The effect of parasite dose on disease severity in the rodent malaria Plasmodium chabaudi.

Experiments were designed to look at the relationship between infective dose and disease severity using 2 clones of Plasmodium chabaudi that differ in virulence. We asked whether there were dose-severity relationships, whether clone differences in virulence were maintained over a range of doses, and whether disease severity could be accounted for by parasite dynamics. Groups of mice were infected with parasite doses differing by an order of magnitude, ranging from 100 to 1 x 10(8) parasites. Infective dose affected the probability of death, but only with the more virulent clone. Dose also affected morbidity. For both clones, higher doses induced greater anaemia. Larger doses caused greater weight loss, but only for infections with the more virulent clone. Here, for a given dose, mice lost a fixed amount of weight, irrespective of their initial weight. Larger doses induced earlier mortality and morbidity than did lower dose treatments. Finally, dose affected parasite dynamics, with earlier and higher peak parasite densities in larger dose infections. All these effects were small relative to clone differences in disease severity, which were apparent across the range of doses. Dose effects were manifested through the timing and/or magnitude of peak parasite densities, broadly supporting the idea that dose affects disease severity by altering the time the host has to control parasite densities and ameliorate the effects of parasites. We discuss the possible efficacy of intervention strategies aimed at reducing human disease severity by reducing infective parasite dose.

Development and testing of the Resistiveness to Care Scale.

A conceptual model and objective scale for measuring resistiveness to care in individuals with advanced dementia of the Alzheimer type (DAT) were empirically generated from the perspective of nursing staff caregivers and through observation of residents with DAT. The resistiveness to care scale (RTC-DAT) was judged to have content validity and reduced to 13 items. Quantifiable scoring procedures and methods for rating videotapes and conducting clinical observations were developed. The RTC-DAT was tested with 68 subjects at three sites. The RTC has a range of 0-156. Initial testing provided reliability estimates of .82-.87 for internal consistency and good to excellent kappas. Criterion-related validity with observed discomfort and construct validity by factor analysis support the RTC-DAT. Measurement issues and recommendations for use in research are discussed.

Maintenance of wakefulness test in obstructive sleep apnea syndrome.

The usefulness of a 40-min per trial version of the maintenance of wakefulness test was assessed in 322 patients with obstructive sleep apnea. This test is a variant of the multiple sleep latency test in which patients are asked to remain awake in a quiet darkened room, and then monitored for electroencephalographic sleep onset. The four trials of the test are each stopped after 40 min. The mean sleep latency for all patients was 26.0 +/- 11.8 (SD) min. In a group of 24 patients who underwent treatment with nasal continuous positive airway pressure, the mean sleep latency increased from 18.0 +/- 12.3 to 31.9 +/- 10.4. The strongest nocturnal correlates of the MWT sleep latency were respiratory arousal index (r = -.35), mean oxygen saturation (r = .30), and weight/height ratio (r = -.25). These correlations were comparable to other studies using the MSLT. There were strong intercorrelations among the variables. In the more severe groups, measures of hypoxemia were more strongly correlated with MWT sleep latency. A two-factor analysis of variance using respiratory arousal index and several measures of oxyhemoglobin saturation indicated that both arousals from sleep and degree of hypoxemia contribute interactively to daytime dysfunction in patients with sleep apnea. The MWT appears useful in evaluating disability from daytime sleepiness.

Safety and possible efficacy of fiberoptic bronchoscopy with lavage in the management of refractory asthma with mucous impaction.

Mucous impaction may be suspected in asthmatic exacerbation when, despite aggressive medical management, patients continue to produce sputum containing mucous plugs and exhibit prominent rhonchi and/or wheezes on chest auscultation. Spirometric measurements in this setting corroborate lack of improvement and reveal significant impairment in indices that may reflect small airways function (FEF25-75). We hypothesized that clearance of inspissated secretions by fiberoptic bronchoscopy with lavage (FOBwL) may promote or hasten the clinical improvement of such patients. Fifty-one therapeutic FOBwL were accomplished in 19 patients during 20 episodes of stabilized yet refractory asthma with mucous impaction. No significant complications were encountered. After FOBwL, spirometric measurements of FEV1, FEF25-75, and FVC increased significantly (P less than .01, paired t test), and correlated with relief of dyspnea and mobilization of secretions with cough. FOBwL can be safely performed in stabilized, refractory asthma, and with apparent efficacy. Further investigation is needed to document the therapeutic utility of FOBwL in refractory asthma.

Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma.

A Phase Ia clinical trial was undertaken to evaluate and compare murine monoclonal antibody KS1/4 and KS1/4-methotrexate immunoconjugate in patients with Stage IIIB or IV non-small cell carcinoma of the lung. Six patients received KS1/4 alone and five patients received KS1/4-methotrexate conjugate. The maximal total dose received per patient in both groups was 1661 mg. Mild to moderate side effects in both groups included fever, chills, anorexia, nausea, vomiting, diarrhea, anemia, and brief transaminasemia. One patient who received antibody alone had an apparent acute immune complex-mediated reaction. Ten of 11 patients had a human anti-mouse response. Posttreatment carcinoma biopsies revealed binding of monoclonal antibody KS1/4 and deposition of C3d and C4c complement fragments. Monoclonal antibody binding and complement deposition correlated with increasing doses of infused antibody. There was one possible clinical response.

Effect of triazolam on sleep and arterial oxygen saturation in patients with chronic obstructive pulmonary disease.

We compared the effects of a placebo with 0.125 and 0.25 mg of triazolam (Halcion) on sleep quality, oximetry, and respiratory events during sleep in ten stable outpatients with chronic obstructive pulmonary disease. The subjects had a forced expiratory volume in 1 s ranging from 17% to 76% of the predicted value (mean +/- SD, 38.1% +/- 19%) and a waking arterial oxygen pressure from 46 to 84 mm Hg (mean +/- SD, 67 +/- 12 mm Hg). Polysomnography was done on three nights within a two-week period after the patients received on a "blinded" basis either placebo or 0.125 or 0.25 mg of triazolam. Triazolam produced improvements in total sleep duration, time spent in stage 2 nonrapid eye movement (NREM) sleep, and subjective of sleep quality. For most patients, there was a nighttime drop in arterial oxygen percentage of saturation (SaO2) in the placebo condition, but triazolam did not cause a significant worsening, of the mean SaO2, minimum SaO2, or the number of apneic and hypopneic events. Across all experimental conditions, we documented little desaturation during wakefulness (mean low, 87.2% +/- 10.2%), more during NREM sleep (mean low, 83.2% +/- 12.6%), and most desaturation in REM sleep (mean low, 80.1% +/- 15.7%). We conclude that single-night use of triazolam improved the quality and duration of sleep in patients with chronic obstructive pulmonary disease. In patients without severe waking hypoxemia and without carbon dioxide retention, triazolam did not increase either nocturnal hypoxemia or respiratory events during sleep.

Stress-induced release of pituitary beta-endorphin may be mediated by activation of the brain stem defence areas.

In anaesthetized cats, electrical stimulation within the fore-brain defence areas evoked a marked increase in the plasma level of immunoreactive beta-endorphin which reached a peak after 5 minutes. Multiple immunoreactive peptides including "biologically-active" beta-endorphin-(1-31) were detected. It is suggested that the release of pituitary beta-endorphin during emotional stress results from the natural activation of the defence areas.

Nocturnal myoclonus: treatment efficacy of clonazepam and temazepam.

Clonazepam (1 mg h.s.) and temazepam (30 mg h.s.) were studied in 10 patients diagnosed as having insomnia with nocturnal myoclonus. Each subject underwent two nocturnal polysomnographic recordings while drug-free, two during treatment with clonazepam, and two during treatment with temazepam. Treatment sessions were 7 days long, and recordings were done on nights 6 and 7 of the treatment sessions. A 14-day washout period separated the treatment sessions. The order of drugs used in the first and second treatment sessions was randomized. Objective and subjective sleep laboratory data showed that both drugs improved the sleep of patients with insomnia in association with nocturnal myoclonus. Neither drug significantly reduced the number of nocturnal myoclonic events. Sleep changes were consistent with those produced by sedative benzodiazepines in general. Thus, the data support clinical reports that clonazepam, a benzodiazepine marketed for the indication of seizure, is useful in improving sleep disturbances associated with nocturnal myoclonus. Temazepam, a benzodiazepine marketed for the indication of insomnia, was found to be a suitable alternative to clonazepam in the treatment of insomnia associated with nocturnal myoclonus. The present data and other studies suggest the need for a model that explains why leg movements and sleep disturbances may wax and wane independently.

Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline.

Methylphenidate, pemoline, and protriptyline were studied for their treatment efficacy in narcolepsy. A low, intermediate, and high dose level of each drug was studied for 1 week. For methylphenidate the doses were 10, 30, or 60 mg/day; for pemoline, 18.75, 56.25, or 112.5 mg/day; and for protriptyline 10, 30, or 60 mg/day. The order of dose levels was random from subject to subject and the daily dose was divided into thirds and taken in identically appearing capsules morning, noon, and afternoon. Subjects were 6 narcoleptic patients studied on methylphenidate (5 women and 1 man; mean age 54.5 + 11.7 years), 7 narcoleptic patients studied on pemoline (5 women and 2 men; mean age 43.0 + 7.1 years), and 4 narcoleptic patients studied on protriptyline (2 women and 2 men; mean age 42.5 + 16.9 years). Testing consisted of day-long sessions occurring at the end of each dose level and involving a clinical status questionnaire as well as maintenance of wakefulness, Wilkinson addition, and Digit-Symbol Substitution tests. Results were compared with 9 control subjects with no sleep disorder (5 women and 4 men; mean age 39.2 + 8.4 years) who were given placebo that was purported to be a "stimulant drug" and tested in a similar manner. Results demonstrated profound differences in ability to stay awake and perform between narcoleptic patients and controls. Data also suggested that methylphenidate significantly improves ability to stay awake. Pemoline seems to improve ability to perform. Protriptyline does not significantly alter ability to stay awake or to perform.

Acute effects of oxygen treatment upon information processing in hypoxemic COPD patients.

The present study investigated the effects of oxygen therapy upon human information processing for hypoxemic COPD patients. Each of ten patients was admitted to a general clinical research center for a two-day period. In a randomly counter-balanced factorial design, patients breathed either room air or enriched oxygen for either six hours or 20 minutes prior to testing. The tests evaluated speed of information processing, ability to detect correct sequence of tones, and serial memory. In addition, patients were evaluated on critical flicker fusion and story recall. The results suggested that acute oxygen therapy does not reverse information processing deficits observed in hypoxemic COPD patients.

The effect of short-term oxygen supplementation on oxygen hemoglobin affinity in patients with chronic obstructive pulmonary disease.

In 12 hypoxemic patients with chronic obstructive pulmonary disease, the partial pressure of oxygen at which hemoglobin is 50% saturated (P50) and levels of 2,3-diphosphoglycerate (2,3-DPG) were determined under 3 study conditions: (1) while breathing room air, (2) during oxygen supplementation for 72 h sufficient to increase PaO2 above 70 mmHg, and (3) at 72 h after the period of oxygen supplementation. The data showed that in the control period in hypoxemic (PaO2, 52 +/- 6 mmHg), mildly hypercapnic (PaCO2, 47 +/- 6 mmHg) patients with a borderline elevation of pH (7.42 +/- 0.03), there was an increase in P50 (28.6 +/- 1.6 versus a normal value of 26.5 +/- 1; p less than 0.005), and a concomitant increase in 2,3-DPG (19.02 +/- 1.77 mg/g Hb versus a normal value of 13.52 +/- 1.27; p less than 0.005). Nine patients received oxygen for 24 h, and 5 received oxygen for 72 h. In these 5 patients, oxygen supplementation resulted in a shift in P50 to a normal value of 26.7 +/- 1.8 (this value was different from the patients' level while breathing room air and not different from that of the normoxemic control subjects) and a decrease in 2,3-DPG toward but not to a normal value (16.34 +/- 1.92; p less than 0.01). This shift in P50 to the left could be related to the decrease in 2,3-DPG. Accordingly, in patients with COPD who are treated with supplemental oxygen, the net effect on oxygen transport would be a function of the changes produced in PaO2 versus those in hemoglobin-oxygen affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease.

At six centers, 203 patients with stabilized hypoxemic chronic obstructive pulmonary disease were evaluated hemodynamically during a continuous or 12-hour oxygen therapy program. Neither oxygen therapy program resulted in correction or near-correction of the baseline hemodynamic abnormalities. The continuous oxygen therapy group did show improvement in pulmonary vascular resistance, pulmonary arterial pressure, and stroke volume index. The improvement in pulmonary vascular resistance was associated with improved cardiac function, as evidenced by an increase in baseline and exercise stroke volume index. The nocturnal oxygen therapy group showed stable hemodynamic variables. For both groups, changes in mean pulmonary artery pressure during the first 6 months were associated with subsequent survival after adjustment for association with the baseline mean pulmonary artery pressure. Continuous oxygen therapy can improve the hemodynamic abnormalities of patients with hypoxic chronic obstructive pulmonary disease. The hemodynamic response to this treatment is predictive of survival.

Validity of a quality of well-being scale as an outcome measure in chronic obstructive pulmonary disease.

This paper evaluates the validity of the Quality of Well-being Scale (QWB) as an outcome measure for research on Chronic Obstructive Pulmonary Disease (COPD). The Quality of Well-being Scale was originally designed for use as a general health outcome measure. One criticism of this approach has been that it may not be valid in studies limited to a specific disease or condition. We report correlations between the QWB and a variety of other outcome measures obtained in an experimental trial evaluating the benefits of behavioral programs for COPD patients. The data from the trial suggest that the QWB is substantially correlated with both performance and physiological variables relevant to the health status of COPD patients. An advantage of the QWB is that it can be transformed into well-year units for cost-effectiveness studies. It is concluded that the QWB has many advantages as an outcome measure for specific disease groups.

Ventral medullary relay neurones in the pathway from the defence areas of the cat and their effect on blood pressure.

In cats anaesthetized with Althesin, the efferent descending pathway from the brain-stem defence areas has been traced through the medulla by identifying sites at which electrical stimulation evoked the characteristic pattern of the visceral alerting (defence) response. This response includes an increase in arterial blood pressure resulting from increased heart rate and cardiac output and vasoconstriction in renal and splanchnic beds, accompanied by active vasodilation in skeletal muscle. The efferent pathway runs as a narrow strip, about 3 mm from the mid line, ventral to the superior olive and the nucleus of the trapezoid body, extending caudally to the rostral portion of the inferior olive where it lies ventral to the facial nucleus. It was found to lie very close to the ventral medullary surface just rostral to and within the area at which bilateral topical application of glycine results in a profound fall in arterial blood pressure and cessation of respiration. On bilateral application of glycine to the sensitive area of the ventral medulla, the visceral alerting response evoked by stimulation in the defence areas of the amygdalo-hypothalamic complex, or the mid-brain central grey or tegmentum, was attenuated in parallel with the fall in arterial pressure, the vasoconstrictor responses being most strongly reduced. As soon as arterial blood pressure had fallen to its lowest level the visceral alerting response was virtually abolished. A small radio-frequency lesion made in the ventral medullary efferent pathway, in the rostral part of the 'glycine-sensitive area', had the same effect as that produced by unilateral application of glycine: it resulted in little respiratory or cardiovascular effect itself, but application of glycine to the contralateral area then produced the full effect otherwise seen only on bilateral application of glycine. It is suggested (1) that the effects of glycine result from blockade of a synaptic relay, close to the ventral surface of the medulla, in the efferent pathway from the defence areas to the preganglionic sympathetic neurones, and (2) that the neurones which receive an input from the alerting (defence) areas normally provide an essential, tonic excitatory drive to the sympathetic output and probably to respiration also. After sudden withdrawal of this drive, vasomotor tone and the normal level of arterial blood pressure are not maintained.

Deciding who should receive outpatient oxygen therapy.

Comprehensive treatment of advanced chronic airway obstruction includes consideration of outpatient oxygen therapy. A physician's decision as to whether a patient should receive this form of therapy rests on the clinical and investigative information that defines the benefits and problems.