Search PubMed⌕ Search

Biomedical subjects

D J Lang

Publications and source records attributed to D J Lang.

At least 55 records · Page 3Linked to original sources
PubMed1983

Interferon-induced biochemical changes in cell membranes: possible role of cellular enzyme superoxide dismutase.

Interferon exhibits pleotropic effects on homologous cells. Interferons may be used clinically for both antiviral and antitumor therapy. A better understanding of how interferon achieves its hormonal effects should be useful in developing more judicious and specific applications of these natural substances in therapy. Interferon induces increased activity of two enzymes, 2'5'-oligoadenylate synthetase and a protein kinase, that depend on double-stranded RNA for activation. 2'5' A polymerizes ATP into a novel 2'5'-linked oligonucleotide, which in turn can activate a latent cellular nuclease (RNase L) which degrades mRNA. The second dsRNA-dependent enzyme, a protein kinase, phosphorylates a protein of approximately 67,000 daltons as well as the small subunit of eukaryotic initiation factor (eIF-2). The phosphorylation of eIF-2 results in the inhibition of protein synthesis. The extent of sensitivity to exogenous interferon could be influenced by several factors, including the number of cell surface receptors for interferon and the rate and efficiency at which ligand binding and "processing" is achieved. Prostaglandins, cyclic nucleotides, and oxygen-free radicals could participate in modulation of interferon action at this level. Interferon induces specific changes in the composition of membrane lipids. These changes included loss of unsaturated fatty acids from phospholipids, significant increases in levels of unesterified fatty acids, and moderate increases in concentrations of triglycerides and cholesterol esters. The changes were absent in cells treated with interferon in the presence of inhibitors of fatty acid cyclooxygenase or superoxide dismutase. Whether or not interferon-associated lipid changes directly participate in interferon action is not yet clear. Apparent diversity in its mechanistic approach to virus inhibition may be the key to the success of interferon as a wide-spectrum antiviral agent. Heterogeneity in molecular species of interferon may signify its molecular evolutionary adaptations to specific needs and the eventual development of a "fool-proof" system that we now perceive as the "interferon-system." The observed pleotropic effects may be due to linkage to a broader cellular machinery that operates to identify and effectively handle "foreign" substances.

Animals↗
PubMed1983

Thyroid hormone responses in hemorrhagic shock: study in dogs and preliminary findings in humans.

One hour of hemorrhagic shock in the dog produces alterations in thyroid hormone metabolism far exceeding those seen after elective surgery or thermal injury. The changes in plasma thyroid hormone levels cannot be fully explained by carrier protein loss. Plasma concentrations of total thyroxine (T4) and triiodothyronine (T3) were significantly decreased after only 20 minutes of shock, continued to decrease throughout shock and resuscitation, and remained depressed for several days thereafter. Both hormones reached nadirs during volume replacement of 42% and 17% of baseline, respectively. The total T4 level normalized by the fifth postshock day, but the T3 concentration was still depressed on the ninth day. Plasma albumin, the principal canine thyroid hormone carrier, was significantly reduced 20 minutes after hemorrhage and remained low throughout convalescence. Concentrations of free T4 and T3 decreased during shock, but not as much as the total T4 and T3 concentrations. Reverse T3 levels, corrected for albumin loss, and T3 uptake values were increased during shock and resuscitation. Similar alterations in circulating thyroid hormone concentrations were seen in three patients with major traumatic injury and/or shock. The thyroid hormone changes in shock may represent another example of the "euthyroid sick syndrome."

Adult↗
PubMed1982

Effectiveness of acycloguanosine and trifluorothymidine as inhibitors of cytomegalovirus infection in vitro.

The effectiveness of acycloguanosine (acyclovir) and trifluorothymidine (TFT) as inhibitors of cytomegalovirus (CMV) infection was tested using a plaque-reduction assay. Two laboratory strains and seven clinical isolates were employed. The results indicated that both acyclovir and TFT were ineffective in inhibiting viral cytopathic effect (CPE) below the concentration of 50 microM. At concentrations of 100 microM or more, greater than a 50 percent inhibition was achieved by both acyclovir and TFT on all clinical isolates. Although complete inhibition of plaque formation was seldom achieved even at a drug concentration as high as 200 microM, a reduction of plaque size was consistently observed at drug concentrations above 100 microM. When a low dose of virus was used for infection, ED50 could be achieved at an acyclovir concentration of 50 microM. Laboratory strains of CMV were found to be more resistant than the clinical isolates to inhibition of acyclovir.

Acyclovir↗
PubMed1982

Aggravating effect of alcohol on admission serum insulin patterns of patients with trauma and in a state of shock.

The effect of alcohol upon admission serum insulin levels was studied in 114 injured patients with mean blood alcohol levels of 130 +/- 71 milligrams per deciliter, ranging from 10 to 350. These data were compared with those of 133 similar patients with no measurable blood alcohol levels and with those of 47 healthy volunteers. Whereas marked hyperglycemia caused by trauma or shock was unaffected by alcohol ingestion, insulin levels were more depressed in patients with blood alcohol levels 29.5 +/- 15.3 microunits per milliliter versus 37.8 +/- 36.7 microunits per milliliter, p less than 0.025. In fatally injured patients with measurable alcohol concentrations, insulin and glucose levels were markedly different from those for the corresponding surviving patients, p less than 0.001 and less than 0.01, respectively, with particularly large differences in the insulin-glucose ratio, p less than 0.001. The spontaneous reappearance of the insulin response to hyperglycemia was dependent upon the elapsed time and the severity of injury. Regardless of the blood alcohol concentrations, in patients admitted within two hours, there was no correlation between the levels of insulin and glucose. In patients admitted within two to eight hours, a significant correlation was found only in those with no detectable alcohol blood levels, p less than 0.001. In addition, a remarkable similarity of mean different admission times. These findings suggest that, in alcohol intoxication, recovery of insulin secretions suppressed by acute trauma is delayed; metabolism of alcohol in acute trauma is probably reduced.

Accidents, Traffic↗
PubMed1981

Cytomegalovirus: detection in human colonic and circulating mononuclear cells in association with gastrointestinal disease.

The specificity and strength of the reported association between cytomegalovirus (CMV) and colonic adenocarcinoma were tested by analysis of a consecutive series of surgically resected colons for: CMV-DNA by a DNA-DNA reassociation kinetics (hybridization) procedure; latent virus by co-cultivation of fresh tissue with indicator fibroblasts; and CMV viral antigens by immunofluorescence. Ten of 13 cancer patients whose colonic tissue was able to be examined by all techniques showed evidence of active or prior CMV infection. Four cancer specimens were CMV-DNA (hybridization)- positive; an additional specimen from a cancerous colon was culture-positive. In six instances, CMV DNA was detected in mucosal cells adjacent to colon adenocarcinoma. In tissue from one of three patients with ulcera tive colitis and two of seven patients with other non-neoplastic colonic disease, CMV DNA was also detected. No fresh colonic tissues were demonstrated to have CMV surface or nuclear antigens when examined by immunofluorescence. Culture of peripheral lymphocytes was positive for CMV in three of 14 cancer patients. A CMV specific defect in humoral immunity could not be documented in that most cancer patients, as well as cancer-free patients, exhibited circulating specific antibody to CMV and had a normal capacity for CMV-specific antibody-dependent cellular cytotoxicity. We conclude that CMV, probably in a latent form, is readily detectable in colonic cells of man, including those derived from malignant, pre-malignant and non-malignant tissues. Neither preferential replication in damaged tissue nor carriage of CMV by peripheral lymphocytes homing to gut appear to explain the presence of CMV in colon cells.

Adenocarcinoma↗
PubMed1981

Interferon-resistant cell line lacks fatty acid cyclooxygenase activity.

A clone of L1210 mouse leukemia cells selected for resistance to both the antiviral and anticellular properties of mouse interferon were essentially devoid of fatty acid cyclooxygenase activity. Experiments in which broken cell preparations were mixed or the two cell types were cultivated together failed to indicate the presence of a diffusible enzyme inhibitor. Fatty acid lipoxygenase activity of similar magnitude was detectable in both cell types. A selective impairment of fatty acid cyclooxygenase in interferon-resistant cells is consistent with recently described data suggesting that this enzyme may play a crucial role in mediating the antiviral and anticellular effects of interferon.

Animals↗
PubMed1981

Establishment of the interferon-mediated antiviral state: possible role of superoxide dismutase.

Superoxide dismutase (SOD; superoxide: superoxide oxidoreductase, EC 1.15.1.1) catalyzes the dismutation of O2- free radicals formed during various enzymatic reactions or by ionizing radiation. Genes coding for SOD and sensitivity to exogenous interferon (IF) are syntenic in both mouse and man. Diethyldithiocarbamate (DDC) has been shown to inhibit SOD activity by chelating Cu2+, the metal ion essential for the catalytic activity of the enzyme. Mouse cell lines L, L929, L1210 S6, and L1210 R3 and a human cell line (WISH) pretreated with homologous IF and different concentrations of DDC for various periods of time were tested for their ability to support virus multiplication. Treatment of cells with DDC resulted in dose- and time-dependent inhibition of SOD activity and, simultaneously, in the reduction of antiviral protection by exogenous IF. Cells pretreated for 4 hr with DDC and then washed thoroughly were also resistant to IF, but DDC was without effect if the IF effect was first "established" by a 4-hr exposure to IF before addition of DDC. Under the conditions employed, DDC treatment did not result in any detectable inhibition of DNA, RNA, or protein synthesis in these cells. The data suggest that SOD or a related Cu2+-requiring enzyme may be necessary for the establishment of the IF-induced antiviral state in both human and murine cells.

Animals↗
PubMed1981

Murine cytomegalovirus infection: hematological, morphological, and functional study of lymphoid cells.

Mice were studied for 3 to 4 months after murine cytomegalovirus (MCMV) infection. Serial hematological parameters were evaluated. It was found that MCMV infection of mice were accompanied by the appearance of many atypical lymphocytes similar to those seen in association with the hematological features of mononucleosis associated with human CMV infection. Certain functions of splenocytes were studied in infected and uninfected animals during the 4 months after MCMV infection. Three periods were identifiable by the functional response of splenocytes during the course of MCMV infection. The initial phase was characterized by an elevated response of splenocytes to a T cell mitogen and a B cell mitogen (phytohemagglutinin and lipopolysaccharide, respectively). The intermediate phase was marked by productive virus replication in the salivary gland, injury to lymphoid elements, a depressed response of splenocytes to mitogens (phytohemagglutinin and lipopolysaccharide), and decreased humoral splenocytes to phytohemagglutinin stimulation was again increased, and a nonproductive latent infection was established. Study by scanning electron microscopy of splenocytes during the course of infection revealed morphological changes which were correlated with functional alterations.

Animals↗
PubMed1981

A microtiter assay for cell-mediated cytotoxicity to cytomegalovirus antigens.

The cell-mediated immune response is important to host defense against viruses, yet techniques with which to measure the contribution of lymphocytes (particularly K cells) to anti-viral cytotoxic reactions are not well-established. We describe a new procedure for measuring lymphocyte-mediated antibody-dependent immunity to cytomegalovirus. Central to the assay is the use of 51Cr-containing red blood cells labeled with purified viral antigen, which can be easily quantitated and readily stored for at least 72 hours. High sensitivity was observed, as sera with a 1: 512 complement fixation titer could be diluted 10,000-fold without extinguishing the detectable cytotoxic response. A set of conditions (target/effector ratio; dilution of serum; source and age of target cells; and incubation medium and time) was defined that optimized sensitivity, maintained a low level of background release, yet utilized small amounts of reagents. A kinetics study revealed that 80% of specific release of radioisotope occurred in the first 4 hours. Investigation of the epidemiology, diagnosis, and management of disease caused by CMV may be greatly aided by this new method for quantitating specific cell-mediated anti-viral immune reactivity.

Animals↗
PubMed1981

An evaluation under code of new techniques for the detection of cytomegalovirus antibodies: sensitivity of assays and importance of immune complexes.

Given the morbidity and occasional mortality associated with cytomegalovirus infection and the requirement for good seroepidemiologic tools, assays of high sensitivity and reliability are needed for detection of cytomegalovirus-specific antibody. We report the successful application of two sensitive techniques, antibody-dependent cellular cytotoxicity (ADCC) and the enzyme-linked immunosorbent assay (ELISA) for the measurement of these antibodies and document their favorable comparison with conventional techniques, complement fixation (CF) and indirect hemagglutination (IHA). A coded panel of 48 sera from patients with culture-proven cytomegalovirus infection and disease controls was tested in a controlled fashion by all four procedures. Among 18 CF-positive sera, specific antibody was detected by IHA, ADCC and ELISA in dilutions 100 to 1000-fold higher than measurable by the CF test. Ten of 15 sera, seronegative by CF, were nevertheless found to be cytomegalovirus antibody-positive when assessed by the other procedures. Further, the importance of circulating antigen-antibody complexes upon ADCC test results was documented. Eight sera, known to be antibody-positive by other techniques but with an unexpectedly low (or negligible) capacity to induced ADCC, were found to be immune complex-positive by the Raji cell assay. Ultracentrifugation, useful in precipitating antigen-antibody complexes, enhanced ADCC activity in five of six sera known to be complex-positive. It is suggested that the simultaneous application of multiple antibody detection systems, particularly the newly-developed ones (ADCC, ELISA) will provide both earlier diagnostic information as well as a more comprehensive understanding of the human host's immune response to infection with cytomegalovirus.

Antibodies, Viral↗
PubMed1980

Establishment of the interferon-mediated antiviral state: role of fatty acid cyclooxygenase.

Inhibitors of fatty acid cyclooxygenase 8,11,14-icosatrienoate, hydrogen donor:oxygen oxidoreductase, EC 1.14.99.1) were found to suppress the establishment of the interferon-mediated antiviral state. The prevention, by these compounds, of the development of interferon protection correlated with the degree as well as the duration of cyclooxygenase inhibition. Anti-inflammatory substances lacking cyclooxygenase inhibitory activity did not interfere with the establishment of interferon protection. The addition of exogenous prostaglandins was not found to replace the need for a functional cyclooxygenase and, in some instances, could be shown to diminish the establishment of interferon protection. It is proposed that fatty acid cyclooxygenase is an essential component in the optimal induction of the interferon antiviral state.

Animals↗
PubMed1980

Murine cytomegalovirus: detection of latent infection by nucleic acid hybridization technique.

The technique of nucleic acid hybridization was used to detect the presence of murine cytomegalovirus (MCMV)-specific deoxyribonucleic acid (DNA) in cell cultures and salivary gland tissues. The presence of approximately 4.5 and 0.2 genome equivalents per cell of MCMV-specific DNA was identified in cultures of salivary (ISG2) and prostate gland (IP) cells, respectively. These cells, derived from animals with experimentally induced latent infections, were negative for virus-specific antigens by immunofluorescence and on electron microscopy revealed no visible evidence of the presence of herpesviruses. A cell line derived from the salivary gland of an uninoculated animal (NSG2) was also found to possess MCMV-specific DNA (0.2 genome equivalents per cell). For this reason, salivary gland tissues from uninoculated animals supplied as "specific pathogen-free" mice by three commercial sources were tested upon arrival for the presence of MCMC-specific DNA. MCMV-specific DNA was detectable in pooled salivary gland extracts from uninoculated animals derived from two commercial sources. All of these animals were seronegative and virus negative by conventional infectivity assays.

Animals↗
PubMed1979

Cytomegalovirus infection and chronic hemodialysis.

Serologic and virologic studies of cytomegalovirus (CMV), a virus infection often disseminated in immunosuppressed patients, were initiated among hemodialysis patients, home dialysis partners, hemodialysis center personnel, and several groups of patients. No evidence was found of activation or persistence of CMV infections in connection with chronic renal disease or in association with hemodialysis. Evidence of increased CMV activation and/or infection was found among individuals who had re-entered the dialysis program following renal allograft rejection. The data indicate that dialysis personnel and home dialysis partners are not at increased risk for CMV infection. The findings of this study, which contrast with those pertaining to hepatitis B infection, suggest that different mechanisms are responsible for establishing both infection and persistence of CMV and hepatitis B.

Adult↗
PubMed1979

The unexpected increase of serum insulin levels in patients soon after trauma.

Serum insulin values elevated above the normal fasting range, i.e., 19.0-43.4 microU/ml (mean 27.9 +/- 6.4) were found on admission in 18.2% of patients with various forms of acute injury. Concomitant mean serum glucose level was 184 +/- 59 mg/100 ml compared with 81 +/- 6 mg/100 ml found in overnight fasting normal subjects. In this group of patients, the mean and the highest insulin elevations above the control mean value were 170% (85 microU/ml) and 940% (290 microU/ml) respectively. In individuals admitted directly from the scene of an accident, the mean insulin increase was significantly smaller (95%; p less than 0.01) than in patients transferred from other hospitals-203% (68 microU/ml ) in contrast to 940% (290 microU/ml) found in the transfer subgroup. Mean serum glucose concentrations in both subgroups differed similarly (p less than 0.02). The magnitude of the insulin increase did not correlate with severity or type of injury but showed a strong dependence on the time elapsed following trauma. Strong hyperinsulinemia appears to be less detrimental to survival than severe hypoinsulinemia manifested with a very low insulin-to-glucose ratio. Since both forms of insulinemia may occur under similar clinical conditions, early routine determinations of serum insulin levels are recommended in order to introduce effective therapeutic measures.

Adolescent↗
PubMed1978

Viral infection-homograft interactions in a murine model.

The effects on some host defenses of murine cytomegalovirus (MCMV) and(or) EL(4), a mouse ascites homograft, were studied in mice. Assays of cellular and humoral immunity in response to either or both of these perturbations were carried out by quantitation of various immune activities.Limited studies demonstrated no effect of EL(4) inoculation on the host response to MCMV by organ viral titer, duration of viral persistence, or anti MCMV complement-fixing antibody titer. Prior infection with MCMV, however, resulted in greatly reduced numbers of splenocytes, the source in this study of immune effector cells. Residual splenocytes demonstrated less response to both phyto-hemagglutinin and lipopolysaccharide, particularly in the 2-3-wk interval after infection. Similarly, responder cells in mixed lymphocyte cultures were less reactive when derived from infected animals. Lymphocyte-mediated cytolysis of EL(4) was significantly less in mice infected on the day of and 7, 14, and 21 days before the tumor homograft with a return to control levels by 28 days. 90% of the cell-mediated cytolysis could be eliminated by treatment with anti-theta serum. Serum-mediated cytolysis of EL(4) was also reduced in infected animals. No suppressor cells or serum inhibitory factors could be identified in infected animals. Although alternative explanations exist, this study suggests that in infected animals there is a significant reduction in both the number and function of bone marrow-derived and thymus-derived cells directed against the alloantigens in EL(4).

Animals↗