Neuropsychiatric Presentation of COVID-19: A Case Report of Disinhibition in an Acute SARS-CoV-2 Infection.

Description Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection is notable for a high degree of symptom diversity. Emerging evidence suggests viral invasion of the central nervous system. Therefore, serious neurological and psychiatric manifestations are anticipated. We present the case of a 67-year-old male physician who has a history of stable bipolar disorder for decades and was recently hospitalized for persistent COVID-19 symptoms with documented positive serology. He presented with new and acute onset neuropsychiatric symptoms of disinhibition proximate to the viral infection. We postulate neuroinvasion as the putative origin of the patient's psychiatric instability. Furthermore, an investigation is needed to expand upon our understanding of the potential for neuropsychiatric morbidity related to SARS-CoV-2 for prompt diagnosis and appropriate management. There are also no current studies addressing the risks for neurological and psychiatric symptomatology in SARS-CoV-2 infected patients with persistent chronic mental illness.

Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders.

This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

OBJECTIVES: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). METHODS: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). RESULTS: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups). CONCLUSIONS: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death.

OBJECTIVE: To determine whether cardiac mortality is abnormally high on days considered unlucky: Chinese and Japanese people consider the number 4 unlucky, white Americans do not. DESIGN: Examination of cardiac and non-cardiac mortality on and around the fourth of each month in Chinese and Japanese subjects and white controls. SETTING: United States. SUBJECTS: All Chinese and Japanese (n=209 908) and white (n=47 328 762) Americans whose computerised death certificates were recorded between the beginning of January 1973 and the end of December 1998. MAIN OUTCOME MEASURES: Ratio of observed to expected numbers of deaths on the fourth day of the month (expected number was estimated from mortality on other days of the month). RESULTS: Cardiac mortality in Chinese and Japanese people peaked on the fourth of the month. The peak was particularly large for deaths from chronic heart disease (ratio of observed to expected deaths = 1.13, 95% confidence interval 1.06 to 1.21) and still larger for deaths from chronic heart disease in California (1.27, 1.15 to 1.39). Within this group, inpatients showed a particularly large peak on the fourth day(1.45, 1.19 to 1.81). The peak was not followed by a compensatory drop in number of deaths. White controls, matched on age, sex, marital status, hospital status, location, and cause of death, showed no similar peak in cardiac mortality. CONCLUSIONS: Our findings of excess cardiac mortality on "unlucky" days are consistent with the hypothesis that cardiac mortality increases on psychologically stressful occasions. The results are inconsistent with nine other possible explanations for the findings-for example, the fourth day peak does not seem to occur because of changes in the patient's diet, alcohol intake, exercise, or drug regimens.

Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling.

Wiskott-Aldrich syndrome proteins, encoded by the Wiskott-Aldrich syndrome gene family, bridge signal transduction pathways and the microfilament-based cytoskeleton. Mutations in the Drosophila homologue, Wasp (Wsp), reveal an essential requirement for this gene in implementation of cell fate decisions during adult and embryonic sensory organ development. Phenotypic analysis of Wsp mutant animals demonstrates a bias towards neuronal differentiation, at the expense of other cell types, resulting from improper execution of the program of asymmetric cell divisions which underlie sensory organ development. Generation of two similar daughter cells after division of the sensory organ precursor cell constitutes a prominent defect in the Wsp sensory organ lineage. The asymmetric segregation of key elements such as Numb is unaffected during this division, despite the misassignment of cell fates. The requirement for Wsp extends to additional cell fate decisions in lineages of the embryonic central nervous system and mesoderm. The nature of the Wsp mutant phenotypes, coupled with genetic interaction studies, identifies an essential role for Wsp in lineage decisions mediated by the Notch signaling pathway.

Rate of cognitive change in Alzheimer's disease: methodological approaches using random effects models.

Subtraction of serial scores, Least Squares Estimators, and Best Linear Unbiased Predictors (BLUPs) were compared for estimating rates of cognitive change for Mini-Mental State Exam (MMSE) and Dementia Rating Scale (DRS) scores for 299 probable Alzheimer's disease patients. The BLUPs provided cleaner group estimates of subjects' intercepts and slopes and are preferred. Regression analysis of the BLUP estimates of rate of change indicated that steeper declines were associated with higher levels of education and older age at onset. These effects were much smaller than those due to estimated initial cognitive test score. Differences in longitudinal metric characteristics of the MMSE and DRS were found, with the DRS yielding more precise change estimates. We discuss modeling these longitudinal data, and discuss use of the estimates of rate of change and intercept as data in their own right.

Measuring cognitive change in a cohort of patients with Alzheimer's disease.

Annualized rates of cognitive change in Alzheimer's disease (AD), an important index of disease progression, show marked variability. To determine factors leading to such variability, we computed rates of change in a cohort of patients with AD tested annually with the Mini Mental State Examination (MMSE) and the more detailed Dementia Rating Scale (DRS). Estimates of rates of change (slopes) and intercepts were calculated using least squares and best linear unbiased predictors (BLUPs). Potential predictors of rates of change were examined using multivariate linear regression analysis. We found that the MMSE had more noise than the DRS. For the MMSE, slopes showed a moderate floor effect and a slight ceiling, depending on initial MMSE scores. These effects were less prominent for the DRS, for which slopes increased as intercepts decreased. In analyses of predictors of change, the MMSE was less useful than the DRS. In multiple linear regression models using DRS data, predictors showed statistically stronger effects and explained a greater extent of variation of slopes than did similar models using MMSE data. For example, among patients who died and underwent brain examination at autopsy, neuropathology of Lewy bodies plus AD (Lewy Body variant; LBV) was associated with significantly faster rates of cognitive decline compared to pure AD in analyses that used the DRS, but only trends were identified with the MMSE. The metric properties and longitudinal characteristics of cognitive tests and the statistical methods used to calculate change are key factors in obtaining reliable estimates of change in studying cohorts of patients with AD.

Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources.

OBJECTIVE: To identify the sources of HIV virions in CSF by modeling treatment-associated HIV dynamics. BACKGROUND: We postulated a model in which cell-free CSF virions originate from two major sources, namely, systemic non-CNS and CNS tissues, the latter including brain parenchyma and meninges. The model predicted that with initiation of antiretroviral therapy, the acute-phase decline in CSF HIV RNA levels would be controlled by the kinetics of the dominant virion source (systemic versus CNS). Based on prior observations, we hypothesized that the dominant source of CSF virions would shift from systemic to CNS in more advanced disease. METHODS: Three patient groups were studied: Group 1 (n = 5): nondemented, with early HIV disease (CD4+ lymphocytes > or = 400/microL) or pleocytosis (CSF leukocytes > or = 4/microL); Group 2 (n = 5): nondemented, with advanced HIV disease (CD4+ < 400/microL) and no pleocytosis; Group 3 (n = 2): patients with HIV-associated dementia (HAD). All patients began a new, highly active antiretroviral treatment regimen and underwent serial lumbar punctures and phlebotomies. RESULTS: For patients in Group 2, the rate of decline in CSF HIV RNA was slower than in plasma (p < 0.00001). For Group 1, the rate of decline in CSF was not different from plasma (p > 0.25). Patients with HAD showed high CSF HIV RNA after 5 to 6 weeks of treatment despite a 100-fold decrease in plasma HIV RNA. CONCLUSIONS: CSF and plasma HIV dynamics became increasingly independent in advanced HIV disease, and the compartmental discrepancy was largest in HAD. Our findings suggest that viral replication in CNS tissues may constitute a major, independent source of CSF HIV RNA. In patients with HAD, brain parenchyma itself may be the principal CNS tissue source, and CNS-targeted treatment strategies may be required to eradicate this infection.

Extending the p-plot: heuristics for multiple testing. HNRC group.

In the problem of large-scale multiple testing the p-plot is a graphically based competitor to the notoriously weak Bonferroni method. The p-plot is less stringent and more revealing in that it gives a gauge of how many hypotheses are decidedly false. The method is elucidated and extended here: the bootstrap reveals bias and sampling error in the usual point estimates, a bootstrap-based confidence interval for the gauge is given, as well as two acceptably powerful blanket tests of significance. Guidelines for use are given, and interpretational pitfalls pointed out, in the discussion of a case study linking premortem neuropsychological and postmortem neuropathologic data in an HIV cohort study.

Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity.

To understand the relative efficacy of noradrenergic and serotonergic antidepressants as analgesics in chronic back pain without depression, we conducted a randomized, double-blind, placebo-control head-to-head comparison of maprotiline (a norepinephrine reuptake blocker) and paroxetine (a serotonin reuptake blocker) in 103 patients with chronic low back pain. Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects. The intervention consisted of an 8-week course of maprotiline (up to 150 mg daily) or paroxetine (up to 30 mg daily) or an active placebo, diphenhydramine hydrochloride (up to 37.5 mg daily). Patients were excluded for current major depression. Reduction in pain intensity (Descriptor Differential Scale scores) was significantly greater for study completers randomized to maprotiline compared to placebo (P=0.023), and to paroxetine (P=0.013), with a reduction of pain by 45% compared to 27% on placebo and 26% on paroxetine. These results suggest that at standard dosages noradrenergic agents may provide more effective analgesia in back pain than do selective serotonergic reuptake inhibitors.

Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group.

OBJECTIVE: To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. DESIGN: Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. SETTING: Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. PARTICIPANTS: Eighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. MAIN OUTCOME MEASURES: Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. RESULTS: Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count. CONCLUSIONS: In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.

Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group.

To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV-1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV-1 RNA levels were quantified by using a reverse transcriptase-polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) (<200 CD4+ lymphocytes), NP impairment was associated with significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most impaired subjects met criteria for HIV-associated dementia or minor cognitive-motor disorder. In subjects without AIDS, CSF RNA and NP impairment were unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we found elevated CSF HIV-1 RNA levels in NP impaired subjects with AIDS. Before AIDS, systemic viral replication, possibly through CD4+ mononuclear cell trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion may unmask a correlation between increased productive central nervous system HIV infection and clinical neurocognitive disorders.

Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group.

OBJECTIVE: To determine if mortality is increased in individuals with human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders less severe than frank dementia. DESIGN: A prospective cohort study; median duration of follow-up was 2.4 years. Kaplan-Meier analysis and Cox proportional hazards models were used to compare survival times according to neurocognitive classification. SETTING: University-based research unit. PARTICIPANTS: A volunteer sample of 414 individuals seropositive for HIV-1. Subjects were classified at their baseline evaluation as neuropsychologically (NP) normal or abnormal (impaired in > or = 2 NP test domains). A subgroup of NP abnormal subjects met operational criteria for HIV-associated minor cognitive motor disorder; the remaining subjects were designated NP impaired. Subjects with frank dementia were excluded. MAIN OUTCOME MEASURE: Mortality. RESULTS: At the baseline evaluation, 256 (62%) of 414 subjects were designated normal; 109 (26%). NP impaired; and 49 (12%), minor cognitive motor disorder. One hundred six participants (26%) died during follow-up. Compared with the NP normal group, the unadjusted relative risk (RR) of death for all NP abnormal subjects (minor cognitive motor disorder and NP impaired) was significantly increased (RR, 1.7; 95% confidence interval [CI], 1.2-2.6; P < .005). After adjusting for concurrently measured predictors of survival (CD4 lymphocyte counts, Centers for Disease Control and Prevention HIV disease classification, hemoglobin concentration, and serum beta 2-microglobulin) in proportional hazards models, mortality for all NP abnormal subjects remained elevated (RR, 1.8; 95% CI, 1.2-2.8; P < .01). The elevation in mortality risk for subjects with minor cognitive motor disorder was statistically significant (RR, 2.2; 95% CI, 1.2-3.8; P < .01); for NP impaired subjects it was marginally significant (RR, 1.6; 95% CI, 1.0-2.8; P = .06). CONCLUSIONS: The HIV-infected individuals with NP impairment had a higher risk of dying than those without impairment. This was particularly true for those meeting syndromic diagnostic criteria.

Repeated exposure to the Mini-Mental State Examination and the Information-Memory-Concentration Test results in a practice effect in Alzheimer's disease.

We analyzed short-term variation of Mini-Mental State Examination (MMSE) and Information-Memory-Concentration (IMC) Test scores in 39 patients with Alzheimer's disease (AD), tested four times over 6 weeks. Although analysis of variance had failed to show a significant "learning" effect or other trends, we reexamined the data using repeated measures models, with and without a learning effect. In the model without a learning effect, mean MMSE scores decreased minimally and mean IMC scores decreased by 0.84 points over 6 weeks. In the model that allowed a potential learning effect between the first and second test sessions, scores increased significantly, by 1.12 +/- 0.47 points for the MMSE and 1.04 +/- 0.43 points for the IMC Test. Patients' test scores predicted from the models had less variability than did their raw scores. The short-term practice effect, although small, should be considered in interpreting changes in scores, especially in therapeutic studies in AD.

Evaluation of outpatient experience with vitreoretinal surgery.

The experience of 55 consecutive individuals undergoing outpatient vitreoretinal surgery was evaluated. Objective variables, including preoperative and intraoperative information, subjective postoperative pain, and discomfort were measured with a previously validated 100 mm visual analogue scale. Patients also ranked the overall experience. Average pain and discomfort scores in the recovery room were 21.8 and 22.6 and overnight were 26.7 and 30.4 (scale 0 to 100), respectively. Eighty eight per cent of subjects were satisfied with the experience. Elevated pain and discomfort scores were statistically correlated with scleral buckling, prolonged surgical or recovery room time, requirement for parenteral pain medications, and high intraocular pressure on the first postoperative visit. None of the patients needed further hospital treatment. This study suggests that vitreoretinal surgery in an appropriately selected population does not require routine inpatient care.

Blood pressure reactivity to exercise: stability, determinants, family aggregation, and prediction.

Previous studies have shown blood pressure reactivity to exercise predicts future resting blood pressure. Subjects in this study were 206 healthy Mexican-American and Anglo-American families with fifth or sixth grade children. A total of 539 children (mean age = 12 years) and parents (mean age = 37 years) had complete data at baseline, and 79% were remeasured 48 months later. Blood pressure was measured during a submaximal cycle ergometer fitness test. Reactivity measures included systolic blood pressure at 70% of maximal heart rate (SBP70) and slope of the blood pressure-heart rate association during exercise (SLOPE). Stability of reactivity measures over 24 months varied from .22 to .63 (all p less than 0.001). Correlates of blood pressure reactivity in parents included resting heart rate, gender, age, and sodium intake. Correlates of reactivity in children included resting heart rate, body mass index, and age. Modest but significant levels of family aggregation of blood pressure reactivity were observed. In stepwise multiple regression analyses, SBP70 at baseline predicted resting blood pressure 48 months later in parents but not in children. The present results confirm previous studies indicating systolic blood pressure reactivity to exercise is a significant predictor of later resting blood pressure.

The evolution of lymphadenopathy and hypergammaglobulinemia are evidence for early and sustained polyclonal B lymphocyte activation during human immunodeficiency virus infection.

To examine whether polyclonal activation of B lymphocytes as measured by hypergammaglobulinemia contributes to lymphadenopathy in human immunodeficiency virus (HIV) infection, correlates of adenopathy were examined in 240 homosexual men. Lymph node size was measured in 12 sites semiannually over 4 years. Both adenopathy and hyperglobulinemia developed within 1 year after seroconversion and persisted at high levels. Adenopathy declined near diagnosis of AIDS whereas serum IgG decreased 8-16 months after diagnosis. Adenopathy attributable to HIV occurred in all palpable node groups. By logistic regression, HIV-positive men were best discriminated from HIV-negative men by size of posterior cervical nodes and the number of sites with enlarged nodes. In a repeated measures model of covariance, adenopathy in HIV-positive men was associated with more CD4+ cells (P less than .002), elevated serum globulins (P less than .01), and lower platelet counts (P less than .05). Adenopathy declined over time (P less than .001) and with diagnosis of AIDS or AIDS-related complex (P less than .03). Thus, adenopathy and hypergammaglobulinemia are correlated and follow a similar course through various stages of HIV infection, suggesting that both are caused by polyclonal B cell activation.

A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group.

BACKGROUND: Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial. METHODS: A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy. RESULTS: Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms. CONCLUSIONS: Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia.

Longitudinal study of cytomegalovirus retinitis in acquired immune deficiency syndrome.

The authors prospectively evaluated 67 consecutive patients with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis during a 33-month period to assess the clinical patterns of retinal infection, efficacy of treatment, long-term survival, and relationship of retinitis to immune function. Immediately sight-threatening retinitis presented in six patients (9%) with peripapillary disease; primary foveal infection was not observed. Eighty-seven percent of patients were treated with ganciclovir. Thirty-nine patients (58%) presented with unilateral disease and contralateral infection developed in 15% of those while on ganciclovir. Smoldering (incompletely responsive) retinitis was seen in 33% of the 21 patients whose retinitis progressed while receiving ganciclovir. Progression of treated retinitis was associated with a lower lymphocyte count (P = 0.04). Median survival after diagnosis of CMV retinitis was 8 months. This represents the largest reported prospective study of CMV retinitis and indicates that (1) CMV infrequently poses an immediate threat to vision on presentation, (2) response to therapy may be related to immune function, and (3) smoldering retinitis should be recognized as an important clinical entity associated with treatment failure.

Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethyldithiocarbamate or atomic absorption spectroscopy.

The pharmacokinetics of the cisplatin (DDP) species detected by measurement of diethyldithiocarbamate (DDTC)-reactive species (DDTC-DDP) were compared to the pharmacokinetics of the species detected by measurement of total ultrafilterable platinum in patients receiving DDP alone or in combination with the nephroprotective agent sodium thiosulfate. The doses of DDP studied were 100 mg/m2 (11 courses given to eight patients) and 202.5 mg/m2 (five courses given to four patients) given as 2 h i.v. infusions, the latter with concurrent thiosulfate. When DDP was given alone (100 mg/m2) the two assays yielded the same area under the curve (AUC) values for DDTC-DDP and total ultrafilterable platinum during the first 4 h after the start of infusion; however, beyond 4 h post-infusion, the AUC for total ultrafilterable platinum was consistently greater than that for DDTC-DDP. When DDP was given with thiosulfate (202.5 mg/m2), the AUC for total ultrafilterable platinum was significantly greater than that of DDTC-DDP during the whole sampling period. The ratio of the AUC for total ultrafilterable platinum to DDTC-DDP, when DDP was given with thiosulfate, was barely significantly greater than that when DDP was given alone. These data indicate that during and immediately following a short infusion of DDP the major platinum-containing species present in plasma ultrafiltrate are still capable of reacting with nucleophilic sites on molecules such as DDTC; however, as the reactive species are eliminated, longer half-lived non-reactive ultrafilterable platinum species begin to predominate. They also indicate that although thiosulfate does neutralize a measurable amount of DDP in the plasma on the schedule employed, this degree of neutralization is not sufficient to explain the protection against DDP-induced nephrotoxicity produced by thiosulfate.