Onset Of Acquired Immunodeficiency Syndrome Research Articles

Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma.

If Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma, serologic evidence of infection should be present in patients before the disease develops. Using an immunoblot assay for two latent nuclear antigens of KSHV, we tested serum samples from homosexual male patients with the acquired immunodeficiency syndrome (AIDS) with and without Kaposi's sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and HIV-seronegative patients with high titers of antibodies against Epstein-Barr virus (EBV). Serial serum samples obtained from patients with Kaposi's sarcoma before the diagnosis of the disease were tested for evidence of seroconversion. Of 40 patients with Kaposi's sarcoma, 32 (80 percent) were positive for antibodies against KSHV antigens by the immunoblot assay, as compared with only 7 of 40 homosexual men (18 percent) without Kaposi's sarcoma immediately before the onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected men with hemophilia, none were seropositive. When studied by the immunoblot assay over a period of 13 to 103 months, 21 of the 40 patients with Kaposi's sarcoma (52 percent) seroconverted 6 to 75 months before the clinical appearance of Kaposi's sarcoma. The median duration of antibody seropositivity for KSHV-related latent nuclear antigens before the diagnosis of Kaposi's sarcoma was 33 months. In most patients with kaposi's sarcoma and AIDS, seroconversion to positivity for antibodies against KSHV-related nuclear antigens occurs before the clinical appearance of Kaposi's sarcoma. This supports the hypothesis that Kaposi's sarcoma results from infection with KSHV.

P-12-32 - Temperament, character, and molecular genotypes as predictors of antidepressant response

This study carried out to survey the relationship between personality traits and Acquired Immunodeficiency Syndrome (AIDS) in patients with human immunodeficiency virus. This case-control study was conducted on 79 AIDS patients of Triangle Clinic in Arak (case group) and 80 healthy people of Valiasr Hospital in Arak (control group). Demographic information checklist and Cloninger’ Temperament and Character inventory (TCI) were two instruments applied in the study. SPSS software V.19 and tests independent t-tests, Chi squared and Spearman correlation coefficient were used for data analysis with significant level of <0.05. The average of innovativeness variables (M:74.12), harm avoidance (M: 65.17), reward dependence (M:50.030), and self-directedness (M:35.02) in case group in comparison with control group was significantly higher, and there was a significant difference between two groups variables (P-0.000). The novelty seeking had the highest average in the AIDS patients with a history of addiction (M:74.00), and there was statistically significant difference between perseverance variable (P-0.021) and cooperativeness variable (P-0.041) in the two groups of AIDS patients. There was a significant relationship between novelty seeking and age at the onset of AIDS (P-0.038), harm avoidance and age at the onset of addiction (P-0.046), persistence and age at the onset of AIDS (P-0.035) and the time infected with HIV (P-0.033). It is found that two groups are different due to the personalities, so it is essential to consider the personality traits in order to prevent AIDS and also successfully treat patients suffering from AIDS.

Natural History of Vertically Acquired Human Immunodeficiency Virus-1 Infection

Objective. To describe the natural history of vertically acquired human immunodeficiency virus (HIV) infection. Design. This was a prospective follow-up study. Setting. Ten centers of the European Collaborative Study participated. Subjects. One hundred twenty-four HIV-infected children were born to women known to be infected at or before the time of delivery since 1986. Main outcome measures. Deaths, acquired immunodeficiency syndrome (AIDS), and HIV-related symptoms and signs were assessed. Results. In this cohort, treatment before the onset of AIDS was not universal. Less than 10% of children were treated with Zidovudine or intravenous gamma globulin before 6 months of age, with a steady increase to about 40% after 3 years of life. An estimated 23% (95% confidence interval: 15% to 31%) of infected children develop AIDS before the age of 1 year, and nearly 40% (27% to 50%) by 4 years. Ten percent (5% to 16%) die before age 1 year and 28% (16% to 41%) before age 5 years. Twenty-four months after the AIDS diagnosis, an estimated 48% (36% to 70%) of the children are still alive. Although after the age of 1 year immunologic abnormalities became increasingly common, the proportion of infected children with significant HIV-related symptoms or signs declined. Conclusion. The progression of disease in this cohort of vertically infected children was not as fast as previously suggested, even though treatment was not widespread. Although infected children have a high risk of developing some manifestation of HIV infection early in life, serious HIV-related symptoms became less frequent with increasing age. This has important implications for health planning and care provision.

A Nonparametric Analysis of the Transmission Rate of Human Immunodeficiency Virus from Mother to Infant

Infants born to mothers who are infected with the human immunodeficiency virus (HIV) may or may not become infected by perinatal transmission. Unfortunately, passively transferred maternal antibodies make it hard to determine the infant's infection status from HIV antibody testing, because shortly after birth it is not possible to distinguish passively transferred maternal antibodies from antibodies produced by an infected infant. Usually, the infection status is unobservable for each infant, unless the infant reaches the age of 15 months or develops an HIV-related disease such as the acquired immunodeficiency syndrome (AIDS). Traditionally, statistical analyses of the perinatal transmission rate of HIV are based on infants who had been born at least 15 months before the date of analysis. Such analyses can be both inefficient and biased. In this note, we define a mixture model underlying the onset time of AIDS and then obtain the nonparametric maximum likelihood estimators of the HIV transmission rate and of the distribution function of AIDS onset time for infected infants. Nonparametric tests are also derived for detecting differences in HIV transmission rates among different groups of infants. Finally, the methods are applied to the Mothers and Infants Cohort Study in New York City. The transmission rate of HIV from infected mothers to their infants was estimated to be 30.0% with 95% confidence interval (22.3%, 39.1%).

Redistribution of HIV outside the lymphoid system with onset of AIDS

Summary The basis for many of the symptoms and pathological changes found in patients with the acquired immunodeficiency syndrome (AIDS) remains poorly understood. We have used a quantitative polymerase chain reaction technique to investigate the extent to which direct infection with human immunodeficiency virus (HIV) produces the disease manifestations of AIDS. In five patients who died with AIDS-defining illnesses (Centers for Disease Control and Prevention class IV), we found variable, but in many cases extensive, infection by HIV at various sites, including brain, lung, colon, and liver. By contrast, in three HIV-positive subjects who died without HIV-related disease (CDC class II), we found no evidence of significant infection of any non-lymphoid organ. In both groups of patients there were high levels of infection in cells of the spleen, lymph nodes, and peripheral blood. Pathological examination of tissues from the AIDS patients revealed many abnormalities, of which some, such as giant-cell encephalitis in the brain, were specifically associated with the presence of high levels of HIV infection. These findings suggest that spread of HIV outside cells of the immune system is a late event in HIV infection and is extremely sensitive to the degree of immunosuppression in the patient.

Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter AIDS Cohort Study.

Among patients infected with human immunodeficiency virus type 1 (HIV-1), early and widespread use of prophylactic regimens against Pneumocystis carinii is changing the pattern of illnesses related to the acquired immunodeficiency syndrome (AIDS). We conducted a subcohort analysis of 844 men with AIDS (87 percent of whom have since died) from a prospectively followed cohort of 2592 HIV-1-infected homosexual men. A total of 138 men received prophylaxis before the diagnosis of AIDS, but 39 (28 percent) nevertheless had P. carinii pneumonia at some time. Only four illnesses occurred more frequently in men who received P. carinii prophylaxis before the onset of AIDS: Mycobacterium avium complex disease, which developed in 33.4 percent, as compared with 17.3 percent of the 706 men who did not receive early prophylaxis; wasting syndrome (18.4 percent vs. 6.4 percent); cytomegalovirus disease (44.9 percent vs. 24.8 percent); and esophageal candidiasis (21.3 percent vs. 12.8 percent). Collectively, these four diseases accounted for the initial AIDS-related illness in 42.7 percent of those who received prophylaxis before the onset of AIDS, as compared with 10.7 percent of those who did not. During the three six-month periods before the diagnosis of AIDS (0 to 6, > 6 to 12, and > 12 to 18 months), the geometric mean CD4+ cell counts were 48, 87, and 147 per cubic millimeter, respectively, in men who received prophylaxis against P. carinii, as compared with 118, 211, and 279 per cubic millimeter in those who did not. M. avium complex disease, esophageal candidiasis, wasting syndrome, and cytomegalovirus disease are more common in HIV-infected patients who have received prophylaxis against P. carinii than in those who have not. Prophylaxis may delay the first AIDS illness for 6 to 12 months.

Epidemiologic analysis of Kaposi's sarcoma as an early and later AIDS outcome in homosexual men.

The authors separately studied the epidemiology (risk and risk factors) of Kaposi's sarcoma occurring as an initial acquired immunodeficiency syndrome (AIDS) outcome (early Kaposi's sarcoma) and later after a different initial AIDS outcome (later Kaposi's sarcoma) in a cohort of 2,591 human immunodeficiency virus type 1-infected gay men of the Multicenter AIDS Cohort Study between 1984 and 1992. Among 844 AIDS cases, 202 presented with early Kaposi's sarcoma, 101 subsequently developed later Kaposi's sarcoma, and 541 were not diagnosed with Kaposi's sarcoma. Overall, 37.4% of AIDS cases were diagnosed with Kaposi's sarcoma prior to death. Kaposi's sarcoma diagnosed on the skin was significantly more common with early Kaposi's sarcoma (77.3%) than with later Kaposi's sarcoma (65.1%). Men presenting with an AIDS outcome other than Kaposi's sarcoma were at high risk for later Kaposi's sarcoma. Later Kaposi's sarcoma onset in men with a previous AIDS outcome was associated with the following characteristics: 1) lower immune status prior to AIDS and 2) longer post-AIDS survival. A Kaposi's sarcoma diagnosis in a man with a previous AIDS illness approximately doubled the risk (hazard) for death. Histories of urethral gonorrhea and scabies prior to study entry were more common in early Kaposi's sarcoma cases than in later Kaposi's sarcoma cases. However, self-reported sexual activity at study entry and prior to AIDS onset was highest in the later Kaposi's sarcoma group. In this cohort, cigarette smoking had a protective association against all Kaposi's sarcoma in univariate and multivariate models. Only 21.0% of the later Kaposi's sarcoma and 25.0% of the early Kaposi's sarcoma men smoked at least one-half pack of cigarettes daily at study entry compared with 33.8% of non-Kaposi's sarcoma and 35.5% of seroprevalent men still AIDS free. The reasons for this surprising association are unclear. However, other evidence which documents that habitual smoking alters the immune system (and possibly cytokine levels) in ways that could perhaps influence Kaposi's sarcoma pathogenesis should be considered.

Cryptococcus neoformans infection in patients with acquired immunodeficiency syndrome: Clinical forms and therapeutic possibilities

The incidence of cryptococcosis in patients with the acquired immunodeficiency syndrome (AIDS) is approximately 10% and most probably will increase in coming years. The two drugs most commonly used to treat these infections, amphotericin B (with or without flucytosine) and fluconazole, produce successful results in only 42% of all cases. Published reports indicate that there is a great deal of uncertainty regarding drug doses and combinations, as well as the duration of acute-phase treatment, and results are often difficult to interpret. A more precise classification of patients could help resolve many of these difficulties. First, cryptococcal infections that herald the onset of AIDS (primary forms) must be distinguished from those occurring in patients whose general conditions have already been compromised by other opportunistic infections (secondary forms). Clinical diagnoses should also be supported by microbiologic and histologic data. Finally, cryptococcal meningitis has received much more attention than disseminated forms of the disease (with or without meningitis), and these latter types of infections are probably more difficult to eradicate. This report provides a retrospective examination of 20 nonrandomized cases of cryptococcosis, 18 of which were treated with one or more drugs. Twelve of the infections were primary and eight were secondary. Clinical and microbiologic findings indicated that seven patients had cryptococcal sepsis and meningitis, three had only sepsis, and ten had only meningitis. Sixteen of the infections were acute in onset; four were subacute. Three of the seven patients treated with fluconazole alone were cured. Seven others received amphotericin B plus flucytosine; in three of these the infections were eradicated. One patient was successfully treated with amphotericin followed by fluconazole. Only one of the three who received fluconazole, followed by amphotericin plus flucytosine, was cured. The number of cases examined here is small, and no one treatment approach can be considered to be superior on the basis of the results obtained. We feel, however, that early initiation of treatment with both amphotericin and fluconazole might allow a more rational utilization of each drug's advantages, and reports of results will be easier to interpret if cases are classified according to the criteria suggested above.

Trends in the incidence of outcomes defining acquired immunodeficiency syndrome (AIDS) in the Multicenter AIDS Cohort Study: 1985-1991.

Incidence of clinical outcomes defining acquired immunodeficiency syndrome (AIDS) may be expected to change as a consequence of progressive immunosuppression and use of chemoprophylaxis before the onset of AIDS. Using Poisson regression methods, we examined trends in the incidence of initial and secondary AIDS-defining illnesses from 1985 to 1991 among 2,627 homosexual men participating in the Multicenter AIDS Cohort Study who were seropositive for human immunodeficiency virus type 1. The incidence of Pneumocystis carinii pneumonia rose steeply until 1987 but has declined since then (p < 0.001), while the other AIDS-defining conditions have showed significant (p < or = 0.039) upward trends. Trends for Kaposi's sarcoma, lymphoma, neurologic disease, and cytomegalovirus/herpes simplex virus infections were explained by progressive immunosuppression, but residual downward and upward trends were present for P. carinii pneumonia and other opportunistic infections (bacterial, fungal, and protozoal infections and wasting syndrome). Despite selection bias, those receiving P. carinii pneumonia chemoprophylaxis showed a significantly lower incidence of P. carinii pneumonia (relative risk = 0.32, 95% confidence interval 0.16-0.63), and the time trends of P. carinii pneumonia were explained by progressive immunosuppression and use of prophylaxis. No significant effects on all other diagnoses were seen in those selected to receive antiretroviral therapy. Secondary diagnoses showed a strongly significant (p < 0.001) increase in non-P. carinii pneumonia and non-Kaposi's sarcoma among those with initial diagnoses of Kaposi's sarcoma. Overall, the trend observed in the incidence of other opportunistic infections underscores the need for developing and testing new strategies to curtail or delay the onset of these diseases.

HIV INFECTION AND AIDS AMONG U.S. PRISON INMATES

ABSTRACT Compared to the general population, U.S. prison inmates have a high prevalence of human immunodeficiency virus (HIV) infection and an elevated incidence of the resulting acquired immunodeficiency syndrome (AIDS). Inmates at highest risk of being HIV-positive are those with a pre-incarceration history of intravenous drug use. In some state prison systems, AIDS has become the leading cause of death among inmates. Prisoners have a constitutional right to adequate health care, interpreted by many to include voluntary HIV testing and treatment to delay the onset of AIDS. More research is needed in order to better design and fund HIV testing treatment, and risk-reduction programs for inmates. To this end, a research agenda is outlined.

Estimating the AIDS Incubation Period from a Prevalent Cohort

Data from a cohort study of 177 homosexual or bisexual men enrolled in Los Angeles in 1982 and 1983 are used to estimate the incubation period distribution of acquired immunodeficiency syndrome (AIDS). The statistical method used is parametric modeling of the joint distribution of the date of human immunodeficiency virus infection and the time from infection to the onset of AIDS. With this method, the unknown dates of infection and the fact that individuals who developed AIDS prior to the enrollment date are excluded from the sample is taken into account. The estimated proportion of individuals who develop AIDS within 4 years of infection is 0.10 (95% confidence interval 0.05-0.21) and that within 8 years of infection is 0.45 (95% confidence interval 0.30-0.60). These proportions are consistent with those obtained from other cohort studies and through other statistical approaches.

Projections of the Incidence of Non-Hodgkin's Lymphoma Related to Acquired Immunodeficiency Syndrome

Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset, others continue to develop NHL following AIDS diagnosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis, on estimates of improved survival following AIDS diagnosis, and on projections of future AIDS incidence, we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV), imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.

Individual probability for onset of full-blown disease in patients infected with human immunodeficiency virus type 1

Increased concentrations of neopterin, a marker for cell-mediated immune activation, and decreased numbers of CD4+ T cells, are predictors for progression of disease after infection with human immunodeficiency virus type 1. Previous studies have demonstrated different rates of onset of full-blown acquired immunodeficiency syndrome (AIDS) for groups of patients, defined by laboratory marker values, who were initially symptom-free. By re-analysis of one such study, we demonstrate how for an individual patient, the individual marker values, together with a prior risk estimate, can be converted into current or accumulated post-test probability of onset of AIDS at a certain time. We used a statistical technique suggested by Albert et al. (Clin Chem 1984;30:69-76), which allows incorporation of fixed and time-dependent covariates. Besides allowing individual projections, the method shows that the predictive abilities of CD4+ T cell numbers and of neopterin concentrations do not vary greatly with regard to time of observation; both laboratory markers independently modulate the underlying prior probability of AIDS onset, which is significantly increased with the passage of time.

Predictive value of cytomegalovirus viraemia for the occurrence of CMV organ involvement in AIDS

In HIV-infected patients, the presence of cytomegalovirus (CMV) viraemia is predictive of the development of acquired immunodeficiency syndrome (AIDS), but it is not known whether it predicts further occurrence of CMV organ involvement. To assess the predictive value of CMV viraemia in the occurrence of CMV organ involvement, CMV blood cultures were performed at the onset of AIDS in 71 patients. They were prospectively followed up for at least 6 months, with a mean of 16.6 +/- 7 months (6-36 months). CMV viraemia was present in 28/71 patients (39.5%) at the onset of AIDS. CMV organ involvement occurred in 18/71 patients (25.4%) after 8.7 +/- 3.3 months. Fourteen of the 28 patients (50%) with early CMV viraemia developed CMV organ involvement after 7.7 +/- 6.3 months as compared with 4/43 patients (9.3%) who were not viraemic at the onset of AIDS with a mean follow-up of 11.8 +/- 3.8 months (P less than 0.001). At the time of CMV organ involvement, CMV viraemia, however, was present in 94.4% of the cases. No differences in survival was observed between initially viraemic and non-viraemic patients. No difference has found in mean CD4 cell count between viraemic and non-viraemic patients. This high predictive value of early CMV viraemia in AIDS for the occurrence of CMV organ involvement underlines the need for repeated search for CMV organ involvement when CMV viraemia is detected, and for less toxic antiviral drugs that might be used earlier.

Cumulative AIDS Incidence And Altered Mortality from Bacterial Infections

To determine whether populations with high cumulative incidence of acquired immunodeficiency syndrome (AIDS) experienced increased deaths from sepsis, central nervous system abscess, or endocarditis, New Jersey AIDS patients were grouped according to their age, sex, race, and residence-specific cumulative incidence of AIDS since the onset of the AIDS epidemic. Between 1980 and 1986, among 25-44 year olds in the highest cumulative incidence group for AIDS, sepsis mortality increased from 3.3 to 15.2 deaths/100,000/year, an increase of 11.9 deaths/100,000/year (95% confidence interval (6.9, 17.0) deaths/100,000/year); mortality from central nervous system abscesses increased from zero to 1.7 (0.1, 3.2) deaths/100,000/year; and mortality from endocarditis increased from 0.8 deaths/100,000/year to 2.4 deaths/100,000/year, an increase of 1.6 (-0.5, 3.7) deaths/100,000/year. Age-matched New Jersey patient populations with low cumulative incidence of AIDS did not sustain a similar increase. The HIV disease-associated increase in sepsis mortality among young populations represents a new component of the substantial increase in U.S. sepsis mortality that occurred over the last two decades, but was previously limited to older populations.

Drug use and unprotected anal intercourse among gay men.

Conducted a longitudinal study of 604 New York City gay men to examine the link between unprotected insertive and receptive anal intercourse and drug use with sex. Data spanning four 12-month periods from 1980 to 1987 indicated that the link between drug use and high-risk sex diminished as the acquired immunodeficiency syndrome (AIDS) epidemic progressed. Strong and significant cross-sectional associations (average r = .30, p less than .0001) were found between drug use with sex and both types of anal intercourse in the year prior to the onset of AIDS. By 1987 the magnitude of these associations was markedly reduced (average r = .09, p less than .05). Longitudinal results indicate that, although cessation of drug use with sex is associated with subsequent lower rates of unprotected anal intercourse, initiation of drug use with sex is not associated with subsequent increases in this sexual activity. These findings support both causal and noncausal interpretations of the link between substance use and high-risk sex among gay men.

From persistent generalised lymphadenopathy to AIDS: who will progress?

The current rate of progression of persistent generalized lymphadenopathy to acquired immunodeficiency syndrome (AIDS) was tested in a cohort of 105 homosexual men in London, UK. 5 patients were lost to follow-up, and the remaining 100 were seen every 3 months. All tested positive for the human immunodeficiency virus antibody. Previous clinical observations had shown oral candida; anemia; leucopenia; thrombocytopenia; enthrocyte sedimentation rate 15 mm in the 1st hour to be possible predictors of AIDS. 5 of the 13 patients who developed AIDS during a mean follow-up period of 22 months (range 12-32) developed Pneumocystis carinii; 5 Karposi's sarcoma; 1 both; 1 P carinii and cryptosporidiosis; and 1 cryptococcal meningitis. A life table technic calculation showed that over 3 years the probability of patients with persistent generalized lymphadenopathy progressing to AIDS was 20.9%. Of the clinical features examined, those most likely to indicate progression to AIDS were Oral candida (relative risk (RR)=12); Lymphopenia (RR=7); Erythrocyte sedimentation rate 15mm (RR=7); and anemia (RR=6). There were figures for median time before AIDS onset and the range of variation of these median times for these symptoms, e.g. oral candida, 8 months median; range of 1-24 months. Similar prospective studies performed in the US are reviewed. It is determined that a clinical examination and hematological measurements are useful in determining progression risk.

Acquired immunodeficiency syndrome among patients attending hemophilia treatment centers and mortality experience of hemophiliacs in the United States.

The acquired immunodeficiency syndrome (AIDS) was first recognized among hemophiliacs in 1982. The authors have conducted investigations to determine the onset and incidence of AIDS among hemophiliacs and to determine trends in hemophilia mortality since the introduction of clotting-factor concentrates in the late 1960s. A survey of United States hemophilia treatment centers, supported by the Centers for Disease Control and the National Hemophilia Foundation, defined a population of hemophiliacs which was monitored for AIDS cases through June 1984. Death reports from the United States Vital Statistics System and from the hemophilia treatment center survey provided mortality trends for 1968-1979 and for 1978-1982, respectively. The results of these investigations demonstrate the following points. 1) The AIDS epidemic is a new and important cause of illness and mortality among hemophiliacs, although a very low incidence of AIDS among hemophiliacs prior to 1982 cannot be ruled out. 2) The AIDS cases who attended the surveyed hemophilia treatment centers were distributed throughout the United States and were older than hemophilia treatment center patients without AIDS. AIDS cases also used more lyophilized clotting-factor concentrate, but only a small number of cases were reported with this information. 3) Improved care for hemophilia, including the use of clotting-factor concentrates, dramatically reduced hemophilia mortality rates during the 1970s. 4) In 1982, hemorrhage was the major cause of death among hemophiliacs. Deaths from non-alcoholic liver disease were also increased. AIDS incidence among hemophilia treatment center attendees was stable at 0.6 cases per 1,000 hemophilia treatment center attendees per year during 1982 and 1983 but increased sharply to 5.4 cases per 1,000 during the first quarter of 1984.