Vitamin C status of a campus population: college students get a C minus.

Diet and the vitamin C status of two samples of college students were examined. Nonsmoking participants were recruited from a campus population during the fall and winter months. The prevalence of vitamin C deficiency (plasma vitamin C concentrations less than 11 mumol/L) ranged from 1% to 2% in the sampled campus populations. Marginal vitamin C status (plasma vitamin C concentrations from 11 to less than 28 mumol/L) was observed in 12% of the fall sample and 16% in the winter sample. Participants with marginal vitamin C status consumed significantly fewer servings of fruits and vegetables daily than participants with adequate vitamin C status. Marginal vitamin C status, which is even more pronounced in smokers, has been associated with fatigue and increased severity of respiratory tract infections. Because the vitamin C status of many college students, both smokers and nonsmokers, may be inadequate, health promotion or wellness programs for all students should emphasize the importance of adequate fruit and vegetable consumption.

Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults.

OBJECTIVE: The purpose of this study was to determine whether carnitine metabolism or histamine degradation would be useful parameters for investigating the optimal requirement for vitamin C. METHODS: Twenty-two non-scorbutic subjects with subnormal vitamin C status (plasma vitamin C < 28 mumol/L) were placed on a metabolic diet low in vitamin C for 3 weeks and repleted with graded doses of vitamin C: 10, 30 and 60 mg vitamin C daily (group 1) or 10,125 and 250 mg vitamin C daily (group 2) for weeks 1, 2 and 3, respectively. Fasting blood samples were collected weekly and analyzed for plasma vitamin C, plasma free carnitine and blood histamine. RESULTS: Group 1 subjects remained in a subnormal vitamin C state throughout the 3-week study, and blood histamine and plasma free carnitine were not impacted by the experimental treatment. Plasma vitamin C in group 2 subjects rose significantly during the study, and these subjects finished the study with an ample vitamin C status indicative of vitamin C intakes above the recommended dietary allowance. Both blood histamine and plasma free carnitine were inversely related to vitamin C status in group 2 subjects. CONCLUSIONS: These data indicate that blood histamine and plasma free carnitine are altered in individuals with subnormal, non-scorbutic vitamin C status and provide evidence that metabolic changes independent of collagen metabolism occur prior to the manifestation of scurvy. Thus utilizing scurvy as an end-point to determine vitamin C requirements may not provide adequate vitamin C to promote optimal health and well-being.

Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial combined experience.

Parenchymatous intracerebral hemorrhage (ICH) is a serious, infrequent complication of thrombolytic therapy for acute myocardial infarction. We studied the clinical and radiologic features, manner of presentation, associated factors, and temporal course in 23 patients with ICH associated with 150 mg or 100 mg recombinant tissue-type plasminogen activator (rt-PA) and heparin therapy for acute myocardial infarction in the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial. In TIMI II, 13 of the 23 ICH patients developed or maintained systolic blood pressure > or = 160 mm Hg or diastolic blood pressure > or = 90 mm Hg during the rt-PA infusion and before the onset of neurologic symptoms. Six patients (26%) had life-threatening ventricular arrhythmias, five before onset of neurologic symptoms. A decreased level of consciousness was the earliest neurologic abnormality in 15 (65%) and the most common initial physical finding (in 19, or 82%). Onset was usually gradual (70%), but time to maximal deficit was frequently (61%) within 6 hours of onset. The locations of the primary ICH sites were lobar in 16 (70%), thalamic in four (17%), and brainstem-cerebellum in three (13%), but the putamen was never the primary site. Multiple lobar hemorrhages occurred in six cases (26%). The timing and size of ICH was similar among patients treated with 150 mg rt-PA and 100 mg rt-PA. Brain CT demonstrated an arteriovenous malformation in one case. Four patients had hypofibrinogenemia, which was profound in three patients. Pathologic findings were available for five patients. Of these, three patients had cerebral amyloid angiopathy, and one had hemorrhagic transformation of an ischemic cerebral infarction found at autopsy. We conclude that ICH following rt-PA and heparin therapy for acute myocardial infarction presents as a distinctive clinical syndrome. Intracerebral bleeding after combined thrombolytic and antithrombotic therapy may be associated with cerebral amyloid angiopathy and other vascular lesions. Acute or persistent hypertension before or during rt-PA infusion, life-threatening ventricular arrhythmias, and hypofibrinogenemia, either alone or in combination, may play roles in some cases. Care should be exercised when considering thrombolytic therapy for patients with risk factors for ICH.

Coronary artery bypass graft surgery after thrombolytic therapy in the Thrombolysis in Myocardial Infarction Trial, Phase II (TIMI II).

OBJECTIVES: We examined the results of coronary artery bypass graft surgery after thrombolytic therapy in the Thrombolysis in Myocardial Infarction trial, Phase II (TIMI II) with particular emphasis on patient characteristics, the impact of antecedent percutaneous transluminal coronary angioplasty and morbidity and mortality in certain subgroups. BACKGROUND: Coronary bypass surgery is frequently used after thrombolytic therapy, but there is relatively little information with regard to early and late outcomes. METHODS: We analyzed 3,339 patients enrolled in the TIMI II trial. Bypass surgery was performed in 390 patients (11.7%): 54 (14%) within 24 h after entry into the trial or within 24 h of coronary angioplasty and 336 (86%) between 24 h and 42 days after entry. RESULTS: Perioperative mortality rates were, respectively, 16.7% and 3.9% (p < 0.001); perioperative myocardial infarction rates were 5.6% and 6.2%, respectively; and major hemorrhagic events occurred in 74% and 50.9%, respectively (p = 0.002). On multivariate analysis, the only independent predictor of perioperative mortality was bypass surgery within 24 h after entry or after coronary angioplasty. Among patients undergoing bypass surgery within 24 h of entry or after coronary angioplasty, the prevalence of multivessel disease (59.1% vs. 77.8%) and use of the internal thoracic artery (18.5% vs. 62.5%) were lower than in the remaining surgical patients. Among the 322 perioperative survivors, the 1-year mortality rate after discharge was only 2.2% and 1.9%, respectively, in the two groups. Only one patient had a documented recurrent myocardial infarction during the first year. CONCLUSIONS: The increased mortality rate with bypass surgery after thrombolytic therapy, particularly in patients undergoing operation within 24 h of coronary angioplasty or during the involving phase of infarction, must be balanced against the excellent 1-year prognosis and perioperative survivors, who are in general a group at higher risk of death or recurrent infarction. These data provide a basis for comparison for future studies.

Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Study Group.

OBJECTIVES: The aim of this study was to provide insight into the mechanism of acute myocardial infarction by determining the modifiers of timing and possible triggers of onset of infarction. BACKGROUND: A higher frequency of onset of acute myocardial infarction has been reported in the morning with a peak in the 1st 3 h after awakening. This observation suggests that the onset of infarction may be triggered by activity in the morning and at other times of the day. METHODS: The clinical history of the 3,339 patients entered into the Thrombolysis in Myocardial Infarction phase II study was analyzed to determine characteristics predicting a higher frequency of infarction between 6 AM and noon, and onset of infarction during exertion. RESULTS: A higher proportion (34.4%) of infarctions began in the morning (6 AM to noon) compared with other times of the day. Characteristics independently predicting a higher frequency between 6 AM to noon were no beta-adrenergic blocking agent use in the 24 h before infarction, no discomfort other than the index pain in the preceding 48 h, occurrence of the infarction on a weekday and no history of current smoking. In 18.7% of patients, infarction occurred during moderate or marked physical activity. Independent predictors of exertion-related infarction included male gender, no history of current smoking, white race, no use of calcium channel blocking agents or nitrates in the preceding 24 h, the absence of either chest pain at rest in the 3 weeks before infarction or any pain in the preceding 48 h, the absence of new onset angina and the presence of exertional pain in the preceding 3 weeks. Compared with patients whose infarction occurred at rest or during mild activity, those with exertion-related infarction had fewer coronary vessels with > or = 60% stenosis (p = 0.002) and were more likely to have an occluded infarct-related vessel after thrombolytic therapy (p = 0.01). CONCLUSIONS: Further study of the timing and activity at onset of infarction may provide insight into the pathophysiologic mechanisms causing acute myocardial infarction and provide clues to preventive measures.

Transcutaneous determination of tissue dihematoporphyrin ether content. A device to optimize photodynamic therapy.

Photodynamic therapy involves the use of light of appropriate wavelength to excite a photosensitizer resulting in tissue destruction. The photosensitizer dihematoporphyrin ether is selectively retained in tumors allowing for tumor destruction while sparing normal structures. Accessibility of skin tumors makes them well suited for photodynamic therapy. Tissue and tumor dihematoporphyrin ether content is estimated based on the amount of dihematoporphyrin ether administered. In our study, skin dihematoporphyrin ether content was measured in guinea pigs transcutaneously by a hand-held fluorometer and compared with dihematoporphyrin ether determinations done on skin biopsy specimens. Fluorometry was performed on guinea pigs receiving 0, 2.5, 5, 10, and 25 mg/kg of dihematoporphyrin ether. Transcutaneous measurements of skin fluorescence increased with increasing dihematoporphyrin ether dose and correlated well with skin dihematoporphyrin ether content as determined by extracting dihematoporphyrin ether from skin samples. Transcutaneous fluorescent measurements of guinea pigs given 0 and 2.5, 2.5 and 5, 5 and 10, and 10 and 25 mg/kg of dihematoporphyrin ether differed in a statistically significant manner. Transcutaneous fluorometric determination of dihematoporphyrin ether content and extraction of dihematoporphyrin ether from skin samples were able to reflect differences in dihematoporphyrin ether dosing and presumably skin dihematoporphyrin ether content. However, transcutaneous fluorometry provides an instantaneous estimate of tissue dihematoporphyrin ether without the need for a tissue sample. This may provide a clinical tool to predict more accurately the optimal light dose necessary to maximize photodynamic therapy.

Association of hepatitis B surface antigen and core antibody with acquisition and manifestations of human immunodeficiency virus type 1 (HIV-1) infection.

We examined the associations between seropositivity for hepatitis B virus (HBV) with the presence or development of antibodies to human immunodeficiency virus (HIV-1) and with HIV-1 induced T-helper lymphocyte deficiency or acquired immunodeficiency syndrome (AIDS). Serologic data on HBV and HIV-1, cytometric enumeration of CD4+ lymphocytes, clinical events (AIDS by Centers for Disease Control criteria) and hepatitis B vaccination histories were available on 4,498 homosexual participants in the Multicenter AIDS Cohort Study, Men were classified as to previous infection with HBV and prevalent or incident infection with HIV-1. Although there was an association between seropositivity for HBV infection and HIV-1 infection at enrollment (odds ratios anti-HBc 2.6; HBsAg 4.2), the relation between HBV seropositivity and subsequent seroconversion to HIV-1 was weaker (odds ratios 1.3 and 1.6). HIV-1 seroconversion was also associated with a history of certain other sexually transmitted diseases, but predisposing sexual practices did not account for the association between HBV and HIV-1 infection. Seropositivity for HBV infection at entry was not related to initially low or more rapid subsequent decline in T-helper lymphocyte counts and was not associated with an increased incidence of AIDS during 2.5 years of follow-up. History of vaccination against HBV did not appear to decrease susceptibility to HIV-1 infection or to subsequent progression of immunodeficiency. We conclude that prior HBV infection is unlikely to be specifically associated with acquisition of HIV-1 infection and is unrelated to more rapid progression of HIV-1-induced immunodeficiency.

The Thrombolysis in Myocardial Infarction (TIMI) Trial phase II: additional information and perspectives.

Given the many thrombolytic agents and the number of ways in which they can be combined with mechanical revascularization, the treatment of acute myocardial infarction has been the subject of active study and lively debate, which are likely to continue for some time. Several studies, including TIMI IIA (2,3,10,22), have suggested that immediate catheterization and angioplasty offer no clinical benefit and have a greater complication rate than a more delayed invasive strategy, but TIMI II (1) and SWIFT (16) trials have suggested that an even more conservative strategy of reserving catheterization and coronary angioplasty after thrombolytic therapy for patients with recurrent spontaneous or exercise-induced ischemia may be the most desirable approach for the majority of patients similar to those entered into these trials.

Tissue plasminogen activator followed by percutaneous transluminal coronary angioplasty: one-year TIMI phase II pilot results. TIMI Investigators.

The TIMI phase II pilot study enrolled 288 patients with acute myocardial infarction who were treated with recombinant tissue plasminogen activator (rt-PA) within 4 hours of symptom onset and who were assigned to coronary angioplasty of the infarct-related vessel 18 to 48 hours after rt-PA treatment. The patients were followed to ascertain (1) vital status; (2) whether they suffered a recurrent myocardial infarction; (3) whether they received coronary angioplasty or bypass grafting; and (4) whether they were rehospitalized for a cardiac event. Risk factors for these events or combination of these events were identified and reported. The estimated 6-week, 6-month, and 1-year cumulative event rate of death or myocardial infarction was 9.1 +/- 1.7%, 12.9 +/- 2.0%, and 13.6 +/- 2.0%, respectively. With the exception of repeat hospital admissions, most of the above cardiac events occurred early during the patients' follow-up course. Cox proportional hazard analyses revealed that continuing chest pain after rt-PA administration, history of congestive heart failure, low systolic blood pressure at the time of initial evaluation, and history of hypertension increased the risk of death or recurrent myocardial infarction, while a history of chest discomfort at baseline evaluation and older age was predictive of future hospitalization or a revascularization procedure.

The use of tissue-type plasminogen activator for acute myocardial infarction in the elderly: results from thrombolysis in myocardial infarction Phase I, open label studies and the Thrombolysis in Myocardial Infarction Phase II pilot study. The TIMI Investigators.

The impact of age on hospital mortality, incidence of major hemorrhagic events and transfusion requirements was examined in 756 patients with acute myocardial infarction enrolled in the Thrombolysis in Myocardial Infarction (TIMI) Phase I, open label studies and the TIMI Phase II pilot study. The mortality rate significantly increased with age and was 3.5%, 11.5% and 12% in patients less than 65, 65 to 69 and 70 to 76 years of age, respectively (p less than 0.001). Logistic regression analyses selected female gender, diabetes mellitus, extensive coronary artery disease, history of congestive heart failure, continuing chest pain immediately after recombinant tissue-type plasminogen activator (rt-PA) administration, low systolic blood pressure at the time of admission and advanced age as variables predictive of in-hospital death. The incidence of major hemorrhagic events among patients not undergoing cardiac surgery during hospitalization was 8.7%, 14.5% and 24.7% in patients aged less than 65, 65 to 69 and greater than or equal to 70 years, respectively (p less than 0.001). The majority of hemorrhages were secondary to cardiac catheterization or puncture wounds. Variables related to a major hemorrhagic event included protocol, age, rt-PA dose/kg body weight and elevated diastolic blood pressure on admission. Of five intracranial bleeding events, three occurred in patients greater than 65 years. Transfusion requirements significantly increased with age (p less than 0.001). Reperfusion status at 90 min in the TIMI Phase I and open label studies A to C was similar in the three age groups studied and ranged from 60% to 71%.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine.

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.

Mechanisms of effects of intrathecal serotonin on nociception and blood pressure in rats.

The effects of intrathecal (i.t.) serotonin (5-HT) and a number of serotonergic receptor agonists on nociception and blood pressure were examined in rats. Intrathecal 5-HT produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 100.0 micrograms) and dose-dependent depressor effects. The 5-HT1A agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin and the 5HT1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969) also produced depressor effects but, in contrast to 5-HT, facilitated the tail-flick reflex, whereas the 5-HT2 agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212) and quipazine produced dose-dependent antinociception and had little or no effect on blood pressure. These results suggest that the antinociceptive and depressor effects of i.t. 5-HT are mediated by spinal 5-HT2 and 5-HT1 receptors, respectively. In other experiments, rats chronically treated with i.t. 5-HT developed tolerance to its antinociceptive effects, whereas chronic i.t. morphine or clonidine did not produce cross-tolerance to i.t. 5-HT. These results suggest that serotonergic spinal antinociceptive mechanisms are distinct from the mechanisms by which opioid receptor and alpha-2 adrenoceptor agonists produce antinociception in the spinal cord.

Intrathecal morphine and clonidine: antinociceptive tolerance and cross-tolerance and effects on blood pressure.

The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. Chronic treatment with morphine (32.0 micrograms/day for 7 days) produced tolerance to the antinociceptive effects of morphine in conscious rats, and chronic morphine or chronic clonidine (32.0 micrograms/day for 7 days) reduced the antinociceptive potency of morphine in lightly anesthetized rats. The pressor effects of morphine were attenuated by chronic morphine and were converted to marked, dose-dependent depressor effects by chronic clonidine. Clonidine dose dependently inhibited the tail-flick reflex in lightly anesthetized rats (ED50 = 1.7 micrograms) and produced biphasic effects on blood pressure; lesser doses (0.1-3.2 micrograms) produced depressor effects whereas a greater dose (10.0 micrograms) produced a pressor response. Yohimbine, but not naloxone, antagonized the antinociceptive effects of clonidine, whereas both yohimbine and naloxone altered the dose-response function for the effects of clonidine on blood pressure. Tolerance developed to the antinociceptive effects of clonidine in the hot-plate, but not in the tail-flick, test in conscious rats. In lightly anesthetized rats, the antinociceptive potency of clonidine was reduced by chronic clonidine or chronic morphine, whereas chronic clonidine, but not chronic morphine, shifted the dose-response function for effects of clonidine on blood pressure to the right. These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.

Human immunodeficiency virus and hepatitis delta virus in homosexual men. A study of four cohorts.

The prevalence of hepatitis delta virus antibodies was determined in four cohorts of homosexual or bisexual men positive for hepatitis B surface antigen who were evaluated between April 1984 and April 1985. Antibodies to hepatitis delta virus were found in 16 of 106 men in Los Angeles (15.1%; 95% confidence interval [Cl], 8.3% to 21.9%); 6 of 64 men in San Francisco (9.4%; 95% Cl, 3.5% to 19.3%); 1 of 76 men in Pittsburgh (1.3%; 95% Cl, 0.03% to 7.1%); and 0 of 52 men in Chicago (0%; 95% Cl, 0% to 5.6%). From 44.0% to 65.4% of men negative for hepatitis delta virus and all men positive for hepatitis delta virus but one (P less than 0.0001) were positive for antibodies to human immunodeficiency virus (HIV). In multivariate analysis, infection with hepatitis delta virus was associated with intravenous drug use (adjusted odds ratio [OR] = 6.7, P less than 0.01), with sexual activity as measured by number of partners (adjusted OR = 8.4, p less than 0.01), and probably with rectal trauma (adjusted OR = 3.9, P = 0.17). As with HIV infection, prevalence of hepatitis delta virus infection in homosexual men differs by location and is most likely transmitted both sexually and parenterally.

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice.

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the mu-opioid agonists morphine (0.1-10.0 mg/kg) and levorphanol (0.1-3.0 mg/kg), the kappa-opioid agonist ethylketazocine (0.03-3.0 mg/kg), the mixed mu-/delta-opioid agonist metkephamid (0.1-10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0-100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.

Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties.

Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or beta-dioxadrol in monkeys experienced with ketamine self-administration. The order of potency in displacing bound 1-[1-(2-thienyl)cyclohexyl]piperidine from binding sites in rat brain homogenates was dexoxadrol much greater than levoxadrol = beta-(+/-)-dioxadrol. Viewed in the context of previous studies with stereochemical probes of the PCP receptor, these results extend and confirm the supposition that dexoxadrol and levoxadrol are the stereochemical probes of choice in the study of effects mediated through PCP receptors. The absolute configuration of dexoxadrol was determined to be 4S, 6S by X-ray crystallography, thus defining the optimum chirality necessary for receptor binding and PCP-like activity in the dioxadrol series. Based on these and other considerations, receptor-active conformations of dexoxadrol and PCP are proposed.

Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study.

In 1984 a large prospective study of gay and bisexual men was begun to elucidate the natural history of the human immunodeficiency virus (HIV) infection. At two successive semiannual examinations, clinical or hematologic abnormalities were found up to 13 times more often among HIV-seropositive men (n = 1611) than HIV-seronegative men (n = 2646). More than 30% of the seropositive participants had persistent generalized lymphadenopathy, independent of T-helper lymphocyte (CD4) counts and most other signs and symptoms. Other clinical manifestations such as thrush, anemia, thrombocytopenia, neutropenia, fever, and fatigue occurred with only slightly reduced CD4 counts (400 to 700/mm3) and appeared to increase exponentially with progressively lower counts. A simple systematically derived clinical index using these manifestations identified more than 70% of the seropositive men with significant T-helper cell depletion. This kind of clinical index may be useful for assessing groups of HIV-infected persons, especially those whose T-lymphocyte numbers and function cannot be readily measured.