2',3'-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis.

The antiretroviral action of 2',3'-dideoxycytidine (ddCyd) depends on its intracellular conversion to the 5'-triphosphate metabolite ddCTP. The effect of natural pyrimidines and pyrimidine nucleosides, as well as of a number of inhibitors of pyrimidine nucleotide synthesis (i.e.

A simple method for the rapid determination of the stereospecificity of NAD-dependent dehydrogenases applied to mammalian IMP dehydrogenase and bacterial NADH peroxidase.

The stereospecificity of IMP dehydrogenase (IMP:NAD+ oxidoreductase, EC 1.1.1.

Intussusception: evolution of current management.

The records of 583 children who were treated for intussusception at the Children's Hospital of Buffalo in the period 1930-1985 were reviewed. Following a change in management in 1970 from operative treatment to hydrostatic reduction of the intussusception by barium enema, two main groups are defined. In earlier years 95% of patients underwent operative reduction whereas in the latter period 92% had barium reduction attempted.

The disposition and metabolism of 2',3'-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys.

The pharmacokinetics and metabolism of the anti-human T-lymphotrophic virus type III/lymphadenopathy-associated virus agent 2',3-dideoxycytidine have been examined in BDF1 mice and rhesus monkeys, with ancillary enzyme studies carried out on tissue derived from both the latter species and also from human subjects. For the pharmacokinetic studies, 2',3-dideoxycytidine and its catabolic product 2',3-dideoxyuridine have been separated and measured in plasma, urine, and cerebrospinal fluid by a reverse HPLC method. For metabolic studies, tritium-labeled drug (labeled in the 5- and 6-positions of the pyrimidine ring) has been employed, utilizing an ion exchange HPLC analytical method suitable for the separation of the parent nucleoside from its mono-, di-, and triphosphates in cell extracts and in tissue homogenates.

Unimpaired coupling of phosphorylated, desensitized beta-adrenoceptor to Gs in a reconstitution system.

Heterologous desensitization of turkey erythrocyte beta-adrenoceptors correlates with receptor phosphorylation and impaired receptor-Gs coupling, as assessed by fusion of purified desensitized receptors with X. laevis erythrocytes [(1984) Science 225, 837-840]. We have purified beta-receptors from desensitized and untreated turkey erythrocytes and have compared the abilities of these two receptors to couple with pure turkey erythrocyte Gs in a reconstituted system.

Functional and structural characterization of the two beta 1-adrenoceptor forms in turkey erythrocytes with molecular masses of 50 and 40 kilodaltons.

We have previously described a specific protease in turkey erythrocytes that converts the larger 50-kDa (P50) form of the beta 1-adrenoceptor to a smaller 40-kDa (P40) form [Jürss, R., Hekman, M., & Helmreich, E.

Inosine monophosphate dehydrogenase and myeloid cell maturation.

In previous studies of purine ribonucleotide metabolism in the human myeloid leukemia cell line HL-60, we observed that there is a down-regulation of guanine ribonucleotide biosynthesis from the central intermediate, inosine monophosphate (IMP) and a depletion of intracellular guanosine triphosphate (GTP) and guanosine diphosphate (GDP) pools that occur during the induced maturation of these cells. We also found that inhibitors of IMP dehydrogenase, the enzyme that catalyzes the first step of guanylate synthesis from IMP, are potent inducers of HL-60 maturation. Because of these observations we specifically investigated the activity of IMP dehydrogenase in HL-60 cells and in a new inducible human myeloid leukemia cell line, RDFD2-25, both during maintenance culture and during induced maturation of the cells.

Merbarone: an antitumor agent entering clinical trials.

Merbarone was developed to clinical trial stage on the basis of its 'curative' activity against P388 and L1210 leukemias and moderate activity against B16 melanoma and M5076 sarcoma. Its activity appears to be schedule-dependent favoring a longer duration of administration. The mechanism of action of merbarone is not yet established but it does induce single strand breaks in DNA apparently without binding to DNA.

Advances in the management of infected urachal cysts.

Persistent urachal remnants are uncommon congenital anomalies. Unless an umbilical fistula exists, infection may be the first indication of this abnormality. Five children received initial treatment for this problem at the Children's Hospital of Buffalo during a 20-year period, 1964 to 1984, and a sixth was seen secondarily.

Effect of magnesium citrate on the adsorptive capacity of activated charcoal for sodium salicylate.

The effects of an added saline cathartic (magnesium citrate) on the in vitro adsorption of sodium salicylate by activated charcoal were determined at different pH levels. At low pH added magnesium citrate reduced salicylate adsorption. However, at high pH added magnesium citrate enhanced adsorption.

Lymphoid cell populations in splenectomized and nonsplenectomized SJL/J mice bearing Hodgkin's disease-like reticulum cell sarcoma.

Using the reticulum cell sarcoma (RCS) of the SJL/J mouse as a model for Hodgkin's disease, the effects of tumor growth and splenectomy on the T-cell and B-cell populations were evaluated. Although splenectomy improved survival and reduced gross observable tumor growth in secondary tumor sites, no effect on T-cell and B-cell populations was detected. We conclude that tumor growth appears to be undetected by the immune system; previously reported immunosuppression in RCS-bearing mice must be due to functional changes and not cell population changes; and splenectomy contributes to survival and suppression of tumor cell growth in secondary sites.

Studies on the mechanism of action of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide). VI. Biochemical and pharmacological studies on the degradation of thiazole-4-carboxamide adenine dinucleotide (TAD).

In order to exert its antitumor effects, the C-nucleoside tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted to the dinucleotide TAD (thiazole-4-carboxamide adenine dinucleotide), an inhibitor of IMP dehydrogenase (IMPD). With few exceptions, sensitive tumors (such as the P388 leukemia) have been found to accumulate substantially more of this inhibitory dinucleotide than resistant strains (exemplified by the colon 38 carcinoma). Previous studies have attributed this difference to a depressed capacity to synthesize TAD on the part of tumors refractory to tiazofurin.

Potent and selective anti-HTLV-III/LAV activity of 2',3'-dideoxycytidinene, the 2',3'-unsaturated derivative of 2',3'-dideoxycytidine.

2',3'-Dideoxycytidinene (ddeCyd), the 2',3'-unsaturated derivative of 2',3'-dideoxycytidine (ddCyd) is, like ddCyd itself, a potent and selective inhibitor of HTLV-III/LAV in vitro. This conclusion is based on the relatively high ratio of effective antiviral dose (0.3 microM) versus cell growth inhibitory concentration (20-35 microM) and the lack of any appreciable inhibitory activity against a series of non-oncogenic RNA and DNA viruses.

Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogues stable to phosphodiesterase hydrolysis.

Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4.

Arabinosyl-5-azacytosine: mechanisms of native and acquired resistance.

Factors influencing the activity of the nucleoside analogue arabinosyl-5-azacytosine (ara-AC) were studied in P388 murine lymphoblasts in vitro and in vivo, in variants of these cells with artificially acquired resistance, in the naturally resistant colon 38 carcinoma in vivo, and in a panel of six human tumors maintained in continuous culture. Differences were noted not only between the sensitive and artificially developed resistant variants of P388, but also between the naturally sensitive (P388) and naturally resistant (colon 38) tumors. The artificially developed resistant P388 cell lines showed an inhibited capacity to accumulate nucleotides derived from ara-AC and deoxycytidine, whereas the accumulation of cytidine nucleotides remained unchanged.

Percutaneous central venous catheterization in children: first line choice for venous access.

Percutaneous central venous (CV) catheters using the jugular and subclavian veins have been widely used for hemodynamic monitoring and for venous access in difficult clinical situations. However, peripheral venous cutdowns (PVC) still remain the primary mode of short-term venous access in children. To evaluate percutaneous CV line insertion as a routine procedure, a prospective study of 115 patients (75 CV and 40 PVC) was performed.

The impact of computed tomography scanning on the child with renal trauma.

A six-year experience using computed tomography (CT) in the diagnosis of blunt abdominal trauma was reviewed to assess the impact of CT scanning on a patient with renal injury. Three questions were evaluated: Does the increased sensitivity of the CT scan alter the indications for surgery? Does the CT scan help predict the course and eventual outcome of nonoperative therapy? Are there circumstances when the CT scan is not the most efficient and cost effective method of diagnosis? One hundred seventy six consecutive patients with suspected renal trauma were reviewed. One hundred thirty eight were evaluated by CT scan and IVP, the other 38 by excretory urogram alone.

Presentation of congenital diaphragmatic hernia past the neonatal period.

Congenital diaphragmatic hernias (CDHs) presenting beyond the neonatal period are a rare and unusual problem; they occurred in 11 of 83 children at our institution. Two discrete clinical groups were apparent: (1) younger children, with mainly respiratory symptoms; and (2) older children with gastrointestinal (GI) complaints. Chest roentgenograms suggested CDHs, but GI contrast studies were necessary for confirmation in eight patients.

The avoidable excesses in the management of perforated appendicitis in children.

During a five-year period from 1979 to 1985, 100 consecutive children with perforated appendicitis were managed at our institution. These patients were divided into two groups, which were determined by length of illness and physical findings. Group A consisted of 88 children with signs and symptoms of peritonitis from appendiceal perforation.

Enteral feedback control of pancreatic hypertrophy: the role of pancreatic biliary secretions.

Chronic diversion of pancreatic and biliary secretions away from the proximal small intestine resulted in rapid increases in pancreatic size and protein content in adult rats. The effect was detectable as early as 10 days postsurgery. Differential changes in pancreatic enzymes were evident after bypass.

Arabinofuranosyl-5-azacytosine: antitumor and cytotoxic properties.

Arabinofuranosyl-5-azacytosine (ara-AC), a nucleoside combining the structural elements of 5-azacytidine and arabinofuranosylcytosine, exhibited unusually wide therapeutic activity against several murine leukemias and all three human xenografts of the National Cancer Institute tumor panel. Activity was observed following either a daily or an intermittent regimen of treatment in the i.p.

Cholecystokinin: a factor responsible for the enteral feedback control of pancreatic hypertrophyphy.

Chronic diversion of pancreatic and biliary secretions away from the proximal small intestine results in pancreatic hypertrophy in adult rats. Serum levels of cholecystokinin (CCK) were measured in age-matched control and surgically diverted rats at various times after operation by a radioimmunoassay method that was specific for the sulfated form of CCK. The concentration of CCK was markedly increased in bypassed rats as compared with controls.