Showing papers by "St. Jude Children's Research Hospital published in 1982"

Molecular mechanisms of variation in influenza viruses

Abstract: Influenza is unique among the viruses in its capacity to vary. Because of antigenic variation, it has proved impossible to control influenza by vaccination, and variation in virulence, host range and transmissibility influence the spread and severity of influenza epidemics. This variation is caused by sequence changes in the genes of the virus and this review summarizes recent information on the structure of the genes and their products, the way in which these vary and the effects of the changes on the biological activities of the virus.

Mass mortality of harbor seals: pneumonia associated with influenza A virus

Abstract: More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, and causes mild respiratory disease in experimentally infected seals. Concurrent infection with a previously undescribed mycoplasma or adverse environmental conditions may have triggered the epizootic. The similarities between this epizootic and other seal mortalities in the past suggest that these events may be linked by common biological and environmental factors.

Natural Mode of Acquisition for de Novo Infection with Pneumocystis carinii

Abstract: Axenic rats maintained in germfree isolators were found to be free of Pneumocystis carinii after three months of immunosuppression with dexamethasone. This P. carinii-free rat model was used to identify the mode of acquisition of P. carinii from the natural environment. Germfree were exposed in selective manner to potential sources of P.carinii, including air, water, and food. Animals exposed in the isolator with filtered (sterile) air and to regular (unsterile) water and food did not acquire P. carinii. Rats exposed in open cages to room air but maintained on sterile water and food acquired the infection. Animals fed lung tissue infected with P. carinii did not acquire the infection. These findings show that P. carinii is naturally acquired as an airborne organism in a de novo infection.

Virulence of Avian Influenza A Viruses for Squirrel Monkeys

Abstract: Ten serologically distinct avian influenza A viruses were administered to squirrel monkeys and hamsters to compare their replication and virulence with those of human influenza A virus, A/Udorn/307/72 (H3N2). In squirrel monkeys, the 10 avian influenza A viruses exhibited a spectrum of replication and virulence. The levels of virus replication and clinical response were closely correlated. Two viruses, A/Mallard/NY/6874/78 (H3N2) and A/Pintail/Alb/121/79 (H7N8), resembled the human virus in their level and duration of replication and in their virulence. At the other end of the spectrum, five avian viruses were restricted by 100- to 10,000-fold in replication in the upper and lower respiratory tract and were clearly attenuated compared with the human influenza virus. In hamsters, the 10 viruses exhibited a spectrum of replication in the nasal turbinates, ranging from viruses that replicated as efficiently as the human virus to those that were 8,000- fold restricted. Since several avian viruses were closely related serologically to human influenza viruses, studies were done to confirm the avian nature of these isolates. Each of the avian viruses plaqued efficiently at 42°C, a restrictive temperature for replication of human influenza A viruses. Avian strains that had replicated either very efficiently or very poorly in squirrel monkeys still grew to high titer in the intestinal tracts of ducks, a tropism characteristic of avian, but not mammalian, influenza viruses. These observations indicate that some avian influenza A viruses grow well and cause disease in a primate host, whereas other avian viruses are very restricted in this host. These findings also provide a basis for determining the gene or genes involved in the restriction of replication that is observed with the attenuated avian viruses. Application of such information may allow the preparation of reassortant viruses derived from a virulent human influenza virus and an attenuated avian virus for possible use in a live attenuated vaccine for prevention of influenza in humans.

Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma.

Abstract: The incidence and clinical characteristics of anaphylactoid reactions to intravenous asparaginase were assessed in 196 patients given E. coli asparaginase and 49 patients given Erwinia asparaginase. All patients were given a 50 IU intravenous test dose followed in 30 min by the full dosage (10,000 IU/m2), if no reaction occurred to the test dose. Twenty-nine of 196 patients (14.8%) given E. coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The probability of an anaphylactoid reaction was significantly greater in those patients not receiving concomitant prednisone-vincristine and patients with a hiatus between courses of asparaginase therapy. By logistic regression analysis, other variables such as age, sex, race, diagnosis, total number of doses and concurrent methotrexate or arabinosylcytosine did not contribute significantly to the probability of a reaction. Twenty-three of the patients who had reacted to E. coli asparaginase and 26 patients who had not reacted to E. coli asparaginase were subsequently given Erwinia asparaginase. Seven of these 49 patients (14%) had an anaphylactoid reaction. The probability of a reaction to Erwinia asparaginase was significantly related to a prior reaction to E. coli asparaginase, concomitant prednisone-vincristine therapy, total number of asparaginase doses, number of prior E. coli asparaginase doses, and diagnosis, when assessed by a logistic regression model. However, after adjusting for prior reaction to E. coli asparaginase and the total number of asparaginase doses given, the other variables did not contribute significantly to the probability of a reaction. Only 5/29 patients reacting to E. coli asparaginase and 1/7 reacting to Erwinia asparaginase had a reaction to the test dose. None of the reactions were fatal.

Pharmacokinetics of Teniposide (VM26) and etoposide (VP16-213) in children with cancer.

Abstract: The clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography—electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDc, VDss, and Cls all being smaller for VM26. Systemic clearances determined by model-independent methods were 5.2±1.0 ml/min/m2 (mean±SD) for VM26 and 17.8±11.2 ml/min/m2 for VP16-213. The major metabolites detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.

Frog Virus 3 DNA Replication Occurs in Two Stages

Abstract: Viral DNA synthesis in frog virus 3 (FV3)-infected cells occurs both in the nucleus and in the cytoplasm (Goorha et al., Virology 84:32-51, 1978). Relationships between viral DNA molecules synthesized in these two compartments and their role in the virus replication were examined. The data presented here suggest that (i) FV3 DNA replicated in two stages and (ii) nucleus and cytoplasm were the sites of stages 1 and 2 of DNA replication, respectively. Stages 1 and 2 were further distinguished by their temporal appearance during infection and by the sizes of the replicating DNA as determined by sedimentation in neutral sucrose gradients. In stage 1, replicating molecules, between the size of unit and twice the unit length, were produced early in infection (2 h postinfection). In contrast, stage 2 of DNA replication occurred only after 3 h postinfection, and replicating molecules were large concatemers. Results of pulse-chase experiments showed that the concatemeric DNA served as the precursor for the production of mature FV3 DNA. Denaturation of concatemeric DNA with alkali or digestion with S1 nuclease reduced it to less than genome size molecules, indicating the presence of extensive single-stranded regions. Analysis of replicating DNA by equilibrium centrifugation in CsCl gradients after a pulse-chase suggested that these single-stranded regions were subsequently repaired. Based on these and previous data, a scheme of FV3 replication is presented. According to this scheme, FV3 utilizes the nucleus for early transcription and stage 1 of DNA replication. The viral DNA is then transported to the cytoplasm, where it participates in stage 2 DNA replication to form a concatemeric replication complex. The processing of concatemers to produce mature viral DNA and virus assembly also occurs in the cytoplasm. This mode of replication is strikingly different from any other known DNA virus.

Reassortant virus derived from avian and human influenza A viruses is attenuated and immunogenic in monkeys

Abstract: An influenza A reassortant virus that contained the hemagglutinin and neuraminidase genes of a virulent human virus, A/Udorn/72 (H3N2), and the six other influenza A virus genome segments from an avirulent avian virus, A/Mallard/New York/6750/78 (H2N2), was evaluated for its level of replication is squirrel monkeys and hamsters. In monkeys, the reassortant virus was as attenuated and as restricted in its level of replication in the upper and lower respiratory tract as its avian influenza virus parent. Nonetheless, infection with the reassortant induced significant resistant to challenge with virulent human influenza virus. In hamsters, the reassortant virus replicated to a level intermediate between that of its parents. These findings suggest that the nonsurface antigen genes of the avian parental virus are the primary determinants of restriction of replication of the reassortant virus in monkeys. Attenuation of the reassortant virus for primates is achieved by inefficient functioning of the avian influenza genes in primate cells, while antigenic specificity of the human influenza virus is provided by the neuraminidase and hemagglutinin genes derived from the human virus. This approach could lead to the development of a live influenza A virus vaccine that is attenuated for man if the avian influenza genes are similarly restricted in human cells.

Undifferentiated non-Hodgkin's lymphomas (Burkitt's and non-Burkitt's types). The relevance of making this histologic distinction.

Abstract: A retrospective study of 66 cases of undifferentiated non-Hodgkin'S lymphomas at the National Cancer Institute over a 22-year period suggests that the histologic distinction between Burkitt'S and non-Burkitt'S types is clinicopathologically meaningful. Thirty-nine patients with Burkitt'S lymphoma had a median age at presentation of ten years. The primary site of disease in these patients was more commonly extranodal; at the time of diagnosis 26 (66%) of these cases revealed intra-abdominal involvement; 25 (64%) of the cases were Stage IV. The 27 patients with non-Burkitt'S lymphomas had a median age at presentation of 34 years; the primary site of disease was more commonly nodal (peripheral adenopathy was often present at the time of diagnosis); only nine (33%) of the cases were Stage IV. Median survival was essentially equivalent in the two groups, 9.5 months for Burkitt'S lymphoma and 10.0 months for the non-Burkitt'S lymphoma. Overall, survival was not significantly different among the two patient populations; however, patients with Burkitt'S lymphoma had a longer survival than those with non-Burkitt'S lymphoma. Estimates of five-year survival (with 95% confidence) are 42% for Burkitt'S lymphoma and 11% for non-Burkitt'S lymphoma, respectively, which are significantly different (P = 0.01)).

Human influenza A viruses in pigs: isolation of a H3N2 strain antigenically related to A/England/42/72 and evidence for continuous circulation of human viruses in the pig population.

Abstract: An influenza virus strain isolated in Northern Italy in 1977 was identified as belonging to the H3N2 subtype (A/swine/Italy/1850/77). A close antigenic relationship to the human strain A/England/42/72 was demonstrated. Serologic surveys of 548 pig sera from 53 farms in two provinces in Northern Italy demonstrated the existence of antibodies to the swine/Italy/1850/77 strain and to A/Hong Kong/1/68, A/Victoria/3/75 and H1N1 (Hsw1N1) strains in the pig population.

The natural history of colorectal carcinoma in adolescents

Abstract: The symptoms, histology, extent, and course of disease of 24 adolescents with colorectal carcinoma who were admitted to St. Jude Children's Hospital between 1964 and 1980 are presented. Twenty of the patients were referred between October 1974 and June 1980. Most patients presented with vague abdominal complaints. Twenty-one of the 24 patients had poorly differentiated mucin-producing adenocarcinoma. Extensive disease at diagnosis and unresponsiveness to medical management was reflected in the eight-month median survival from diagnosis. Only two of the 24 patients survive free of disease 15 and 130 months from diagnosis. Two other patients survive with disease at four and 24 months.

Failure to detect hemagglutination-inhibiting antibodies with intact avian influenza virions.

Abstract: Avian influenza viruses replicate in a variety of mammals and birds, yet hemagglutination inhibition tests show that postinfection sera from these animals (e.g., ferrets and ducks) have insignificant levels of antibodies (Hinshaw et al., Infect. Immun. 34:354-361, 1981). This suggested that avian influenza viruses, in contrast to mammalian viruses, may not induce a significant humoral response. Studies reported here indicate that avian influenza viruses do induce high levels of antibodies in ferrets, ducks, and mice and produce long-lived memory for cytotoxic T-cells in mice. The failure to detect hemagglutination-inhibiting antibodies to avian viruses was explained by the finding that antibodies to avian influenza viruses were not detectable in hemagglutination inhibition tests with intact virus yet were readily demonstrable when hemagglutinin subunits were used. In addition, these sera contained high levels of neutralizing antibodies to the avian virus. These findings suggest that the hemagglutinins of avian and mammalian influenza viruses may differ in their accessibility to antibodies or the biological consequence of antibody attachment or both. The practical consequence of these studies is that hemagglutination inhibition tests with intact avian viruses fail to detect antibody and do not correlate with virus neutralization. The avian virus used in these studies, A/Mallard/NY/6870/78 (H2N2), replicated and caused mortality in BALB/c mice, emphasizing that the host range and virulence of avian viruses extends to mammals. The above findings suggest that avian viruses could infect mammals in nature, yet seroepidemiological studies with conventional hemagglutination inhibition tests could give misleading results.

Acute megakaryoblastic leukaemia associated with intrinsic platelet dysfunction and constitutional ring 21 chromosome in a young boy

Abstract: A 3-year-old boy with pancytopenia and a paucity of circulating blast cells was found to have acute megakaryoblastic leukaemia. Histopathologic investigation of the bone marrow biopsy disclosed replacement by megakaryoblasts and mild-to-moderate reticulin fibrosis, the megakaryocytic origin of these cells was confirmed by their staining properties and by cross-reactivity with rabbit anti-rat platelet serum. Treatment with adriamycin and cytosine arabinoside induced a complete remission of this otherwise rapidly fatal disease. Before chemotherapy, the patient's platelets showed decreased aggregation in response to thrombin and adenosine diphosphate, as well as a defective thrombin-induced serotonin release reaction. Neither functional defect resolved after remission induction, indicating that the platelets were intrinsically abnormal. Most striking was the finding of a constitution chromosomal defect, a ring No. 21 chromosome, in addition to an abnormal malignant stem line. This appears to be the first reported instance of a constitutional r(21) chromosome associated with acute leukaemia.

The effects of diltiazem in dystrophic hamsters.

Abstract: Calcium accumulates in muscles of dystrophic hamsters (DH) and patients with Duchenne muscular dystrophy. Various Ca antagonists were beneficial to the cardiomyopathy of DH, but had only minor effects on skeletal muscle. We administered a new Ca antagonist, diltiazem, 25 mg/kg/day orally to normal and dystrophic hamsters from ages 37 to 92 days. We observed a marked reduction in muscle Ca in DH treated with diltiazem: 73% in the heart, 61% in the diaphragm, and 48% in the rectus femoris. Plasma CK was significantly lower (by 37%) in treated DH, while the elevated rate of noncollagen protein synthesis in the diaphragm was not diminished. Histologically, the most important change was a reduction in Ca deposits in the heart. Diltiazem was well-tolerated by all animals and did not modify Ca content in normal hamsters. This study suggests that diltiazem may have therapeutic value in those conditions that are accompanied by excessive accumulation of Ca in tissues, such as muscular dystrophy.

Peroxidase Antimicrobial System of Human Saliva: Hypothiocyanite Levels in Resting and Stimulated Saliva

Abstract: The antimicrobial oxidizing agent hypothiocyanite ion (OSCN-) was measured in resting (drooling) and stimulated (expectorated) whole saliva. Stimulation of the saliva flow rate resulted in a rapid decrease in OSCN- concentration, whereas the thiocyanate ion (SCN—) concentration and peroxidase activity were increased. The decrease in OSCN — levels was greater than could be accounted for by dilution of the whole saliva volume. Assuming that the antimicrobial activity of the salivary peroxidase system is proportional to OSCN- concentration, this system may be more effective in resting saliva than in stimulated saliva.

Nodular histiocytic lymphoma: factors influencing prognosis and implications for aggressive chemotherapy.

Abstract: Twenty-five patients with Stage III and IV nodular histiocytic lymphoma (NH), entered on three different Eastern Cooperative Oncology Group protocols from 1972-78, were analyzed for response and survival. A complete response (CR) rate of 44% was observed, with 40% partial responders (PR). Four of the 11 CRs are continuing in their original remission. Median survival for CRs was 52 months; for PRs it was 30 months. The six patients treated with cyclophosphamide-prednisone had a median survival of 18 months versus 51 months for the 19 patients treated with more aggressive combination chemotherapy programs. No significant difference in survival was noted between those patients with both nodular and diffuse histology and those with a pure nodular pattern. The median survival of the 25 NH patients was 47 months and is similar to a group of 101 patients with nodular mixed lymphoma (NM) entered on the same ECOG protocols during this time. This survival is intermediate between the nodular lymphocytic poorly differentiated subtype and diffuse histiocytic lymphoma. It suggests that patients with NH histologies be treated with aggressive combination chemotherapy programs designed to achieve complete remission and prolonged disease-free survival.

Regulation of transferrin receptor expression in concanavalin A stimulated and Gross virus transformed rat lymphoblasts.

Abstract: Expression of the cell surface receptor for the serum glycoprotein transferrin has been correlated with cellular proliferation in normal lymphocytes undergoing mitogen or antigen induced proliferative responses In the present study, the expression of transferrin receptor in Concanavalin A stimulated rat lymphocytes or Gross virus transformed lymphoma cells has been examined with respect to the following questions: (1) is expression of receptor activity related to blastogenesis or to the subsequent IL-2 dependent DNA synthetic activity, and (2) is transferrin receptor expression regulated in similar fashion in both normal and malignant lymphoblasts? Scatchard analysis of saturation binding data illustrated that binding site number increased and subsequently decreased during the response while the receptor affinity for transferrin remained constant These findings were confirmed by SDS-polyacrylamide gel electrophoretic analysis of radiolabeled cell surface proteins which specifically interact with transferrin Examination of nonproliferating normal lymphoblasts (96 hr post Con A stimulation) compared with the same population of cells stimulated to reinitiate DNA synthesis with a partially purified preparation of Interleukin 2 (IL-2) showed that transferrin receptor expression was tightly linked to the IL-2 dependent stimulation of DNA replication This coordinate regulation of receptor expression was markedly less stringent in retrovirus transformed thymic lymphoma cells

Metastatic epidural tumors in children

Abstract: Spinal cord compression is a rare but serious complication of malignant diseases in children. Epidural cord compression was noted in 81 patients within the past 17 years at this center. The complication developed at different times during the course of the primary disease. For 29 of our patients, cord dysfunction was one of the initial signs of cancer--Ewing sarcoma, neuroblastoma, Hodgkin disease, and malignant lymphoma. By contrast, for most of the patients with osteosarcoma and rhabdomyosarcoma, it appeared later in their clinical course. The treatment outcome of patients who were paraplegia with complete loss of sensory function for greater than or equal to 48 hours was poor. Only four of 22 in this group became ambulatory. Ten patients with osteosarcoma did not undergo laminectomies because they all had multiple metastases and terminal disease. Paraplegia developed in all ten. There was no difference in ambulatory rates among other patients, with or without laminectomies.