Changes of amino acid serum levels in pediatric patients with higher-risk acute lymphoblastic leukemia (CCG-1961)

BACKGROUND: Deamination of asparagine (Asn) and glutamine (Gln) by asparaginases (ASNase) is associated with good prognosis in acute lymphoblastic leukemia (ALL). Chemotherapy drugs used for ALL may accelerate catabolism of other amino acids (AA). MATERIALS AND METHODS: We studied ASNase activity and changes of Asn, Gln, serine (Ser), threonine (Thr), histidine (His), proline (Pro) and arginine (Arg) levels and sought relationships in sera from 73 pediatric ALL patients, who received ASNase-containing chemotherapy. RESULTS: Asparaginase activity averaged 0.4+/-0.34 IU/ml (mean+/-SDEV) in all specimens. All AA decreased after treatment, ranging from 18.6%-82.6% of control. Asparaginase activity of 0.7 IU/ml provided 90% Asn and Gl deamination. The data were dichotomized in subsets of low ASNase (range 0.02-0.39 IU/ml, mean=0.17+/-0.09 IU/ml) and high ASNase (range 0.4-1.69 IU/ml and mean=0.72+/-0.32 IU/ml). Asparagine and Gln % deamination values were correlated with ASNase activity (p=0.0002 and p=0.0001). Similarly, decreases of Arg and Ser levels were also correlated, p =0.0009 and p=0.032, respectively. In the high ASNase subset, a 39% decrease of Arg and 26% of Ser was obtained. Low ASNase activity was correlated with lower Asn and Gln % deamination and with moderate decrease of Ser (14.6%) and Arg (19.6%). Threonine, Pro and His also decreased, but no correlations were obtained with ASNase activity. CONCLUSION: Asparagine, Gln and five other AA declined during ASNase treatment. Asparagine and Gln % deamination values are highly correlated with serum ASNase activity. Asparaginase may indirectly cause moderate depletion of serum Arg and Ser levels, providing an enhancement in leukemia blasts apoptosis. Toxicity from the ASNase and other drugs could enhance the decrease of AA serum levels. Further studies are needed to verify these findings and their potential clinical importance in the treatment of ALL patients.     

Study of conjunctival goblet cell morphology and tear film stability in pseudoexfoliation syndrome

Background Tear secretion and tear film stability seem to be influenced by pseudoexfoliation syndrome (PEX). Histopathological evaluation of conjunctival goblet cells in PEX patients might explain the influence on tear film stability.Methods In a prospective, cross-sectional study, 40 eyes of 40 patients with PEX (study group) had measurement of Schirmer test with anesthesia and break-up time prior to cataract surgery. At the end of an uneventful operation, a 1×1.5 mm sample of conjunctival tissue was obtained and light and electron microscopy were performed. Results were compared with a control group. Histology evaluation was masked. Primary outcome measures included Schirmer test with anesthesia, break-up time, goblet cell density and morphological character of conjunctiva and conjunctival goblet cells.Results Both Schirmer test and break-up time values were significantly lower (P=0.01 and P=0.001) in the PEX patients (mean 10.6 mm and 8.6 s respectively) than in the control group (13.4 mm and 12.3 s respectively). The number of goblet cells in patients with PEX compared with the control group showed no statistically significant difference (P=0.66). Use of trichrome stain revealed significant differences in the staining properties of goblet cells between patients with PEX and controls. On electron microscopy, typical pseudoexfoliation filaments were found in the connective tissue of conjunctiva of PEX patients. Remarkable changes of mucin pockets in the study group were also noticed; they had extremely irregular distribution, various forms of size and appearance and even complete collapse.Conclusion Pseudoexfoliation seems to alter basic features of goblet cell morphology, thus affecting tear film stability. Further studies are necessary to determine the exact mechanism.     

Identification of a peptide antagonist to the peripheral-type benzodiazepine receptor that inhibits hormone-stimulated leydig cell steroid formation

Peripheral-type benzodiazepine receptor (PBR) is an 18-kDa high-affinity cholesterol and drug ligand-binding protein involved in various cell functions, including cholesterol transport and steroid biosynthesis. To aid our investigation of the biological function of PBR, we have set out to identify functional antagonists. By screening phage display libraries, we have identified peptides that displace the high-affinity PBR benzodiazepine drug ligand, Ro5-4864 (4'-chlorodiazepam). Among these peptides, STPHSTP was the most potent (IC(50) = 10 microM). All of the isolated peptides showed a conserved motif STXXXXP. The role of these peptides in Leydig cell steroidogenesis was examined using a transducible peptide composed of the TAT domain of human immunodeficiency virus and the peptides under investigation. Synthesized peptides efficiently transduced into MA-10 Leydig cells, and the peptide TAT-STPHSTP inhibited Ro5-4864- and human chorionic gonadotropin-stimulated steroid production in a dose-dependent manner (ED(50) = 5 microM). TAT-STPHSTP behaved as a competitive PBR antagonist, which did not affect 22R-hydroxycholesterol-supported steroidogenesis. These results yield leads for the development of potent PBR antagonists and indicate that endogenous PBR agonist-receptor interaction is critical for hormone-induced steroidogenesis.     

Acute appendicitis: effect of increased use of CT on selecting patients earlier

PURPOSE: To explore the possibility of a relationship between increased use of computed tomography (CT) for diagnosis of appendicitis and increased occurrence of minimal or subtle CT and surgical findings. MATERIALS AND METHODS: Two groups, each with 50 consecutive patients who underwent CT before appendectomy in 1997 and 2000, were compared. CT scans and surgery-pathology reports were evaluated on a six-grade scale from normal to abscess or inflammatory mass. The demographics, surgical techniques, hospital stay, and grade distribution for the two groups were compared, and the CT results were correlated with surgical findings. RESULTS: In 1997, CT was performed in 33% (50 of 152) of patients undergoing appendectomy, as compared with 59% (50 of 85) 3 years later (P <.001). There was excellent correlation between surgical-pathologic and CT grades (weighted kappa, 0.75; P <.001; Spearman rank correlation, 0.83). There was no significant difference in demographics, rate of surgery, or surgical techniques used, but there was a significant decrease in the median surgical-pathologic grades, from 3.0 to 2.5 (P =.05) for all patients and from 3.5 to 2.6 (P =.003) for patients who underwent CT. Similarly, the median CT grade decreased from 4 to 3 (P <.001). Seven patients had subtle CT findings in 1997 compared with 16 in 2000 (P =.004), and there was a significant decrease in mean hospital stay, from 2.8 days +/- 4 (SD) to 1.5 days +/- 2 (P =.008). CONCLUSION: With increased CT use, there were less severe imaging findings, including absence of periappendiceal stranding, and a significant decrease in surgical-pathologic severity of appendiceal disease and hospital stay.     

Detection of pulmonary embolism: comparison of paddlewheel and coronal CT reformations--initial experience

In five patients with acute multilobar pulmonary embolism (PE) who were imaged with multi-detector row CT angiography, maximum intensity projection images were reformatted from axial images into rotated paddlewheel and coronal planes with three slab thicknesses and were reviewed for evidence of PE on a per-vessel basis with consensus of two readers. Paddlewheel reformations had a significantly higher percentage of overall detection of PE than did coronal reformations obtained with equivalent slab thickness (P <.0001). Paddlewheel reformations with 5.0-mm slab thickness had no significantly different percentage of overall detection of PE compared with that of axial images obtained with 2.5-mm collimation.     

Histologic Comparison of Vibrating Guidewire with Conventional Guidewire Technique in an Experimental Coronary In Vivo Model

Purpose: To compare the damage caused by vibrating guidewire manipulation and conventional guidewire manipulation of soft coronary wires in normal sheep coronary arteries. Methods: Using an intact sheep model the two methods of passing a coronary guidewire down a normal coronary artery under fluoroscopic screening control were studied. The resulting arterial damage caused by the two techniques was studied histologically. The severity of damage was scored from 1 (no damage) to 4 (severe damage) and expressed as: (a) percentage of damaged sections, (b) mean damage score per section and (c) percentage of sections suffering the most severe degree of damage (scores 3 and 4). Results: One hundred and sixty-eight sections were studied. The percentage of damaged sections was lower in the vibrating guidewire group (p = 0.004). The mean damage score and the percentage of sections with a damage score of 3 or 4 were smaller in the vibrating guidewire group than in the conventional guidewire manipulation group (p = 0.001 and p = 0.009, respectively). Conclusions: Both methods of guidewire manipulation cause identifiable vascular damage. The extent and severity of damage appear greater when the guidewire is manipulated manually.     

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer

PURPOSE: 5-Fluorouracil-based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS: Patients with Stage II-III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. RESULTS: Thirty-one patients were enrolled at the following dose levels: 1000 mg/m(2)/d (3 patients), 1150 mg/m(2)/d (4 patients) 1300 mg/m(2)/d (6 patients), 1400 mg/m(2)/d (6 patients), 1500 mg/m(2)/d (3 patients), 1600 mg/m(2)/d (3 patients), and 1700 mg/m(2)/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m(2)/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m(2)/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m(2)/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. CONCLUSIONS: The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m(2)/d in this study. This dose is recommended for additional use in Phase II-III studies.     

New sesterterpene metabolites from the Mediterranean sponge Cacospongia scalaris

Two new sesterterpene metabolites, 16-acetoxy-dihydrodeoxoscalarin (1) and astakolactin (2), were isolated from the sponge Cacospongia scalaris, collected from the gulf of Astakos, Greece, along with furoscalarol (3) and deoxoscalarin (4), which have not been reported from C. scalaris in the past. The unpalatability of the sponge to fish was traced by field feeding assays to the fractions containing dihydrofurospongin-2. The structures of the new metabolites were elucidated by interpretation of their NMR data and high-resolution mass spectral measurements.