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Circadian fluctuations of contrast sensitivity in Parkinson's disease.

Spontaneous circadian fluctuations of motor symptoms in Parkinson's disease (PD) often occur, with dysfunction typically less severe in the early morning than in the afternoon. In 23 PD patients with or without a history of circadian motor fluctuations, we studied contrast sensitivity (CS), a non-motor function, considered to be dependent on dopaminergic transmission to see if it exhibits similar circadian variability. We tested CS throughout the day at 2-hour intervals beginning at 8:30 AM. To facilitate multiple testing sessions, we used a rapid, printed, forced choice test of CS not requiring a motor response. We tested CS in 43 eyes in the PD patients and 23 eyes in 12 controls at spatial frequencies of 1.5, 3, 6, 12, and 18 cycles per degree (cpd). At 8:30 AM, CS in PD did not differ from that of controls, but at all other testing times it was significantly worse at 3 or more spatial frequencies. In PD, CS was significantly worse at 2:30 PM than at 8:30 AM at 3 and 6 cpd, but in controls it was unchanged throughout the day. Separate analysis of CS in PD patients, with and without a history of circadian change in motor symptoms, revealed no significant difference between the groups. These results suggest that in PD a non-motor dopaminergic function can exhibit circadian variability and that this pattern can exist in the absence of similar variability in motor symptoms. Circadian variability which parallels the most common pattern of motor variability in PD supports the notion that the CS abnormality in this condition is related to dopamine deficiency.

Aged↗

Quantification of islet cell antibodies by microscope photometry and antibody titration compared.

Islet cell antibodies can predict eventual insulin-dependent diabetes mellitus. In the standard method used by the Immunology of Diabetes Workshop (IDW), predictive power depends on antibody titer as determined by testing multiple serum dilutions. Here I report use of a microscope-based photometry system (MPS) to test whether islet fluorescence intensities from undiluted sera can predict IDW results. MPS testing of 120 undiluted IDW specimens correctly identified 27 of 31 positive and 84 of 89 negative specimens. The relationship between IDW consensus values and MPS readings of undiluted sera is: IDW = 2.45 MPS - 1.44 (r = 0.67, P less than 0.001). Thus, corrected islet intensities from undiluted sera correlated well with IDW values. However, the ability of MPS to predict high IDW consensus values is limited, which may reflect the variable antigenic content of pancreas specimens; moreover, background correction as currently applied is incomplete; nonspecific immunofluorescence appears to emanate from within the islet.

Autoantibodies↗

[Longitudinal distribution of pulmonary vascular resistance in patients with acute respiratory insufficiency].

Effective pulmonary capillary pressure (Pc) is a major factor determining transvascular fluid filtration in the lung. It may easily be estimated from the pressure decay after rapid pulmonary artery occlusion. If Pc is known, the longitudinal distribution of pulmonary vascular resistance (PVR) can be evaluated. The present study was performed to address the following questions: (a) whether the severity of acute lung injury influences Pc and the longitudinal distribution of PVR; and (b) whether pulmonary artery occlusion (PAOP) or wedge pressure represents effective Pc during acute respiratory failure. PATIENTS AND METHODS. The investigation was performed in 45 mechanically ventilated patients. According to Murray's criteria 13 patients showed no lung injury, 19 had mild to moderate lung injury, and 13 had severe lung injury (adult respiratory distress syndrome, ARDS). As described by Holloway, effective Pc was evaluated from the pressure decay after rapid occlusion of the pulmonary artery (Figs. 1 and 2). The precapillary pressure gradient was determined as the difference between mean pulmonary artery pressure and Pc, the postcapillary pressure gradient as the difference between Pc and PAOP. Three measurements were performed and Pc determined as their mean value. The Kruskal-Wallis test and Mann-Whitney U test were performed to check statistically significant differences between groups. A Bonferroni correction was performed for multiple testing; P < 0.05 was accepted. RESULTS. Effective Pc was significantly different between patients with severe lung injury (20 +/- 3 mm Hg) and patients with mild to moderate lung injury (16 +/- 3 mm Hg), and between the latter group and patients without lung injury (12 +/- 3 mm Hg). The postcapillary pressure gradient and the relative amount of pulmonary venous vascular resistance, as well, were significantly influenced by the severity of the lung injury. In patients with ARDS the postcapillary pressure gradient was 4 +/- 1 mm Hg, whereas in patients with mild to moderate and without lung injury the postcapillary pressure gradients were 3 +/- 1 mm Hg and 2 +/- 1 mm Hg, respectively. Two ARDS patients had a postcapillary pressure gradient of 7 mm Hg (Pc 22 mm Hg and 19 mm Hg, PAOP 15 mm Hg and 12 mm Hg). One patient with severe lung injury had a postcapillary pressure gradient of 9 mm Hg (Pc 22 mm Hg, PAOP 13 mm Hg). In patients with severe lung injury 28 +/- 7% of the PVR was located in the postcapillary vascular system, whereas in patients with mild to moderate and without lung injury 22 +/- 7% and 16 +/- 6% of PVR was located in the pulmonary venous system. CONCLUSIONS. The longitudinal distribution of PVR is influenced by the severity of lung injury. PAOP, therefore, may not represent changes in Pc in patients with acute respiratory failure. The routine use of Pc measurement, however, can not be recommended until it has proven more useful than determination of PAOP when managing critically ill patients.

Acute Disease↗

A comparative clinical study of three different endosseous implants in edentulous mandibles.

The purpose of this prospective study was to investigate the clinical outcome and marginal bone resorption of three different endosseous implants placed in the anterior mandibles of 15 elderly patients. Eleven women and 4 men (ranging from 65 to 80 years, mean 71 years) had three different endosseous implants placed in the anterior mandible; one titanium plasma-sprayed cylinder implant (4-mm diameter), one titanium cylinder implant with hydroxyapatite coating (4-mm diameter), and one standard threaded titanium implant (3.75-mm diameter). Three months later, at the second-stage surgical procedure, ball abutments were connected and an overdenture was placed. At 12, 24, and 36 months, marginal bone resorption and Periotest values were recorded. None of the implants was lost in this period. An analysis of variance with repeated measurement was performed annually to test the existence of significant differences between the implants. When differences appeared, paired t tests were used to identify which differences were significant. Bonferroni multipliers were used to adjust for multiple testing. When marginal bone resorption was concerned, threaded titanium and hydroxyapatite-coated implants had significantly better scores than titanium plasma-sprayed cylinder implants. Periotest values for hydroxyapatite-coated implants were significantly better than test values for the other implants after 2 years. After 3 years significance was obtained between hydroxyapatite and screw-shaped implants only (P < .05). It was concluded that titanium plasma-sprayed cylinder implants have a less favorable prognosis than the other implants used in this study.

Aged↗

The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes.

In the absence of pathognomonic clinical features or a definitive laboratory test, multiple sclerosis (MS) remains ultimately a diagnosis of exclusion. Accurate diagnosis is increasingly important with available disease modifying therapy. Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS. In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both. Conditions often confused with MS may be inflammatory (systemic lupus erythematosus, Sjögren's syndrome, vasculitis, sarcoidosis, Behçet's disease), infectious (Lyme disease, syphilis, progressive multifocal leukoencephalopathy, HTLV-1 infection, herpes zoster), genetic (lysosomal disorders, adrenoleukodystrophy, mitochondrial disorders, CADASIL), metabolic (vitamin B12 deficiency), neoplastic (CNS lymphoma) and spinal (degenerative and vascular malformations) diseases. The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.

Central Nervous System Diseases↗

Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps.

The statistical inference on functional imaging data is severely complicated by the embedded multiple testing problem. Defining a region of interest (ROI) where the activation is hypothesized a priori helps to circumvent this problem, since in this case the inference is restricted to fewer simultaneous tests, rendering it more sensitive. Cytoarchitectonic maps obtained from postmortem brains provide objective, a priori ROIs that can be used to test anatomically specified hypotheses about the localization of functional activations. We here analyzed three methods for the definition of ROIs based on probabilistic cytoarchitectonic maps. (1) ROIs defined by the volume assigned to a cytoarchitectonic area in the summary map of all areas (maximum probability map, MPM), (2) ROIs based on thresholding the individual probabilistic maps and (3) spherical ROIs build around the cytoarchitectonic center of gravity. The quality with which the thus defined ROIs represented the respective cytoarchitectonic areas as well as their sensitivity for detecting functional activations was subsequently statistically evaluated. Our data showed that the MPM method yields ROIs, which reflect most adequately the underlying anatomical hypotheses. These maps also show a high degree of sensitivity in the statistical analysis. We thus propose the use of MPMs for the definition of ROIs. In combination with thresholding based on the Gaussian random field theory, these ROIs can then be applied to test anatomically specified hypotheses in functional neuroimaging studies.

Artifacts↗

[Driving fitness/driving capacity of patients treated with methadone].

To answer the question whether or not therapeutic methadone doses significantly reduce traffic-related performance of drivers on medically supervised methadone programmes, 34 methadone substitution patients, all of them volunteers, were subjected to a test series: the focus of the study was a psychophysical test battery consisting of 10 individual performance tests to assess essential functions with regard to driving ability, such as concentration, attention, reaction capability, memory, perception and sensorimotor coordination. In evaluating the results of the psychophysical tests, multiple drug use and subjective methadone influence at the time of the examination were taken into consideration but current methadone blood level was neglected. The results were compared to those of a control group. The methadone group (n = 34) consisted of 25 men and 9 women aged between 18 and 38. At the time of the study, the majority of the test persons (29) were on low dosage methadone maintenance (up to 60 mg/day). In the urine samples of approximately 2/3 of the test persons, evidence was found for multiple drug use together with other psychotropic substances, the most frequent (14) being cannabis metabolites. Referring to their driving practices, a mere 4 out of 29 drivers had not committed any driving offences. A comparison of the psychophysical performance of the whole methadone group (n = 34) with a control group demonstrated that the methadone substitution patients achieved rather lower results in almost all variables. These performance deficits were particularly conspicuous in sustained attention, sensorimotor coordination and reaction capability. 12 "methadone only" participants, i.e. methadone probands without any additional consumption of psychotropic substances showed-partly considerably-better performance than the methadone group as a whole and also achieved normal results in relation to the test norm. Nevertheless, once again, results tended to be of lower level in comparison to the control group. "Methadone only" substitution patients, in particular those volunteers without a current subjective methadone influence-reached practically the same results as the corresponding control subjects, or at least average results based on test norm. However, the study revealed distinctive performance impairment (e.g. in sustained attention, reaction capability) when other psychotropic substances (including alcohol and cannabis!) were taken as well during the subjective methadone phase. The performance deficits were predominantly caused by a slowing down of reactions. Our study illustrates that, under certain conditions, long-term methadone maintenance under strict medical supervision does not have any significant unfavourable impact on the psychophysical performances in driving ability as examined in this study. Thus, these research findings support the previous Zurich experiences, according to which driving ability--and in the end also driving aptitude--of the methadone substitution patients does not depend on the methadone therapy itself, nor on the amount of the daily methadone intake. In making the final medical judgement on driving ability, the presence of a mixed drug use and the personality of the person in question are of far greater importance.

Accidents, Traffic↗

A case study of temporal change in EEG alpha activity in a multiple sleep latency test.

The appearance of electroencephalogram (EEG) alpha activity in a multiple sleep latency test was quantitatively analysed using percentage time alpha. Two components were extracted from the temporal change in smoothed percentage time alpha: a general level showing a progressive decrease and a cyclic variation with a mean interval of 39.8 s. The cyclic variation of percentage time alpha was evident during the period of the general level below 50%. The arousal cycle in the drowsy state is discussed.

Adult↗

HIV update. Diagnostic tests and markers of disease progression and response to therapy.

HIV-1 infection continues to present diagnostic and management challenges on a global scale. Multiple testing strategies currently are used for evaluation of patients and infection status. Serologic testing represents the standard for diagnosis of HIV-1 infection. Molecular methods enable screening of the blood supply, detection of vertical transmission, and viral load testing to monitor patients during therapy. Molecular resistance testing facilitates the assessment of viral quasi species and the presence of specific mutations that confer antiviral resistance. Both genotyping and phenotyping approaches have been adopted for HIV-1 drug-resistance testing and enable rational modification of therapies for patients in whom their current regimens are failing.

Adult↗

Mean versus median for the multiple sleep latency test.

Since its introduction in the mid-1970s, the multiple sleep latency test (MSLT) has become the standard method for evaluating hypersomnolence. The mean sleep latency is usually calculated and constitutes the traditional basis for interpretation. Mean and median are both measures of the central tendency of a distribution, but because the trials of the MSLT are limited to 20 minutes, the median may be more appropriate. The objective of this study was to compare the value of the mean versus the median sleep latency in the interpretation of the MSLT. We retrospectively analyzed 100 MSLTs performed for evaluation of excessive daytime sleepiness. Patients' ages ranged from 6 to 84 years (mean 43). Mean and median sleep latencies were calculated according to standard formulas. We classified each record into one of three categories, using both the mean and the median sleep latencies: normal (> 10 minutes), moderate (> or = 5 and < or = 10 minutes), and severe sleepiness (< 5 minutes). Of the 100 MSLTs, 89 remained in the same category (normal, moderate, severe) whether mean or median was used. In 11 cases, the category changed. All shifts were by one category, that is, no shift occurred between normal and severe. This study suggests that, despite valid theoretical arguments for the use of the median, both measures are equally acceptable for clinical purposes.

Adolescent↗

Electrophysiological assessment (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in humans.

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal-sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low-dose stimulant drugs, the stimulatory effect of ethanol was mild.

Adult↗

Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy.

Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (P=0.001), case-control genotype (P=0.001) and case-control family (P<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly associated with ARM in the case-control allele (P<0.0001), case-control genotype (P<0.0001) and case-control family (P<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. In addition, the CFH variant appears to play a role in exudative and atrophic disease, whereas the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.

Aging↗

A combined testing protocol approach for mutagenicity testing.

The antischistosomal agent, hycanthone methanesulfonate (HMS), was employed to illustrate the utility of carrying out several mutagenicity tests in a single concurrent animal experiment. Several commonly used procedures that were successfully integrated into a multiple testing protocol included (1) metaphase analysis in bone marrow, (2) micronucleus test in bone marrow, (3) analysis of the urine for mutagenic constituents, and (4) the host-mediated assay using Salmonella typhimurium. In addition to these animal studies, in vitro mutagenicity testing with and without activation was carried out using S. typhimurium. HMS produced positive, dose--response effects in in vitro tests, metaphase analysis, micronucleus test, and urine analysis, but not in the host-mediated assay. The results of these integrated techniques suggest that such a protocol may be a benefit to those concerned with mutagenicity testing of chemicals.

Animals↗

Immunoenzymatic test for Q-fever.

An immunoenzymatic test using as antigen purified suspensions of Coxiella burnetti coated by methylglyoxal on microtiter plates was developed. Multiple testing of the same sera gave similar results: two dilutions of serum (1:400 and 1:1600) were used in routine tests. Good agreement between the immunoenzymatic and the indirect immunofluorescent antibody tests was obtained for 41 of 50 sera examined. Five sera negative by the immunofluorescent antibody test were positive by the immunoenzymatic test; this result may be due to the higher sensitivity of the latter test. On the other hand, three sera with higher titers by the indirect immunofluorescent antibody test showed a rather feeble positivity by the immunoenzymatic test. This is probably due to the different specificity of the reacting antibodies in the two methods. The indirect immunofluorescent antibody test permits better distinction of the very high titers (greater than 1:5120) than the immunoenzymatic test. The immunoenzymatic test seems to be the method of choice for seroepidemiology surveys of Q-fever; however, its use for clinical serodiagnosis needs further confirmation.

Antibodies, Bacterial↗

Analyzing multivariate data in crossover designs using permutation tests.

Studies using crossover designs typically involve observations on a large number of response variables made on each of a relatively small number of subjects. Moreover, investigators often observe the responses longitudinally over time. As the number of variates approaches the number of subjects traditional multivariate statistics based on the concept of statistical distance often are not very powerful, and when that number exceeds the total number of subjects in the study, these tests are not defined. In these situations, statisticians frequently analyze each variate separately and adjust for the multiple testing using a technique suitable for correlated data. In the case of a single variate measured repeatedly, we often make the assumption of a patterned covariance matrix and then conduct a univariate mixed-model analysis. We discuss an alternative approach using a variety of data structures in 2 x 2 crossover designs with (1) univariate response in each treatment period, (2) multivariate response in each treatment period, and (3) longitudinal repeated measures on a single variate in each treatment period.

Cross-Over Studies↗

Association mapping of kernel size and milling quality in wheat (Triticum aestivum L.) cultivars.

Association mapping is a method for detection of gene effects based on linkage disequilibrium (LD) that complements QTL analysis in the development of tools for molecular plant breeding. In this study, association mapping was performed on a selected sample of 95 cultivars of soft winter wheat. Population structure was estimated on the basis of 36 unlinked simple-sequence repeat (SSR) markers. The extent of LD was estimated on chromosomes 2D and part of 5A, relative to the LD observed among unlinked markers. Consistent LD on chromosome 2D was <1 cM, whereas in the centromeric region of 5A, LD extended for approximately 5 cM. Association of 62 SSR loci on chromosomes 2D, 5A, and 5B with kernel morphology and milling quality was analyzed through a mixed-effects model, where subpopulation was considered as a random factor and the marker tested was considered as a fixed factor. Permutations were used to adjust the threshold of significance for multiple testing within chromosomes. In agreement with previous QTL analysis, significant markers for kernel size were detected on the three chromosomes tested, and alleles potentially useful for selection were identified. Our results demonstrated that association mapping could complement and enhance previous QTL information for marker-assisted selection.

Chromosome Mapping↗

A noninvasive electromagnetic flowmeter.

The reliability and reproducibility of peripheral blood flow data obtained by a noninvasive electromagnetic flowmeter were tested using seven male and three female volunteers aged 15-46 years. Each subject was studied under multiple testing conditions in which time, subject's metabolic state, and electrode placement were varied. Each condition was repeated within 1 to 8 weeks to obtain test-retest data. Intraclass reliability coefficients of 0.864-0.998 were obtained on all pulsatile components both within a given measurement sessions and from one day to the next. The size and shape of the waveforms obtained from the data did not significantly differ from one another, thus indicating excellent reproducibility. No significant differences were found between data obtained from the right leg and that obtained from the left. The noninvasive electromagnetic flowmeter was found capable of providing reliable and reproducible data. For data analysis, the second of two consecutive curves seems to be the best choice for clinical assessment.

Adolescent↗

Multiple marker screening test: identification of fetal cystic hygroma, hydrops, and sex chromosome aneuploidy.

The goal of this study was to determine if the multiple marker screening test (maternal serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotrophin, and maternal age) detects fetal Turner syndrome or just cystic hygroma/hydrops. Multiple marker screening tests from 4 groups were compared: 1) Turner syndrome with hydrops/ hygroma group (n = 10) = fetuses with cystic hygroma/hydrops and a 45X karyotype, 2) Turner syndrome without hydrops/hygroma (n = 9) = sonographically unremarkable fetal Turner syndrome or Turner mosaic, 3) hydrops group (n = 8) = all cases of fetal cystic hygroma/hydrops excluding Turner syndrome, 4) sex chromosome aneuploidy group (n = 16) = other sonographically normal fetal sex chromosome aneuploidies. Positive screening tests (Down syndrome risk > or = 1:190 or MSAFP > or = 2.5 MOM) were found in 60% (6/10) of the Turner syndrome with hydrops/hygroma group, but only 11% (1/9) of the Turner syndrome without hydrops/hygroma group (P = .04). The incidence of positive screening tests in the Hydrops group was 75% (6/8), while it was only 12.5% (2/16) in the other sex chromosome aneuploidy group. We conclude that the multiple marker screening test identifies fetuses with cystic hygroma/hydrops, and may do so independently of the etiology of the hydrops.

Adolescent↗