimination half-lives in both groups were approximately doubled by quinidine. Mean S-metoprolol/R-metoprolol ratios were 1.39 in both racial groups during the metoprolol phase, and during the metoprolol plus quinidine phase were 0.89 and 1.03 in White subjects and Black subjects, respectively (p < 0.05, Blacks vs. Whites). The percentage of metoprolol metabolism inhibited by quinidine was similar between Blacks and Whites (e.g., 66 +/- 15% and 64 +/- 25% of S-metoprolol apparent oral clearance in Blacks and Whites, respectively). CONCLUSIONS: We conclude that there are no differences between Black subjects and White subjects in metabolism via CYP2D6. There were also no racial differences in the contribution of CYP2D6 to overall metoprolol metabolism. The results of this study suggest that drugs are primarily metabolized by CYP2D6 will not exhibit racial differences in their disposition.     

Bone mineral density assessment in children with inflammatory bowel disease

BACKGROUND & AIMS: Children with inflammatory bowel disease (IBD) are at risk for osteoporosis because of undernutrition, delayed puberty, and prolonged corticosteroid use. The aim of this study was to compare bone mineral density (BMD) in children with IBD with that in normal children and to assess the effects of nutritional and hormonal factors and corticosteroid dosages on BMD. METHODS: One hundred sixty-two subjects (99 with IBD and 63 healthy sibling controls) were enrolled. Patients underwent anthropometric assessment, pubertal staging, bone age radiography, and BMD assessment by dual energy x-ray absorptiometry of the lumbar spine, femoral neck, and radius. Laboratory evaluations included serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, osteocalcin, urinary N-telopeptides, albumin, insulin-like growth factor I, and testosterone or estradiol. Cumulative corticosteroid doses were calculated. RESULTS: BMD Z scores at the lumbar spine and femoral neck were lower in patients with IBD, and lower in those with Crohn's disease compared with those with ulcerative colitis. Low BMD persisted after correction for bone age in girls with Crohn's disease (lumbar spine, P = 0.004; femoral neck, P = 0.002). Cumulative corticosteroid dose was a significant predictor of reduced BMD. BMD did not correlate with measures of calcium homeostasis, except elevated serum phosphate and urine calcium levels in girls. CONCLUSIONS: Low BMD occurs in children with IBD (more in Crohn's disease than in ulcerative colitis), especially pubertal and postpubertal girls. Cumulative corticosteroid dose is a predictor of low BMD, but other factors in Crohn's disease remain undetermined.