Recognition and invasion of human erythrocytes by malarial parasites: contribution of sialoglycoproteins to attachment and host specificity.

The receptivity of human erythrocytes to invasion by Plasmodium falciparum merozoites can be decreased by neuraminidase or trypsin treatment, an observation that supports a role for the erythrocyte sialoglycoproteins (glycophorins) in invasion. We have found that alpha 1-acid glycoprotein (AGP), added to in vitro cultures, can restore invasion of enzyme-treated human erythrocytes. AGP is structurally different from the glycophorins although it does carry 12% sialic acid. Its ability to restore receptivity to desialylated cells is dependent on its sialic acid complement, its concentration, and its binding to the erythrocyte surface. We present evidence that AGP forms a bridge between the merozoite and the enzyme-treated erythrocyte that allows the stronger and more complex interactions of invasion to proceed. We suggest that the glycophorins play the same role on the surface of the intact erythrocyte.

Evidence for a malarial parasite interaction site on the major transmembrane protein of the human erythrocyte.

Soluble oligosaccharides derived from the surface of human erythrocytes were tested for their ability to competitively inhibit invasion of erythrocytes by Plasmodium falciparum, a malarial parasite. Invasion was most effectively inhibited by erythroglycan, a carbohydrate component of the band 3 transmembrane protein. The lactosamine chains of erythroglycan contributed much of the inhibitory activity. This indication of a primary parasite interaction site on band 3 supports a role for this protein in mediating the radical alterations of the erythrocyte cytoskeleton that accompany invasion.

Sleep and depression in combat-related PTSD inpatients.

The sleep of 27 unmedicated Vietnam combat-related posttraumatic stress disorder (PTSD) inpatients was monitored for 3 nights. Depressive comorbidity was considered both as a diagnostic category using DMS-III-R criteria, and as a continuous variable using the Beck Depression Inventory (BDI). Data collected included sleep architecture features that have discriminated unipolar depressives from controls in many prior studies, rapid eye movement (REM) sleep latency, and slow-wave sleep time, as well as two additional indices that have sometimes discriminated depressives from controls in waking studies-baseline heart rate and facial electromyography. Structured Clinical Interview for the DSM-III-R (SCID)-diagnosed PTSD+major depressive disorder (MDD) patients failed to exhibit shorter REM latencies, greater REM percents of sleep, or greater REM densities than PTSD-MDD patients, but did exhibit less slow wave sleep. PTSD+MDD patients also exhibited less facial (mentalis) electromyographic activity. REM densities and baseline heart rates were equivocal. REM density, baseline heart rate, and mentalis electromyography all correlated with the BDI, the former two positively, the last, negatively. In summary, SCID-diagnosed PTSD+MDD patients failed to exhibit the classic REM sleep architectural modifications associated with unipolar depression, despite the fact that several other psychophysiologic indices of dysphoria were detectable in their sleep.

Serum dopamine-beta-hydroxylase activity in depression and anxiety.

Three studies were done to determine whether serum dopamine-beta-hydroxylase (DBH) activity is affected by the symptoms of depression or anxiety. In the population-screening study, serum DBH activity was measured in a heterogeneous sample of 548 medical, surgical, and psychiatric outpatients. No association was found between serum DBH activity and scores on either the Zung Self-rating Depression Scale or the Taylor Manifest Anxiety Scale. In the longitudinal depression study, enzyme activity was measured in 14 patients with major depressive illness treated with imipramine. Serum DBH activity remained unchanged throughout treatment whether or not the patient recovered from the depressive illness. Furthermore, there was no association between enzyme activity and steady state antidepressant plasma levels. In the longitudinal anxiety study, evaluation of 45 anxious outpatients in a placebo-controlled double-blind evaluation of two benzodiazepines (diazepam and alprazolam) indicated that serum DBH activity failed to reflect either state changes in anxiety or pharmacological variables. These results are reviewed with respect to current knowledge regarding neuronal release and extraneuronal disposal of circulating DBH.

Fluphenazine blood levels and clinical response.

The radioreceptor assay for neuroleptics (NRRA) holds out great theoretical promise as a method for monitoring blood neuroleptic levels, but its practical value is yet to be established. In the present study, 12 psychotic patients were followed longitudinally during treatment with oral (n = 9) and/or depot (N = 7) fluphenazine. Neuroleptic blood levels were determined both by the NRRA and by high performance liquid chromatography utilizing an electrochemical detector (HPLC). Clinical status was monitored by the Brief Psychiatric Rating Scale. Although blood levels were near the limits of sensitivity, the NRRA was able to detect the drug in most samples. HPLC was able to detect fluphenazine in less than 20% of the samples. Detectable blood levels by HPLC were associated with high blood levels by the NRRA. There was a significant correlation between blood levels as measured by the NRRA and clinical improvement. This correlation appears to be independent of the dose or route of administration of fluphenazine. Many patients were followed for several months and a few for over a year. A remarkable constancy of blood levels was found, particularly with depot administration. Given these findings, the NRRA may be an important clinical tool for monitoring patients receiving fluphenazine.

Plasma drug and homovanillic acid levels in psychotic patients receiving neuroleptics.

Plasma neuroleptic and homovanillic acid (HVA) levels are reported for a group of psychotic subjects exhibiting clinical improvement in response to neuroleptic medication. Clinically effective plasma neuroleptic levels, measured by a radioreceptor assay and expressed as either nanomolar concentration of parent drug or as haloperidol equivalents, were different for the seven neuroleptics tested. Plasma HVA, measured by high-pressure liquid chromatography with electrochemical detection (LCEC), increased in response to initiation of neuroleptic treatment and decreased when neuroleptic medication was withdrawn. No correlations were found between plasma neuroleptic level and HVA level or between HVA level and clinical response. Mean therapeutic plasma levels of neuroleptics, expressed as nanomolar concentration of parent drug, correlated with the potencies of the same drug in displacing 3H-dopamine from D-1 and D-2 receptors in rat striatal membranes. This represents the first report that clinically measured plasma concentrations are high enough to displace dopamine from its specific receptors in the CNS.

Toward rational pharmacotherapy for posttraumatic stress disorder: an interim report.

There is growing evidence that medication can alleviate symptoms associated with posttraumatic stress disorder (PTSD). Recent research also suggests that PTSD has a unique biological profile consisting of alterations in sympathetic arousal, the neuroendocrine system, and the sleep/dream cycle. This profile distinguishes PTSD from both major depression and panic disorder. Medication appears to alleviate PTSD symptoms associated with sympathetic hyperarousal and intrusive recollections of the trauma but seems ineffective against avoidant symptoms. Pharmacotherapy alone is rarely sufficient to provide complete remission of PTSD. Symptom relief provided by medication facilitates the patient's participation in individual, behavioral, or group psychotherapy.

Current need versus treatment history as predictors of use of outpatient psychiatric care.

The authors conducted a study of treatment utilization and outcome on a sample of 116 psychiatric outpatients at a Veterans Administration (VA) hospital. Utilization and outcome measures were obtained at a follow-up interview 18 months after a baseline assessment. Comparisons between patients with high and low rates of utilization revealed negligible relationships between use of services and severity of illness, clinical change, or demographics. However, previous use of VA outpatient and inpatient psychiatric services and VA psychiatric disability rating predicted utilization of psychiatric care during the study. The authors conclude that use of VA outpatient psychiatric care may reflect patients' help-seeking history more than their current clinical need.

Relationship between utilization of mental health and medical services in a VA hospital.

Previous research has demonstrated a reduction in utilization of medical services following the initiation of psychiatric services for certain patients. The phenomenon has been called the offset effect. The authors investigated the offset effect in a Veterans Administration medical center setting. They found that the offset effect emerged only for patients who had high rates of use of medical services who received mental health services for 1 year or less. They discuss factors related to higher rates of medical care utilization as well as important differences between the present and previous research that require further study.

Premilitary MMPI scores as predictors of combat-related PTSD symptoms.

OBJECTIVE: The authors used data collected before military service to assess predictors of combat-related lifetime symptoms of posttraumatic stress disorder (PTSD). METHOD: The subjects were 131 male Vietnam and Vietnam-era veterans who had taken the MMPI in college and who were interviewed as adults with the Structured Clinical Interview for DSM-III-R. Scores on the basic MMPI scales were used to predict combat exposure, lifetime history of any PTSD symptoms given exposure, and lifetime PTSD classification (symptoms only, subthreshold PTSD, or full PTSD). RESULTS: Group means on the MMPI scales were within the normal range. No scale predicted combat exposure. Hypochondriasis, psychopathic deviate, masculinity-femininity, and paranoia scales predicted PTSD symptoms. Depression, hypomania, and social introversion predicted diagnostic classification among subjects with PTSD symptoms. The effects persisted when amount of combat exposure was controlled for. CONCLUSIONS: Pre-military personality can affect vulnerability to lifetime PTSD symptoms in men exposed to combat.

On the safety of long-term treatment with lithium.

Thirteen patients with bipolar affective illness who had received lithium therapy for 1-5 years were tested retrospectively for evidence of cortical dysfunction. Data on patients younger than 55 show no abnormalities on the Halstead-Reitan Neuropsychological Battery and suggest that chronic lithium therapy is relatively safe. Significantly elevated Halstead Impairment indexes were observed among elderly patients, but these data are difficult to interpret.

Measurement of combat exposure, posttraumatic stress disorder, and life stress among Vietnam combat veterans.

Two scales developed to assess combat exposure and posttraumatic stress disorder symptomatology in Vietnam veterans displayed very high reliability. High levels of posttraumatic stress disorder were associated with more current life stresses and other standardized indices of dysphoria.

Relationship between age and tricyclic antidepressant plasma levels.

Older depressed patients treated with imipramine or amitriptyline developed higher steady-state plasma levels of imipramine, desipramine, and amitriptyline. In imipramine-treated patients this finding was associated with a decreased rate of drug elimination from plasma. These findings provide at least a partial explanation for the increased susceptibility of the older patient to tricyclic antidepressant side effects and also provide a pharmacological rationale for use of lower dosages in this age group.

Clinical correlations in patients with acute myocardial infarction and left ventricular thrombus detected by two-dimensional echocardiography.

Eleven of forty-nine patients with acute myocardial infarction had left ventricular thrombus identified by two-dimensional echocardiography. The patients with thrombi had a greater incidence of transmural infarction, high-grade ventricular ectopy on ambulatory monitoring and lower radionuclide ejection fractions than the patients without thrombi. Most of the patients were receiving full-dose heparin and/or warfarin anticoagulation from the time of admission to the hospital. Thus the thrombi either developed prior to hospital admission or developed during anticoagulation therapy. Two patients with thrombi had peripheral emboli complicating their infarction. One of these patients was undergoing anticoagulation at the time of his embolus.

Multiclinic controlled trial of diltiazem for Prinzmetal's angina.

To assess the efficacy of a new calcium entry blocker, diltiazem (Cardizem), for prophylaxis of Prinzmetal's angina, 48 patients were studied in randomized, multiple crossover multiclinic study (2 weeks single-blind, 8 weeks double-blind). Diltiazem dosage in one crossover phase was 120 mg per day; in the other, 240 mg per day. Therapeutic response was measured by patients' diary records of angina frequency and nitroglycerin tablet consumption. Treatment with 120 mg of diltiazem per day reduced angina by 41 percent from the entry placebo period and 20 percent from the paired placebo period (p less than 0.005). Treatment with 240 mg of diltiazem per day reduced angina frequency by 68 percent from the entry placebo period and 43 percent from the paired placebo period (p less than 0.01). There were similar reductions in nitroglycerin consumption. Adverse experiences that may have been related to the medication were noted in only 5 percent of patients. There were no alterations in blood pressure or heart rate. The PR interval increased 3 percent at the 240 mg dosage level. We conclude that diltiazem is an effective and safe agent for control of symptoms of Prinzmetal's angina.

A new technique for noninvasive evaluation of femoral arterial and venous anatomy before and after percutaneous cardiac catheterization in children and infants.

A new ultrasonic method was applied to image the femoral artery and vein in children for evaluation of short- and long-term effects of cardiac catheterization with femoral percutaneous cannulation. Sixty-six children and infants (aged 5 days to 20 years) were studied with a 9 megahertz electronically focused real time scanner. Adequate studies were obtained in 46 patients before catheterization, in 26 of 30 short-term follow-up studies and in 14 long-term follow-up studies. Femoral arterial size could be quantitatively measured at the inguinal ligament and a correlation existed between imaged femoral arterial diameter and body weight (r = +0.82) or body surface area (r = +0.80). Short-term follow-up ultrasonic imaging studies allowed diagnosis of spasm and other complications of percutaneous femoral arterial puncture. Long-term follow-up studies were performed 4 months to 3 years after catheterization in 14 patients who had no complications recorded at the time of catheterization. These revealed significant differences between vessels on the catheterized and uncatheterized (control) sides in only 3 of the 14. High resolution ultrasonic imaging can provide anatomic and functional information about femoral arteries and veins and appears to be of assistance in planning cardiac catheterization and in studying the short- and long-term effects of percutaneous femoral cannulation.

First night effects in post-traumatic stress disorder inpatients.

Recent data have suggested that first night effects are attenuated in inpatient depressive subjects. We examined first night effects in 80 inpatients hospitalized for post-traumatic stress disorder (PTSD) as well as non-hospitalized PTSD sufferers and non-ill control subjects. PTSD inpatients exhibited attenuated first night effects compared to non-hospitalized PTSD sufferers and non-trauma-exposed controls. Non-ill combat-exposed subjects also exhibited small first night effects. Within the inpatient sample, severity indices of PTSD, depression and anxiety failed to account for variance in first night effects. These data demonstrate attenuation of first night effects in a new inpatient population and suggest their statistical independence vis-a-vis a range of relevant symptoms. Both the attenuation of first night effects in PTSD inpatients and their accentuation in PTSD outpatients may be indicative of enhanced sensitivity to the sleep environment. Conversely, the trend to small first night effects in non-ill combat-exposed subjects may reflect a dimension of their apparent resistance to traumatic stress.

Posttraumatic stress disorder.

This article reviews concepts that help synthesize the data on posttraumatic stress disorder (PTSD), a very complex condition in terms of its etiology, psychobiology, epidemiology, comorbidity, and treatment. At least four neurobiologic systems are involved in PTSD: the catecholamine, the hypothalamic-pituitary-adrenocortical, the thyroid, and the endogenous opioid systems. Six other systems are probably or possibly implicated as well. The avoidance and hyperarousal of PTSD distort the patient's appraisal of the world. The symptoms of PTSD can be understood through models of learning and memory, which form the basis of behavioral treatments. The concepts of tonic and phasic alteration and of allostasis versus homeostasis also shed light on PTSD. In addition to PTSD, there may be other identifiable posttraumatic syndromes that might be diagnosed separately, such as "complex" PTSD. Cross-cultural issues may also affect clinical phenomenology and thereby confuse the diagnosis. Comorbid disorders may actually be clues to subtypes of PTSD. The fact that victims of PTSD are also more vulnerable to medical illnesses makes a closer relationship with primary care providers and other specialists mandatory. New approaches to prevention, treatment of chronic PTSD, psychotherapy, pharmacotherapy, and research hold promise of an improved prognosis for patients with PTSD.

What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy?

This review considers future directions for developing effective drugs for posttraumatic stress disorder (PTSD). At present, we have embarked upon an empirical approach in which pharmacologic research consists of clinical trials with agents, such as antidepressants, anxiolytics, and anticonvulsants, initially developed for different purposes. The approach taken here is theoretical rather than empirical, starting with what is known about the unique pathophysiology of PTSD and then predicting the types of pharmacologic agents that might prove effective in the future. Such classes of compounds include corticotropin-releasing factor antagonists, neuropeptide Y enhancers, antiadrenergic compounds, drugs to down-regulate glucocorticoid receptors, more specific serotonergic agents, agents normalizing opioid function, substance P antagonists, N-methyl-D-aspartate facilitators, and antikindling/antisensitization anticonvulsants.

Depressive symptoms in propranolol users.

Depressive symptoms were measured in 34 white male patients receiving propranolol treatment for cardiovascular illness. The Hamilton Rating Scale for Depression and the Hudson Generalized Contentment Scale were used to measure depressive symptoms. Patients with a positive personal or family history of depression had significantly higher depression scores than those with a negative history. Although there was no correlation between propranolol dosage and depressive symptoms for the population as a whole, among patients with a negative history there was a highly significant positive correlation between propranolol dosage and depression scores.