Structure and metabolism of collagens in various pathologies

Collagen constitutes approximately one third of the body's proteins; it has different functions, and changes in its metabolism and structure accompany almost every pathologic process. This article reviews basic knowledge of the alterations and defects in collagen metabolism and structure which give rise to a number of heritable and acquired diseases, their causes and consequences.     

An empirical study of object relations in adult children of depressed elderly mothers

The present report confirms the presence of Na(+)-K(+)-Mg2+ ATPase in the erythrocyte membranes of the frog Rana balcanica (previously Rana ridibunda) (Schneider et al. 1993; Sofianidou et al. 1994). The Na(+)-K(+)-Mg2+ ATPase activity was 60% reduced by the presence of ouabain. The pH optimum was 8.0, the optimum Mg2+:ATP concentration ratio was 2.2:1. The existence of an ATPase with a high K(m) for ATP (1.48 mmol/l) was postulated. At pH 7.4 and 8.0, the adenine nucleotide pattern of glucose-depleted erythrocytes showed a characteristic reduction in ATP contents. Adenine nucleotide concentrations were higher at pH 7.4 than at pH 8.0. Ouabain inhibited ATP breakdown at both pH values studied. The strongest inhibition was observed at pH 7.4. The decline of the total contents of adenine nucleotides appears to be determined by the rate of AMP breakdown.     

C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential

A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.     

The 3' untranslated region of manganese superoxide dismutase RNA contains a translational enhancer element

A redox-sensitive protein that binds to the 3' untranslated region (UTR) of manganese superoxide dismutase (MnSOD) RNA has been described previously [Fazzone, H., Wangner, A., and Clerch, L. B. (1993) J. Clin. Invest. 92, 1278-1281; Chung, D. J., and Clerch, L. B. (1997) Am. J. Physiol. 16, L714-L719]. In the present study, cross-competition gel retardation and RNase H assays were used to identify a 41-base region located 111 bases downstream of the stop codon as the 3' UTR cis element involved in protein binding. The base sequence of this region is approximately 75% conserved among the 3' UTRs of rat, mouse, cow, and human MnSOD mRNAs at approximately the same distance downstream of the stop codon. The role of this protein-binding region in RNA translation was assessed in an in vitro rabbit reticulocyte lysate system. Translation of MnSOD RNA from which the 3' UTR element was deleted decreased 60% compared with translation of MnSOD RNA containing the 3' UTR cis element. In the presence of a specific competitor oligoribonucleotide that inhibits MnSOD RNA protein-binding activity, translation of MnSOD RNA containing the 3' UTR was decreased by 65%. Thus, both the cis element and RNA protein-binding activity were required for more efficient translation of the MnSOD. An analysis of ribosomal profiles suggests the MnSOD RNA-binding protein participates in the formation of the translation initiation complex. When MnSOD RNA-binding activity was inhibited, initiation complex formation was decreased by 50%. From the data obtained in this study, we propose that the 3' UTR cis element of MnSOD through its interaction with MnSOD RNA-binding protein may function as a translational enhancer.     

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors

PURPOSE: In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS: To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS: Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION: The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.     

Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists

The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethan one, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 microM (IC50) and a functional Ki = 9.1 microM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 microM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.     

Increased incidence of cancer in infants in the U.S.: 1980-1990

BACKGROUND: During the decade between 1980-1990, the rate of cancer in children in the U.S. increased. It is unknown whether cancer in infancy, which is biologically and clinically different from cancer in older children, also increased. METHODS: To evaluate changes in cancer incidence in infants in the U.S. age < 1 year, data from the Surveillance, Epidemiology, and End Results (SEER) program and the U.S. Bureau of the Census were used to construct age specific, population-based cancer incidence rates. RESULTS: Overall, the annual cancer rate in infants increased from 189 cases per million infants between 1979-1981 to 220 between 1989-1991. At both timepoints, female infants had higher cancer rates than male infants. Although the rates for female infants remained stable at 223 between 1979-1981 versus 236 between 1989-1991, rates for male infants increased from 158 to 205 during the same timepoints. Male infants had increased rates of central nervous system (CNS) tumors (P < 0.05), neuroblastoma, and retinoblastoma; female infants had increased rates of teratomas (P < 0.01) and hepatoblastomas. Between 1979-1981, the three most common types of cancer in infants were neuroblastoma, leukemia, and renal tumors (27%, 15%, and 14%, respectively), and were neuroblastoma, CNS tumors, and leukemia between 1989-1991 (27%, 15%, and 13%, respectively). CONCLUSIONS: This study shows that the rate of certain types of cancer in infants in the U.S. is increasing. Studies of both genetic and environmental factors are needed to explain these increased rates and the changing distribution of cancer in the first year of life.     

Pituitary adenylate cyclase activating polypeptide (PACAP) is localized in human dermal neurons and causes histamine release from skin mast cells

OBJECTIVE AND DESIGN: Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide homologous with vasoactive intestinal polypeptide (VIP) which is known to induce histamine release in human skin mast cells. PACAP has not been detected in human skin. The purposes of the study were to investigate the occurrence of PACAP in human skin and to evaluate the histamine releasing activity of the two common pro-PACAP products, PACAP-27 and PACAP-38. MATERIAL: Fourteen human surgical skin samples were obtained. PACAP and VIP were visualized by immunohistochemistry. A microdialysis technique was used to measure histamine release in intact skin samples following intradermal injections of the peptides. RESULTS: PACAP and VIP were localized in dermal nerves in connection with sweat glands. Intradermal injection of 3 or 10 microm PACAP significantly released histamine. Kinetics of histamine release showed peak release 2-4 min after skin challenge. Ten microm of PACAP-27, VIP and somatostatin caused histamine release with similar efficacy, whereas PACAP-38 was less effective. Substance P was twice as efficient as PACAP-27, whereas calcitonin gene-related peptide did not release histamine. CONCLUSIONS: PACAP is found in human skin and is capable of releasing histamine from skin mast cells.     

Ethical issues in gynecology

This review cites new evidence suggesting a link between the recently discovered membrane bound water-selective channel, aquaporin-4 (AQP4), and the mechanism of central osmoreception. AQP4 is found in a number of brain regions associated with the osmoregulation of vasopressin secretion and thirst, including the supraoptic nucleus (SON) and subfornical organ (SFO). AQP4 expression is restricted to ependymal cell membranes in the SFO and astrocyte membranes in the SON, especially perivascular end foot processes, suggesting that glial cells may correspond to Verney's hypothalamic 'vesicular osmometers'. Information on osmotic status may thus be conveyed to the neuronal elements of the 'osmoreceptor complex' by a neurone-glial interaction.