Pupillographic sleepiness testing in hypersomniacs and normals

BACKGROUND: Pupillary oscillations in darkness are considered to be a sign of sleepiness. The purpose of this pilot study was to ascertain whether pupillary oscillations were more pronounced in patients with hypersomnia than in normals. METHODS: Seven patients (four with sleep apnea syndrome, three with narcolepsy) and seven age-matched controls underwent pupillography for 11 min in complete darkness. The changes in pupil size were analyzed mathematically to determine quantitatively the amount of pupillary instability. RESULTS: Hypersomniacs had much higher amounts of pupillary oscillations in darkness than normals. The differences were significant. Baseline pupil size did not differ significantly between the two groups. CONCLUSION: This study showed that a pupillographic sleepiness test based on the evaluation of spontaneous pupillary changes in darkness is applicable in hypersomniacs and may facilitate therapy control, i.e. diagnostic grading by measuring daytime sleepiness objectively.     

Identical effects of indomethacin on renal function in healthy uninephrectomized subjects and in healthy control subjects

1. Animal studies have shown that prostaglandins are important for renal function after unilateral nephrectomy. In order to investigate the importance of prostaglandins for renal function in the fully adapted remnant kidney in healthy uninephrectomized subjects, the acute effects of indomethacin on renal haemodynamics, lithium clearance, urinary excretion rates of prostaglandin E2, sodium and water, and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide and arginine vasopressin were measured in 14 healthy uninephrectomized subjects (median time after nephrectomy 1.7 years) and in 14 matched healthy control subjects. In addition, nine healthy control subjects were studied without indomethacin and served as a time-control group. 2. Before indomethacin ingestion there was a significantly higher single-kidney urinary excretion rate of prostaglandin E2 in the uninephrectomized group (uninephrectomized group, 349.2 fmol/min; control group, 76.6 fmol/min; time-control group, 96.3 fmol/min). 3. Indomethacin ingestion resulted in equal changes in all parameters in both groups. These were significant decreases in glomerular filtration rate (-11.3% versus -14.6%), renal plasma flow (-6.5% versus -13.0%), urinary flow rate (-49.8% versus -49.4%), fractional sodium excretion (-44.5% versus -47.4%), lithium clearance (33.2% versus -23.8%) and urinary excretion rate of prostaglandin E2 (-93.8% versus -86.7%) (uninephrectomized versus control subjects, values are medians). In the time-control group no changes were observed in these parameters. 4. It is concluded that healthy uninephrectomized subjects with a fully adapted remnant kidney have a normal renal response to acute indomethacin-induced inhibition of prostaglandin synthesis.     

Reliability of cephalic thermal thresholds in healthy subjects

Reproducibility and normal variation of cephalic warm and cold detection thresholds were investigated in three healthy subject groups. The face, the mastoid process, and the hands were studied. No significant intra-observer test-retest difference (n = 20) was found. Good reliability (intra-class correlation coefficient [ICC] > 0.4) was found for 13 of 14 measurements. A small significant inter-observer difference (n = 20) was found for cold thresholds. Good reliability (ICC > 0.4) was observed for both cold and warm thresholds in most of the test locations (6 of 8). In general, the largest variability was found in the mastoid and frontal lateral regions. Thermal thresholds varied with investigation site in 56 controls (ANOVA, p < 0.0005). No significant gender differences were found for cephalic warm and cold thresholds. Most cold thresholds (4 of 5) but also some warm thresholds (2 of 5) increased with age at the cephalic sites. Our results reveal the frontal medial, the maxillar medial, and lateral regions as the most reliable cephalic test locations. The mastoid region may also be useful for investigating the upper cervical small-fiber function.     

QT interval dispersion in healthy subjects and survivors of sudden cardiac death: circadian variation in a twenty-four-hour assessment

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.     

Electrocardiographic changes during insulin-induced hypoglycemia in healthy subjects

Hypoglycemia is associated with alterations of the ECG, a phenomenon which might be used for the development of a hypoglycemia detection device. We investigated the reproducibility and magnitude of ECG alterations during insulin-induced hypoglycemia in nine healthy volunteers. The subjects were studied twice with an identical study protocol on two different study days. During hypoglycemia frequent ECG recordings were done with a conventional 12 lead ECG. S.c. injection of 0.15 U/kg of regular insulin induced a fourfold increase in insulinemia on both study days as well as a mean decline in blood glucose by 1.6 mmol/l to a minimum of 2.8 mmol/l within 60 min after injection. Blood potassium levels declined by a mean of 0.25 mmol/l to minimal values of 3.69 mmol/l. On both study days, a progressive flattening of the T-waves was observed during the experiments. R-waves remained constant leading to an increase in RT ratios by at least 50% in comparison to baseline values. These changes were most pronounced in leads I, V3, V5 and V6. The magnitude and reproducibility of the observed ECG changes during hypoglycemia may allow the development of a hypoglycemia detection device.     

Small-intestinal digestion of partially resistant cornstarch in healthy subjects

Primary adenocarcinoma of sweat glands is a rare tumor; approximately 220 cases have been reported in the last 30 years. We reviewed the charts of patients with primary diagnosis of this tumor treated at the Mayo Clinic between 1935 and 1995. We included only cases with initial histology slides available for re-examination. Tumors were classified into five recognizable histologic patterns (solid, ductal, mucinous, microcystic adnexal, and adenocystic carcinoma) and graded by the Broder system. Statistical analysis consisted of Kaplan-Meier product limit method and Cox multiple regression test. In total, 55 patients were identified, and age ranged from 13 to 85 years (mean 59 years). Thirty-six patients (65 percent) presented to the Mayo Clinic for initial treatment; all except one had disease limited to the primary site. Microcystic adnexal carcinoma was the most frequent type, and more than 50 percent were grade 2 tumors. Among these 36 patients, 4 had some type of recurrence. Patients who developed metastasis had a high-grade tumor in the initial biopsy. Nineteen patients were referred with recurrence; 13 had local recurrence, 4 had regional diseases, and 2 had distant metastases. The histologic distribution showed 47 percent solid tumors, and 37 percent of them were grade 3. Multiple regression analysis did not show a difference in recurrence or survival when gender, age, tumor location, or histologic pattern was evaluated. In addition, there was no difference in the outcome between wide surgical resection and micrographic surgery. The only predictive factor for distant metastases and/or death (p < 0.003) was histologic grade. Overall 10-year survival rate was 86 and 60 percent for primary and referred patients, respectively. We conclude that histologic diagnosis of sweat gland carcinoma must be complemented by clinical examination to evaluate metastases. Clinical behavior depends on the histologic type of tumor, degree of differentiation, and clinical stage. On recurrence, the likelihood of further recurrences and mortality increases dramatically. Aggressive initial local ablation with tumor-free margins is recommended. In high-grade tumors, prophylactic regional lymph node dissection may further characterize tumor aggressiveness and may justify adjuvant radiotherapy as part of the primary treatment.     

Effects of buspirone on plasma neurotransmitters in healthy subjects

Buspirone is an anxiolytic drug which exerts several central effects. It antagonizes presynaptic inhibitory DA2 autoreceptors at dopaminergic neurons and acts as an agonist for 5-HT1A inhibitor autoreceptors at serotonergic cells. Thus, buspirone respectively enhances and depresses the firing rates of both type of neurons. At doses which correlate with dopaminergic stimulation, but not 5-HT inhibition, buspirone also increases the firing rates of the central noradrenergic cells. We measured levels of circulating neurotransmitters before and up to 240 minutes after the oral administration of 20 mg of buspirone in 32 healthy volunteers. Buspirone significantly increased levels of noradrenaline, dopamine, and free serotonin but did not affect levels of adrenaline, tryptophane, or platelet serotonin. Small but significant drops in systolic blood pressure and heart rate were observed after buspirone ingestion. Atropine administration before buspirone ingestion annulled the free serotonin increase as well as systolic blood pressure-heart rate decrease. We found significant positive correlations between noradrenaline and dopamine levels. The strength and significance of these correlations were increased by using the noradrenaline/adrenaline ratio instead of noradrenaline absolute values. This finding indicates that increases in both noradrenaline and dopamine arise from sympathetic nerves rather than the adrenal glands. We also found significant negative correlations between free serotonin increases and systolic blood pressure-heart rate decreases. Our results indicate that buspirone stimulates central sympathetic activity. These acute effects of buspirone are reflected in an increased peripheral neural sympathetic activity, but not adrenal sympathetic activity in healthy individuals. In addition, buspirone increases free serotonin plasma concentrations and decreases systolic blood pressure plus heart rate levels through mechanisms associated with parasympathetic activation.     

Quantitative criteria of a rhinocytogram of healthy subjects

Cytomegalovirus infection (CMV) complicated the posttransplant course in 9 of 24 children after liver transplantation. We found specific antibodies (IgG and IgM) to be of very low value in diagnosis and monitoring of CMV infection after liver transplantation. Detection of CMV-DNA by PCR method in the blood or urine was very useful for diagnosis, but less for monitoring of the course of disease and its treatment. Measurements of early immediate CMV antigen (IEA), in peripheral blood leucocytes allowed for very early diagnosis of CMV infection and correlated well with the course of disease and response to treatment of the patient.     

Time perception in organically healthy and brain damaged subjects

The aims of this study were to investigate whether brain lesions are associated with an impairment of time judgement and whether there is any relationship between alterations of time experience and the side and localization of brain lesions. References were made to the literature dealing with different definitions of the concept of time and the notions derived from time as a categorial entity, such as time experience, time perception and time awareness. To begin with, the philosophical and psychological approach was considered. There upon definitions as given by the natural sciences, conceptual classifications, phenomenological investigations as well as psychopathological considerations were analysed. Furthermore, the literature on disorders of time judgement was reviewed against the background of alterations of time experience in patients with brain lesions. In the present study patients with definite single brain lesions were examined and compared with a group of normal subjects. Three methods for testing time judgement (method of production, method of reproduction and time estimation) were applied to each subject. The results showed that in a substantial proportion of brain-damaged patients a subjective impression of changes in the rate at which time passed was reported, mostly in form of an apparent slowing down. No difference could be demonstrated between left or right cerebral lesions or between different localizations within one hemisphere. On the testing for objective time judgement the brain-damaged patients showed a tendency to under-or overestimation of time intervals, often exceeding the pre-established normal boundaries by far. We observed a certain "vulnerability" of the right hemisphere on the tasks for time judgement, especially in the case of right-sided parieto-occipital lesions.     

Effects of smoking tobacco on exercise tolerance in healthy subjects

The aim of the study was to investigate the effects of smoking on exercise tolerance in middle aged smokers. Sixty two healthy subjects 55 males and 7 females with mean age 35 +/- 7 years were studied. There were 47 smokers (smoking 21.5 cigarettes per day for a mean of 16 years) and 15 non-smokers (control group). Resting pulmonary function was normal in both groups, however smokers had significantly lower VC as well as MEF 50 and MEF 75. A maximal incremental exercise on cycloergometer using ramp protocol was performed. Ventilatory parameters (breath by breath method) together with transcutaneous oxygen saturation (every minute), heart rate (continuously) and blood pressure (every minute) were recorded. Significant differences in exercise tolerance in studied groups were observed. Smokers tolerated a lower maximal workload for a shorter time and deferred significantly in both maximal oxygen consumption and oxygen consumption at anaerobic threshold. Five persons, all smokers did not reach the anaerobic threshold. In five smokers a decrease in ECG ST segment was observed. No differences were found in breathing reserve, heart reserve or maximal oxygen pulse. It seems that a decreases exercise performance is due to cardiac limitation.     

Late feedback effects of hypothalamic-pituitary-adrenal axis hormones in healthy subjects

The main aims of the present study were to establish an in vitro/in vivo correlation for multiple-unit capsules of paracetamol by means of statistical prediction models and to investigate the effect of a number of in vitro variables on the discussion rate of paracetamol from the formulation. A fractional factorial screening design was used to investigate the effects of the variables agitation, pH, osmolality, viscosity, and the presence of bile salt on the dissolution rate of paracetamol. The effects were evaluated in two separate partial least-squares models, in which the responses were expressed as the cumulative percentage of paracetamol dissolved at specified time-points (model I) and as the shape (beta) and scale (eta) parameters according to the Weibull function (model II). It was concluded that agitation and viscosity had significant effects on the dissolution rate of paracetamol. Statistical models based on the responses from models I and II were then used to predict the in vitro conditions most closely correlated with the in vitro dissolution of paracetamol after administration of the formulation to 10 healthy volunteers. The predicted optimal in vitro conditions were similar for the two models and not too far from what is expected from the gastrointestinal tract. The experimental verification of the in vitro conditions showed that both models were equally good, and contributed to high degrees of correlation with the in vivo dissolution behavior of the formulation during 9 hr. The relationships obtained when plotting the percentage dissolved in vitro versus in vivo were y = 1.1x (r2 = 0.98) and y = 1.1x (r2 = 0.94) for models I and II, respectively. Based on these results, it is difficult to state a preference for one of the models. Finally, the use of statistical prediction models to develop critical in vitro tests is a successful approach in the establishment of associations between dissolution behavior in vitro and in vivo for oral extended-release systems.     

Influence of hyperglycaemia on maximal gastric secretion in healthy subjects

The influence of a single intravenous glucose load on maximal gastric acid secretion in 25 healthy men when stimulated with pentagastrin was studied. Under the influence of hyperglycaemia, a highly significant decrease of maximal acid output was found. Moreover, in the gastric juice an increase of chloride and calcium concentrations was noted. On the other hand, the output of potassium, chloride and magnesium was lowered. The above differences were statistically significant.     

Monitoring of proteinuria in phase I studies in healthy male subjects

An extended analysis for loss of heterozygosity (LOH) on eight chromosomes was conducted in a series of 82 Wilms tumors. Observed rates of allele loss were: 9.5% (1p), 5% (4q), 6% (6p), 3% (7p), 9.8% (11q), 28% (11p15), 13.4% (16q), 8.8% (18p), and 13.8% (22q). Known regions of frequent allele loss on chromosome arms 1p, 11p15, and 16q were analyzed with a series of markers, but their size could not be narrowed down to smaller intervals, making any positional cloning effort difficult. In contrast to most previous studies, several tumors exhibited allele loss for multiple chromosomes, suggesting an important role for genome instability in a subset of tumors. Comparison with clinical data revealed a possible prognostic significance, especially for LOH on chromosome arms 11q and 22q with high frequencies of anaplastic tumors, tumor recurrence, and fatal outcome. Similarly, LOH 16q was associated with anaplastic and recurrent tumors. These markers may be helpful in the future for selecting high-risk tumors for modified therapeutic regimens.     

Effect of different levels of hyperoxia on breathing in healthy subjects

We have recently shown that breathing 50% O2 markedly stimulates ventilation in healthy subjects if end-tidal PCO2 (PETCO2) is maintained. The aim of this study was to investigate a possible dose-dependent stimulation of ventilation by O2 and to examine possible mechanisms of hyperoxic hyperventilation. In eight normal subjects ventilation was measured while they were breathing 30 and 75% O2 for 30 min, with PETCO2 being held constant. Acute hypercapnic ventilatory responses were also tested in these subjects. The 75% O2 experiment was repeated without controlling PETCO2 in 14 subjects, and in 6 subjects arterial blood gases were taken at baseline and at the end of the hyperoxia period. Minute ventilation (VI) increased by 21 and 115% with 30 and 75% isocapnic hyperoxia, respectively. The 75% O2 without any control on PETCO2 led to 16% increase in VI, but PETCO2 decreased by 3.6 Torr (9%). There was a linear correlation (r = 0.83) between the hypercapnic and the hyperoxic ventilatory response. In conclusion, isocapnic hyperoxia stimulates ventilation in a dose-dependent way, with VI more than doubling after 30 min of 75% O2. If isocapnia is not maintained, hyperventilation is attenuated by a decrease in arterial PCO2. There is a correlation between hyperoxic and hypercapnic ventilatory responses. On the basis of data from the literature, we concluded that the Haldane effect seems to be the major cause of hyperventilation during both isocapnic and poikilocapnic hyperoxia.     

Subgingival microbiota in healthy, well-maintained elder and periodontitis subjects

This investigation compared the site prevalence of 40 subgingival species in 30 periodontally healthy (mean age 36+/-9 years), 35 elders with a well-maintained periodontium (mean age 77+/-5) and 138 adult periodontitis subjects (mean age 46+/-11). Subgingival plaque samples were taken from the mesial aspect of each tooth (up to 28 samples) in the 203 subjects at baseline. The presence and levels of 40 subgingival taxa were determined in 5003 plaque samples using whole genomic DNA probes and checkerboard DNA-DNA hybridization. Clinical assessments including dichotomous measures of gingival redness, bleeding on probing, plaque accumulation and suppuration, as well as duplicate measures of pocket depth and attachment level, were made at 6 sites per tooth. The % of sites colonized by each species (prevalence) was computed for each subject. Differences in prevalence and levels among groups were sought using the Kruskal-Wallis test. Commonly detected species, such as Actinomyces naeslundii genospecies 2, Streptococcus sanguis and Streptococcus oralis did not differ significantly among subject groups. After adjusting for multiple comparisons, 4 species were significantly elevated and at greater prevalence in the periodontitis group. Mean % of sites (+/-SEM) colonized by Bacteroides forsythus was 10+/-3, 12+/-2 and 40+/-2 (p<0.001) for healthy, elder and periodontitis groups respectively. The odds ratio was 14.4:1 that a subject had periodontitis when B. forsythus was detected at > or = 5% of sampled sites. Mean prevalence for Porphyromonas gingivalis in healthy, elder and periodontitis subjects was 4+/-2, 5+/-2 and 23+/-2 respectively (p<0.001); for Treponema denticola 12+/-4, 10+/-3 and 30+/-2 (p<0.001) and for Selenomonas noxia 6+/-2, 7+/-2 and 19+/-2 (p<0.01). Similar differences among subject groups were observed when only sites with PD 0-4 mm were analyzed. The data suggest an etiologic role for B. forsythus, P. gingivalis, T. denticola and S. noxia in adult periodontitis.     

Vitamin D3 enhances mood in healthy subjects during winter

Three known thiocarbamate (TC)- and isothiocyanate (ITC)-related compounds have been isolated from the leaves of Moringa oleifera, a traditional herb in southeast Asia, as inhibitors of tumor promoter teleocidin B-4-induced Epstein-Barr virus (EBV) activation in Raji cells. Interestingly, only niaziminin among 10 TCs including 8 synthetic ones showed considerable inhibition against EBV activation. The structure-activity relationships indicated that the presence of an acetoxy group at the 4'-position of niaziminin is important and indispensable for inhibition. On the other hand, among the ITC-related compounds, naturally occurring 4-[(4'-O-acetyl-alpha-L-rhamnosyloxy)benzyl]ITC and commercially available allyl- and benzyl-ITC significantly inhibited activation, suggesting that the isothiocyano group is a critical structural factor for activity.     

Acute effect of ursodeoxycholic acid on gallbladder volume in healthy subjects

The features of time domain and power spectrum of high frequency electrocardiogram (HF-ECG) were studied in normal Kunming mice using a microprocessor ECG system. The results were as follows (mean +/- SD): (1) P-R interval was 34.9 +/- 4.7 ms (n = 58), about one third of the cardiac cycle. (2) The duration and peak-to-peak amplitude of QRS complex were 9.2 +/- 1.2 ms and 1.456 +/- 0.480 mV (n = 74) respectively. (3) The duration and amplitude of T wave were 10.2 +/- 3.2 ms and 0.336 +/- 0.115 mV, respectively (n = 58). (4) Q-T interval was 19.4 +/- 3.2 ms (n = 58), about one fifth of the cardiac cycle. (5) The total number of notches and slurs of leads II of 73 mice were 3 and 26 respectively. (6) The relative power content of each frequency range was: 0-80 Hz: 45.48 +/- 15.32%; 80-200 Hz: 43.97 +/- 9.95%; 200-300 Hz: 8.89 +/- 7.83%; 300-1000 Hz: 1.66 +/- 2.74%; 80-1000 Hz: 54.52 +/- 15.32%.