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Biomedical subjects

J Mills

Publications and source records attributed to J Mills.

At least 199 records · Page 11Linked to original sources
PubMed1988

Effects of interleukin 2 and large envelope glycoprotein (gp 120) of human immunodeficiency virus (HIV) on lymphocyte proliferative responses to cytomegalovirus.

Lymphocytes from many HIV-infected asymptomatic individuals or patients with AIDS-related conditions (ARC) and from all AIDS patients were unable to proliferate in vitro in response to UV-inactivated cytomegalovirus (CMV). The addition of recombinant IL2 (rIL2) restored proliferative responses of lymphocytes from most HIV-infected asymptomatic individuals and ARC patients to levels similar to those of HIV-seronegative (HIV-) CMV-seropositive (CMV+) individuals. In contrast, rIL2 augmented CMV-specific lymphocyte proliferation of only 33% (6/18) of AIDS patients. Proliferative responses to CMV with or without rIL2 did not correlate well with the levels of CD4+ lymphocytes, HIV antigen levels or ratios of CD4+ and CD8+ lymphocytes. Proliferative responses to CMV were inhibited by relatively high concentrations (greater than or equal to 10 micrograms/ml) of recombinant HIV envelope glycoprotein (rgp120) and this immunosuppression was completely overcome by rIL2. These results indicate that defects in antigen-driven lymphocyte responses of HIV-infected individuals are not simply the result of reduced numbers of CD4+ lymphocytes but are influenced by defects in IL2 pathways and by immunosuppressive effects of HIV gp120.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Cytomegalovirus infection.

The pathogenic importance of cytomegalovirus (CMV) infection in AIDS-associated pneumonitis is controversial. Uncertainty regarding the significance of CMV isolation from pulmonary secretions of AIDS patients results in part from the difficulty in distinguishing CMV infection from CMV disease and from the high frequency of pulmonary CMV co-infection with other opportunistic pathogens. From our review of the literature to date, we have found only three cases in which AIDS patients with hypoxemia and infiltrates on chest x-ray had lung biopsy or autopsy material reported to demonstrate CMV cytopathic effect in the absence of any other pathogen. However, pulmonary CMV co-infection may be a marker of poor outcome in Pneumocystis carinii pneumonia. In this article, appropriate criteria for instituting specific therapy with the antiviral drug ganciclovir are described.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deficiency syndrome: prevalence, natural history, and response to ganciclovir therapy.

Of 760 AIDS patients seen at San Francisco General Hospital in 1986, 5.7 per cent had retinitis and 2.2 per cent had gastrointestinal disease caused by cytomegalovirus. We reviewed the records of 44 patients treated with ganciclovir for culture-confirmed cytomegalovirus retinal (31 patients) or gastrointestinal disease (17 patients) or both (four patients) in 1986. Retinitis stabilized or improved during initial treatment with ganciclovir in 22 of 27 (81.5 per cent) patients. Following a median 10-day induction course, 16 patients with retinitis continued to have serial ophthalmologic assessments: eight patients were maintained on treatment and eight had maintenance treatment deferred. Before treatment, the two groups were comparable in age, Karnofsky scores, hematologic assessment, visual acuity, and history with respect to Pneumocystis carinii pneumonia. Retinitis did not progress for a median 53.8 days in the immediate maintenance group compared to 18.8 days for the deferred maintenance group (p = 0.01). In 17 patients with CMV gastrointestinal disease, nine of 14 (64 per cent) had resolution of pain and eight of 11 (73 per cent) had resolution of diarrhea when treated initially with ganciclovir. In both retinitis and gastrointestinal disease patients, ganciclovir decreased recovery of CMV from urine and blood markedly. Ganciclovir also caused a decrease in mean absolute neutrophil counts to about half of baseline values; decreases in mean platelet count and hemoglobin were also noted but were less than 25 per cent. Neutropenia severe enough to require dose adjustment (less than 800 cells/microliters) occurred in 31 per cent of patients receiving maintenance ganciclovir.

Acquired Immunodeficiency Syndrome↗
PubMed1988

The future of antiviral chemotherapy.

This article has reviewed the principal antiviral agents and their application in the therapy and prevention of viral diseases. Only acyclovir, amantadine, ribavirin, zidovudine, and vidarabine have received FDA approval for therapy of systemic viral infections. Although ganciclovir, phosphonoformate, the acyclovir prodrugs, disoxaril, and the interferons are now being used only on an investigational basis, it is likely that at least some of these agents will soon be licensed. The search for more effective and safer antivirals continues, and with increasing academic and industrial interest, the prospects for this branch of chemotherapy appear promising.

Antiviral Agents↗
PubMed1988

Factors affecting protoplast release from some mesophilic, thermophilic and thermotolerant species of filamentous fungi using Novozym 234.

Factors affecting the release of protoplasts from mycelia of Aspergillus fumigatus, Aspergillus niger, Penicillium ochrochloron and Geosmithia emersonii were investigated. Protoplast yields were found to be greatly dependent on the growth temperature, incubation conditions, lytic enzyme system, mycelial age and mycelial concentration. High yields of protoplasts were obtained from all four organisms after a 3 h incubation with 1 mg/ml Novozym 234 in 0.1 M 2-N-[morpholino] ethane sulphonic acid (MES) buffer at pH 5.0, containing 0.6 M sodium chloride. Supplementation of the incubation medium with 0.03 M calcium chloride enhanced protoplast release in P. ochrochloron but not in the other three fungi.

Aspergillus fumigatus↗
PubMed1987

Inherent sensitivity of cultured human embryonal carcinoma cells to adducts of cis-diamminedichloroplatinum(II) on DNA.

Clinical and experimental data indicate that human embryonal carcinoma cells are unusually sensitive to the antitumor drug cis-diamminedichloroplatinum(II) (cisplatin), but the basis of this sensitivity is unknown. Using colony formation assays we measured survival of cultured human embryonal carcinoma cells following cisplatin treatment and related survival to the amount of platinum bound to DNA, determined by isolation of cellular DNA and flameless atomic absorption spectrometry, over a range of drug doses. Similar measurements were carried out on F9 mouse embryonal carcinoma cells and on a fibroblast cell strain from a patient with the genetic disease Fanconi's anemia, a syndrome associated with hypersensitivity to cytotoxic and clastogenic effects of difunctional DNA-binding agents. These results were compared with similar analyses on a variety of cultured cells from previous studies. The embryonal carcinoma cells and the Fanconi's anemia fibroblast strain were among the most sensitive cells on a dose-response basis. Since the amount of platinum bound to DNA after treatment of these cells was similar to values reported for many other cell types, it follows that mouse and human embryonal carcinoma cells are inherently sensitive to DNA-bound platinum adducts, to a degree approaching the sensitivity of fibroblasts from patients with xeroderma pigmentosum and Fanconi's anemia.

Animals↗
PubMed1987

Cultured stem-cells from human testicular teratomas: the nature of human embryonal carcinoma, and its comparison with two types of yolk-sac carcinoma.

The understanding of differentiation in human teratomas requires a better definition of the phenotype and developmental potential of the stem cells in these tumours. We describe the characterization of 6 new cell lines from human testicular teratomas which are representative of 3 distinct cell types. Cell lines GCT 27, GCT 35, and GCT 48, identified as embryonal carcinoma, comprise epithelial cells which express cytokeratin intermediate filaments and desmoplakins, as determined by indirect immunofluorescence microscopy. A minority of the cells also express vimentin. Most cells in these cultures show surface staining with monoclonal antibodies (MAbs) to stage-specific embryonic antigens SSEA 3 and SSEA 4 but not SSEA 1. Staining with MAb W6/32, which recognizes HLA A,B and C chains in the presence of beta-2 microglobulin, is not above background level. When injected into nude mice, GCT 27 cells form tumours consisting of embryonal carcinoma, somatic tissues, and cells positive in immunocytochemical assays for alphafoetoprotein (AFP) and human chorionic gonadotrophin (HCG); GCT 35 cells form embryonal carcinomas with foci of AFP and HCG-positive cells; and GCT 48 cells form embryonal carcinoma only. A second type of cell (GCT 72) displays some properties of rodent visceral endoderm. GCT 72 cells contain cytokeratin intermediate filaments, but not vimentin, and show very strong staining at cell borders with anti-desmoplakin I + II antibody. At the cell surface, GCT 72 cells express the epitopes recognized by antibodies to SSEA 3, SSEA 4, and SSEA 1; staining with W6/32 is negligible. Levels of AFP in supernatants from GCT 72 cultures are in excess of 500 KIU/I. The tumours formed following inoculation of nude mice with GCT 72 cells are solid yolk-sac tumours, with all cells strongly positive for AFP. A third cell type (GCT 44 and GCT 46), resembles in some ways rodent parietal endoderm. These cells uniformly coexpress keratin and vimentin intermediate filaments, but not desmoplakins. The determinants recognized by MAbs to SSEA 3, 4, or 1 are not detected on the majority of cells in these cultures. In striking contrast to the other teratoma lines, these cells can attach to untreated tissue culture plastic in serum-free medium and may be serially cultivated under these conditions. The tumours formed in nude mice by these 2 cell lines are yolk-sac carcinomas with endodermal sinus tumour histology. Thus, human testicular teratomas consist of epithelial cells which may be nullipotent, pluripotent or committed to extraembryonic endodermal differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Effect of hypoglycin A on insulin release.

Thirty experimental and fifteen control Wistar rats were studied to determine whether hypoglycin A influences insulin levels in the body to contribute to the state of hypoglycemia usually observed in Jamaican vomiting sickness, a condition arising after ingestion of unripe ackees. This fruit also grows in other Caribbean islands, as well as North and Central America. Hypoglycin A is one of the toxic compounds found in unripe ackees and is capable of inducing hypoglycemia. A fall in blood glucose occurred after administration of hypoglycin A. The lowest level of 42.60 +/- 4.84 mg/dl was attained 3 hr after administration of the drug. This alteration of blood glucose from the fasting level of 80.31 +/- 5.20 mg/dl was significant (P less than 0.01). The blood glucose level in the control rats showed no significant change from the fasting level. The insulin level in portal and peripheral blood showed no significant change. Results showed that, although hypoglycin A induced severe hypoglycemia after intravenous application, there was no significant change in insulin levels. This observation suggests that hypoglycin A has a mechanism of action other than an alteration in insulin levels to induce hypoglycemia.

Animals↗
PubMed1987

Effect of combinations of difluoromethylornithine (DFMO) and 9[(1,3-dihydroxy-2-propoxy) methyl]guanine (DHPG) on human cytomegalovirus.

Both the nucleoside analog 9[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir; DHPG) and the polyamine synthesis inhibitor difluoromethylornithine (DFMO) have been reported to inhibit replication of cytomegalovirus (CMV) in vitro. In these studies, DHPG inhibited human CMV replication at concentrations of 0.1 microM or greater, while DFMO was active (and then only inconsistently) at 5 mM or greater. (DFMO was added to cells 3 days before virus to maximize polyamine depletion.) However, DHPG combined with DFMO synergistically inhibited the replication of CMV strain AD169 and one wild-type CMV strain in human foreskin fibroblasts; the effect was evident on both virus yield and plaque formation. The synergistic effect of these two drugs on CMV replication could potentially be exploited clinically to limit drug toxicity or increase efficacy.

Acyclovir↗
PubMed1987

Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus.

Ganciclovir is a congener of acyclovir with in vitro activity against cytomegalovirus. Ninety-seven patients with the acquired immune deficiency syndrome (AIDS) and a serious cytomegalovirus infection received ganciclovir, 3.0 to 15 mg/kg per day. Viremia cleared during drug therapy in 88 percent of patients. Viral shedding from urine and throat ceased or became inapparent during treatment in 78 percent and 68 percent of patients, respectively. Among patients with cytomegalovirus retinitis, 87 percent of evaluable patients had improvement in (30 of 60) or stabilization (22 of 60) of their disease. However, when the drug was discontinued, progression or recurrence of disease always occurred. Long-term suppressive therapy with ganciclovir, 5.0 mg/kg five to seven times weekly, prevented the recurrence of cytomegalovirus disease (p less than 0.001). The drug was eliminated by renal excretion, and in patients without renal impairment (creatinine clearance rates of more than 60 ml/minute/1.73 m2), ganciclovir has a mean half-life of 4.2 hours. Significant neutropenia and leukopenia occurred in 55 percent and 32 percent of patients, respectively.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Comparison of the effects of histamine H1- and H2-receptor agonists on large and small airways in normal and asthmatic subjects.

It is accepted that histamine H1-receptors are present on human bronchial smooth muscle and that they mediate bronchoconstriction. However, the role of the histamine H2-receptor in the airways of man is less certain. In ten non-asthmatic and five asthmatic subjects we have compared the effects of inhalation of a specific H1-receptor agonist, betahistine, a specific H2-receptor agonist, impromidine and the combined H1- and H2-receptor agonist, histamine, on specific airways conductance and measurements from partial expiratory flow-volume curves. Both histamine and betahistine induced reproducible dose-dependent bronchoconstriction in all subjects, as assessed by all measurements made. Impromidine had no effect on measurements of airways function in either group of subjects. These results confirm the presence of bronchoconstricting H1-receptors, and the absence of significant numbers of H2-receptors on human bronchial smooth muscle. There is no difference in the distribution of these receptors in normal and asthmatic subjects.

Adult↗
PubMed1987

Quantitative immunocytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages.

HIV infection of CD4-bearing lymphocytes alone does not fully explain the immune dysfunction of AIDS. Monocyte/macrophages infected with HIV may serve as a reservoir of HIV, may function abnormally and may transmit infection to other susceptible cells, thus playing a central role in the development of the immunodeficiency of AIDS. Quantitative analysis of surface antigens and measurement of HIV antigens in infected cells have been difficult using the conventional approach of immunofluorescent staining of cells on slides. We have developed a system that maintains monocyte/macrophages in suspension culture for at least four months. Through immunocytofluorographic single cell analysis we have shown that CD4 antigen is present on monocytes, and that a tenfold increase in expression occurs during the first two weeks in culture. In contrast, LeuM3 antigens decreased to background levels in the course of long-term culture. Using anti-HIV p24 antibody, we have demonstrated that monocyte/macrophages can be infected with HIV. Up to 70% of cells from individual donors could be infected. The techniques herein described allow in vitro quantitation of some of the mechanisms by which HIV infection of monocyte/macrophages may contribute to the immunodeficiency states associated with AIDS.

Antibodies, Monoclonal↗
PubMed1987

Enzymatic modification of glycocalyx in the treatment of experimental endocarditis due to viridans streptococci.

The presence of abundant surface polysaccharide, or glycocalyx, on viridans streptococci has been associated with failure to eradicate the organism from experimental cardiac vegetations during penicillin treatment. The role of glycocalyx in retarding sterilization was tested by in vivo administration of dextranase, an endohydrolase that attacks internally situated alpha (1-6) linkages. Dextranase and penicillin, either singly or in combination, were used to treat experimental endocarditis. After two days of therapy, 100% of animals treated with penicillin or dextranase alone had infected vegetations, whereas only 25% treated with penicillin and dextranase had infected vegetations (P less than .01). After five days of therapy, 100% of the animals treated with penicillin had infected vegetations, versus none that were treated with penicillin and dextranase (P less than .01). We conclude that glycocalyx acts to retard antibiotic activity in vegetations and that partial enzymatic digestion of the glycocalyx facilitates penicillin sterilization of the infected valve.

Animals↗
PubMed1987

Prevention and treatment of experimental herpes simplex virus encephalitis with human immune serum globulin.

Pooled human immunoglobulin suitable for intravenous administration (IGIV) was evaluated in the prophylaxis and treatment of herpes simplex virus (HSV) type 1 encephalitis in a murine model. Four-week-old BALB/c mice received a single intraperitoneal injection of IGIV or saline 24 h before or up to 24 h after intranasal infection with 10(4.6) PFU of HSV type 1. Treatment with IGIV was protective against death, and the protective effects were dose and time dependent. Treatment with IGIV blocked the production of HSV antibody by infected mice and reduced the number of trigeminal ganglia containing latent virus. Removal of neutralizing antibody from the IGIV pool did not eliminate the protective effect, whereas F(ab)2 fragments of IGIV, which had virus-neutralizing activity that was identical to that of native IGIV, conferred no protection against death. Pooled human IGIV was effective for the prevention and treatment of HSV encephalitis in mice. Antibody-mediated protection required the Fc portion of the immunoglobulin molecule but did not require the direct neutralization of virus.

Animals↗
PubMed1987

Human pharmacokinetics and tolerance of oral ganciclovir.

Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Mechanisms of platelet aggregation by viridans group streptococci.

The direct aggregation of platelets is thought to be an important event in the pathogenesis of viridans streptococcal endocarditis, but the mechanisms for platelet activation are unknown. We evaluated the processes by which two endocarditis-producing strains of viridans group streptococci activated human platelets in vitro, as measured by platelet cyclooxygenase activity, secretion, and aggregation. Addition of either streptococcal strain to platelets suspended in whole plasma resulted in a mean lag phase of 15.3 min, followed by platelet secretion and brisk aggregation. The lag phase duration was dependent on the platelet donor and appeared to be a function of direct platelet-bacterial interaction. Aggregation was partially inhibited by 20 muM [corrected] indomethacin and blocked completely by 1 mg of apyrase, an extracellular ADP hydrolase, per ml. Neither strain aggregated washed platelets suspended in Tyrode solution alone. However, both strains produced maximal aggregation when the platelet suspension was supplemented with 10% (final concentration) normal plasma. Studies with factor-deficient plasmas demonstrated that exogenous fibrinogen was required for aggregation. One or more additional plasma components were needed, which eluted with a molecular weight of 67,000 to 130,000 on gel permeation chromatography. These cofactors have not been described for other platelet agonists, which suggests that viridans streptococci may aggregate human platelets by a novel mechanism.

Adenosine Diphosphate↗