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Recent studies have demonstrated that rhinovirus infections can be prevented in the family setting through use of intranasal interferon sprays which are commenced when another family member develops a cold. One hundred and twenty-seven children aged 4-9 years who had been hospitalized during their first year of life for severe infections caused by respiratory syncytial virus were studied virologically and epidemiologically during a seven-month period which included the winter months. The hypothesis was that a significant part of their respiratory morbidity would be preventable by a contact prophylaxis approach using intranasal interferon. However, the findings suggest that a preventive approach of this kind would not substantially reduce the burden of respiratory illness in these children because: the target children themselves more often introduced illness into the family than did other household members; rhinovirus infections preventable by interferon were associated with little lower respiratory morbidity; and rhinoviruses were minor contributors to the total respiratory illness burden in these respiratory illness-prone children.

Twenty-nine patients with acute myocardial infarction were given recombinant tissue plasminogen activator (tPA) within 6 hr after onset of chest pain (mean: 3.2 hr) with a total dose of 100mg iv drip given within 3hr for thrombolytic therapy. Serial determinations of total FDP, FDP D-Dimer (specific for FbDP), fibrinogen (Fg), PT, APTT, reptilase time (RT), plasminogen, alpha 2-antiplasmin (AAP), euglobulin lysis time (ELT) and antithrombin III (ATIII) were performed before and 1, 2, 4, 6, 12, 24, 48 hr after initiation of tPA injection in the 29 patients in order to evaluate the hemostatic changes after thrombolytic therapy. Decreases of plasminogen, Fg, AAP & ELT were found from 1 hr after therapy and persisted to 24, 12, 24 & 12 hr, respectively, with the maximum decrease usually between 1-4 hr. Increases of FDP, FDP D-dimer, PT, APTT & RT were found from 1, 1, 2, 1 & 1 hr after therapy, respectively, and sustained to 24, 12, 12, 24 & 12 hr, respectively, with maximum increases between 1-4 hr. No significant changes of ATIII were noted during the 48-hr study-period. 4 of these 29 patients (13.79%) had the complication of localized bleeding, 1 of them needed 1 unit of packed red blood cell transfusion. All thrombolysis-related changes recovered within 24 hr after tPA therapy. No parameter we have studied so far could be used for the prediction of the possibility of coronary patency after tPA therapy. But markedly elevated FDP was found to be associated with high risk of bleeding complication. As the coagulation changes persist for 24 hr or longer, careful monitoring of the coagulation tests and close observation of clinical bleeding signs up to 48 hr are necessary in patients treated with tPA.

To understand the mechanism of hemorrhage, coagulation and fibrinolysis in epidemic hemorrhagic fever (EHF), thrombin time (TT), prothrombin time (PT), fibrinogen (FIG), the platelet count (PLAT), plasminogen (PLG), antithrombin-III (AT-III), fibrin-fibrinogen degraded products (FDP) and platelet functions of aggregation and release were studied dynamically with advanced methods in 134 EHF patients. TT and PT were prolonged, FIG, AT-III and PLG were decreased and FDP was increased. Besides, the decrease of PLAT, the platelet functions of aggregation and release were below the normal level. The results showed that the balance of blood coagulation and fibrinolysis was lost from the early stage of the disease.

The expression of transforming growth factor beta type 1 mRNA was increased by conditional expression of ras. A 31-base-pair sequence found approximately 420 base pairs upstream of the gene encoding human transforming growth factor beta 1 acted as a ras-responsive enhancer element in transient transfection assays. The human sequence contains the element TGACTCT that also is found in a murine ras-responsive enhancer. Analysis of nuclear factors present in cells stably transformed by ras indicated that both human and murine sequences were recognized by the same nuclear factor. The role of fos and jun in ras transcriptional activation was analyzed in transfection assays using murine elements that contained either TGACTCT or TGAGTAA. These experiments showed that while both elements are activated by fos/jun expression to nearly the same event, only the former element responded to ras. In addition, activation of reporters containing TGACTCT is 6-fold higher by ras than by fos/jun. Gel retention experiments revealed that the nuclear factor present in cells transformed by ras exhibited the same sequence preference as demonstrated in the transient transfection assays. UV-crosslinking experiments identify a protein of apparent molecular mass 120 kDa that recognizes the ras-responsive element. This work identifies a persistent signal transduction pathway that links ras to nuclear transcription and indicates that a 120-kDa protein is a target of this pathway.

In this study of murine survival, 422 F1 hybrids between DBA/2J (D2) female mice and C57BL/10 (B10) background H-2 congenic male mice (11 strains), 88 F1 hybrids between B10 female mice and B10 background H-2 congenic male mice (3 strains), and 532 control mice from the 11 parental B10 background H-2 congenic mice were bred over a period of 2 yr. Toward the end of the breeding period there was documentation of Sendai infection in the mouse rooms. All analyses were done separately for the two sexes. Although it did not appear that an unusually high number of mice died during the time the colony was infected with Sendai, there was a highly significant tendency for mice who were younger at the time of the Sendai infection to have shorter survival than mice who were older at that time point. The effect of birth date on survival was approximately as significant as the effect of strain on survival. Hence all analyses of genetic effects on survival were either done within subsets of mice born in the same quarter of a particular year or else included date of birth variables in survival models. Of the 18 possible comparisons of pairs of strains which overlapped in birth dates and differed only in the D end of H-2, five were associated with highly significant survival differences. Of the 11 pairs of strains which overlapped in birth date and differed only in the K end of H-2, none was associated with significant survival differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepadnaviruses share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects, including an association with hepatocellular carcinoma (HCC). Epidemiologic evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80-90%) but not all hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC associated with HBV infections, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10-15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism. It is possible, however, that oncogenic mutations could arise via other mutagenic mechanism that may operate in chronic hepatitis B and/or cirrhosis and which do not involve persisting viral integrations. For example, liver regeneration, which is a feature of the cirrhosis associated with chronic HBV infection (and sometimes with chronic hepatitis B) involves proliferation of many cells with HBV integrations, and such integrations have been shown to be unstable and may lead to mutations through post-integration rearrangements of cellular sequences at sites of viral integrations. Viral sequences appear to be lost or deleted at some such sites of rearranged cell DNA. Chronic HBV infection shares pathologic features of liver cell injury and reactive inflammation, liver regeneration, and in man sometimes cirrhosis with other important risk factors for HCC including chronic alcoholic liver disease, chronic non-A, non-B hepatitis, hemochromatosis, and crypogenic cirrhosis, suggesting that this common pathologic process may be carcinogenic by a mechanism that does not depend specifically on the factor which initiates liver cell injury. The pathogenetic role of chronic hepadnavirus infection in such a process would be in causing liver cell injury with reactive inflammation and hepatocyte proliferation (regeneration).(ABSTRACT TRUNCATED AT 400 WORDS)

A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.

Methotrexate (MTX) was linked, via an active ester intermediate, to a purified IgG fraction of rabbit polyclonal antiserum raised against a cell membrane preparation from the human prostatic cell line PC3. The resulting conjugates contained an average of 0.044 mg of MTX per mg of antibody with acceptable losses in both the binding activity of the immunoglobulin (27.5%) and the enzyme inhibitory activity of the drug (32% at a MTX concentration of 3 x 10(-7) M). Using cultures of PC3 cells the antibody-MTX (Ab-MTX) conjugates were observed to be as effective as free drug in causing cell death and more effective than non-immune IgG-MTX (NIgG-MTX) conjugates. When athymic nude mice bearing PC3 tumours were administered with Ab-MTX conjugates, significant reductions in tumour growth rates were observed compared to animals given saline, MTX alone or NIgG-MTX conjugates (P less than 0.01 in all cases). Furthermore, the accumulation of radioactive MTX in the tumour tissue of animals injected with these Ab-MTX conjugates was 16-fold greater than those given free drug and 8.6-fold greater than those administered with NIgG-MTX conjugates. Uptake by the reticuloendothelial system, however, was not significantly different when animals from each treatment group were compared.

No abstract available.

The effect of hepatic iron on the uptake of ferritin was studied by perfusing livers from normal, iron-deficient and iron-loaded rats with 125I-labeled ferritin. Unlabeled ferritin with tracer doses of labeled ferritin in concentrations of 0.02 to 2,700 nmol/L were studied. Rats were made iron deficient by feeding an established iron-deficient diet for 3 wk. Rats were iron loaded by injection of iron dextran (50 mg/wk) for 3 wk. The mean percentage of uptake of ferritin was similar for doses ranging from 0.22 to 22.2 nmol/L of 125I-labeled ferritin. Uptake of ferritin in the normal animal was saturable, with an apparent maximal velocity of uptake of approximately 9.1 pmol/gm/min and a Michaelis-Menten constant of approximately 5 nmol/L at 37 degrees C. Uptake was minimal at 4 degrees C. The mean uptake of ferritin was 78% +/- 10% in the iron-deficient rats (mean hepatic iron = 1.5 mumol/gm), 79% +/- 10% in the normal animals (mean hepatic iron = 9.2 mumol/gm) and 78% +/- 8% in the iron-loaded animals (mean hepatic iron = 192 mumol/gm). In this experimental system, modulation of hepatic iron did not affect uptake of ferritin, suggesting that regulation of the hepatic ferritin receptor may not depend on hepatic iron content. The rapid uptake of ferritin by the liver despite iron overload is consistent with other observations of the nonregulation of non-transferrin-bound iron by hepatic iron and may play a role in the progressive iron overload seen in hemochromatosis.

A tetrasaccharide possessing a biosynthetically permissible structural variability in and adjacent to the antithrombin III (ATIII) binding site has been isolated from heparin lyase depolymerized bovine lung heparin by using strong anion-exchange high-pressure liquid chromatography (SAX-HPLC). On the basis of two-dimensional 500-MHz 1H NMR experiments, including phase-sensitive correlated spectroscopy (COSY) and rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), and fast-atom bombardment mass spectrometry (FAB-MS), the primary structure of this tetrasaccharide was unambiguously established as delta UAp2S (1----4)-alpha-D-GlcNp2S6S(1----4)-beta-D-GlcAp(1----4)-alph a-D-GlcNp2S3S6S (where delta UA represents 4-deoxy-alpha-L-threo-hex-4-enopyranosyluronic acid). The 1H NMR ROESY experiment proved to be particularly valuable in offering sequence information. Heparins from a variety of species and tissue sources were examined by oligosaccharide mapping using SAX-HPLC and gradient polyacrylamide gel electrophoresis. Two of these heparins are used as anticoagulants; they are porcine intestinal mucosal heparin and bovine lung heparin. The predominant ATIII-binding site in porcine heparin contained an N-acetylated glucosamine residue. We now report the structure of the predominant ATIII-binding site in bovine heparin as----4)-alpha-D-GlcNp2S6S(1----4)-beta-D-GlcAp(1----4)-alph a-D- GlcNp2S3S6S(1----4)-alpha-L-IdoAp2S(1----4)-alpha-D-GlcNp 2S6S(1----. This study shows the presence of one or both types of ATIII-binding-site variants in all of the heparins that were examined.

To verify the relationship of mammographic (Mx) patterns of breast cancer to hormone receptor content (ER, PgR) we studied 129 women (59% in postmenopause; average age 55) in the last 3 years. All women had operable breast cancer and were submitted to mammography before surgery. The tumors were classified, according to Mx characteristics, in 5 classes (Broberg, 1983). ER and PgR contents (cut-off for positivity: 10 fmol/mg prot cyt) were analyzed in all patients by means of DCC method. The percentage of ER+ cases was significantly higher in class I than in all other Mx classes (85% vs 57%; p = 0.02), whereas it was lowest in class IV (51% vs 70%; p = 0.03). The percentage of PgR+ cases was significantly different only in class I with respect to class IV (70% vs 41%; p = 0.002). As for ER and PgR mean tumor content, no statistically significant difference was observed between the 5 classes. When the 2 receptors were simultaneously considered the percentage of ER+ PgR+ cases was higher in class I than in all the extant classes (p = 0.01), and the percentage of ER- PgR- was higher in class IV than in the extant ones (p = 0.02). In selected subgroups of patients, Mx classification of breast cancer can help the physician predict the hormone receptor tumor status with sufficient reliability.