Perimetric variability: Importance of criterion level

Perimetry suffers from considerable variability of results. A new technique for estimating individual criterion levels in normal subjects exposes the important role of psychological variables. The analysis depends on features peculiar to acuity perimetry. It can be accommodated in the regular examination. The results can be used to compensate for practice effects in serial examinations and to tighten the range of normal limits. The reduction in variation between normal subjects amounted to 57 per cent.     

Monitoring left ventricular dilation in mice with PET.

Molecular imaging by small-animal PET is an important noninvasive means to phenotype transgenic mouse models in vivo. When investigating pathologies of the left ventricular (LV) myocardium, the serial assessment of LV volumes is important. By this, the presence of LV dilation as a sign of developing heart failure can be detected. Whereas PET is usually used to derive biochemical and molecular information, functional parameters such as ventricular volumes are generally measured using echocardiography or MRI. In this study, a novel method to monitor LV dilation in mice with PET is presented and evaluated using cardiac MRI. METHODS: A semiautomatic 3-dimensional algorithm was used to delineate the LV myocardial wall on static PET images depicting myocardial glucose metabolism ((18)F-FDG PET) for 20 mice: 10 wild-type and 10 genetically modified littermates designed to develop a dilative cardiomyopathy phenotype (cardiomyocyte-specific knockout of survivin). The volume enclosed by the 3-dimensional midmyocardial contour was calculated as a measure for LV volume for each mouse. Data were compared with ventricular volumes measured by MRI in the same animals. RESULTS: LV volumes obtained by PET and MRI correlated well (R = 0.89) for hearts with small and large left ventricles. In accordance with the hypothesis, the LV volumes were increased significantly for transgenic mice examined at an older age compared with those examined at a younger age (MRI: 160.5 +/- 25.7 microL vs. 114.7 +/- 15.2 microL [P = 0.012]; PET: 129.3 +/- 15.3 microL vs. 73.8 +/- 15.0 microL [P < 0.001], all values shown as mean +/- SD; for MRI, mean of end-diastolic and end-systolic volumes are given), whereas they did not for their wild-type littermates (MRI: 106.2 +/- 12.3 microL vs. 94.7 +/- 14.6 microL [P = 0.214]; PET: 82.6 +/- 20.9 microL vs. 65.0 +/- 16.9 microL [P = 0.185]). CONCLUSION: Evaluation and quantitation of LV dilation in both control and cardiomyopathic mice can be reliably and serially performed using small-animal PET and (18)F-FDG, yielding useful functional information in addition to metabolic data.     

Alpha-contingent EEG feedback reduces SPECT rCBF variability.

EEG feedback methods, which link the occurrence of alpha to the presentation of repeated visual stimuli, reduce the relative variability of subsequent, alpha-blocking event durations. The temporal association between electro-cortical field activation and regional cerebral blood flow (rCBF) led us to investigate whether the reduced variability of alpha-blocking durations with feedback is associated with a reduction in rCBF variability. Reduced variability in the rCBF response domain under EEG feedback control might have methodological implications for future brain-imaging studies. Visual stimuli were randomly presented to seven subjects, contingent upon the occurrence of alpha (alpha-contingent stimulation (ACS)) or alpha-blocking (not-alpha-blocking-contingent stimulation (NACS)) events. We employed a within-subjects design. rCBF was measured from multiple, cortical and sub-cortical regions. The primary dependent variables were the Mean, Standard Deviation and the ratio of Mean/Standard Deviation of: 1) the alpha-blocking response durations and 2) the temporally summated rCBF responses within the Visual Associative regions of interest (ROIs). Additional within-subjects rCBF measures were derived to quantify the variance-reducing effects of ACS across multiple, distributed areas of the brain. Both EEG and rCBF measures demonstrated decreased variability under ACS. This improved control was seen for localized as well as anatomically distributed rCBF measures.     

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.     

Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones.

We hypothesized that pro-inflammatory cytokines can act locally in the growth plate to impair longitudinal growth. In a model of cultured fetal rat metatarsal bones, we found that IL-1beta and TNF-alpha act in synergy to inhibit longitudinal growth, an effect linked to decreased proliferation and increased apoptosis of growth plate chondrocytes. IGF-I could partially reverse all these effects. INTRODUCTION: Children with chronic inflammatory conditions, such as Crohn's disease or rheumatoid arthritis, experience impaired longitudinal growth. The inflammatory process itself, which includes upregulation of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha, is believed to be at least partly responsible for the poor growth in these patients. This study aimed to clarify whether these cytokines can act locally in the growth plate to suppress longitudinal growth and whether any negative effects can be reversed by insulin-like growth factor-I (IGF-I). MATERIALS AND METHODS: The effects of cytokines on longitudinal bone growth were studied in fetal (day E20) rat metatarsal bones kept in culture. After a 7-day culture, the bones were sectioned, and chondrocyte proliferation was assessed by bromodeoxyuridine (BrdU) incorporation and apoptosis by TUNEL. RESULTS: When added separately, IL-1beta and TNF-alpha impaired longitudinal bone growth only at a high concentration (100 ng/ml each; p < 0.05 versus control). In contrast, when added in combination, IL-1beta and TNF-alpha potently inhibited growth at far lower concentrations (from 3 ng/ml each; p < 0.001 versus control) and also decreased chondrocyte proliferation and increased apoptosis. Growth failure induced by the combination of IL-1beta and TNF-alpha (10 ng/ml each) could be counteracted by anti-IL-1beta (100 ng/ml; p < 0.001), anti-TNF-alpha (100 ng/ml; p < 0.001), or IGF-I (100 ng/ml; p < 0.01). IL-6 did not affect longitudinal growth even when added in combination with IL-1beta or TNF-alpha (10 ng/ml each). CONCLUSIONS: We show that IL-1beta and TNF-alpha act in synergy to locally suppress longitudinal growth, an effect that can be partially reversed by IGF-I. Although growth hormone (GH)/IGF-I may improve longitudinal growth in children with chronic inflammatory diseases, our results suggest that the inflammatory process itself must be targeted to achieve normal growth.     

Antibodies against 5-hydroxymethyl-2'-deoxyuridine are associated with lifestyle factors and GSTM1 genotype: a report from the Malm? Diet and Cancer cohort.

Plasma autoantibodies (aAbs) against the oxidized DNA base derivative 5-hydroxymethyl-2'-deoxyuridine (5-HMdU) are potential biomarkers of cancer risk and oxidative stress. We examined their association with a number of cancer risk factors: smoking, alcohol habits, body fatness, and absence of the glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in a sample from the population-based Malm? Diet and Cancer cohort (Sweden). This was a cross-sectional study of 264 men and 280 women, 46-67 years of age. Anti-5-HMdU aAb concentration was determined by an ELISA. Data on tobacco exposure were collected through a questionnaire. Alcohol consumption was estimated by a modified diet history method. Body fatness was assessed by a bioimpedance method. The absence or presence of genes coding for GSTM1 and GSTT1 was determined in granulocyte DNA by a multiplex PCR technique. aAb titers were significantly greater in those with high alcohol consumption. Current smokers lacking GSTM1, particularly men, had greater aAb titers compared with nonsmokers or persons expressing GSTM1. Body fatness was inversely associated with antibody titers in men. GSTT1 genotype was not associated with aAb titers. Overall, women had higher aAb titers than men. Adjustment for potential confounders (history of chronic diseases, anti-inflammatory medication, and season of blood sampling) did not change the results. Our study shows that a high alcohol consumption, smoking in combination with lack of GSTM1, and low body fatness (in men) is associated with high titers of anti-5-HMdU aAbs in this population.     

Exteroceptive suppression periods in jaw-closing muscles. Variability and relation to experimental pain and sustained muscle contraction

The duration of the late exteroceptive suppression period (ES₂) of temporal muscle EMG activity has been reported to be reduced in patients suffering from chronic tension-type headache. Methods of recording and analysing ES₂ have varied between centers and reproducibility of results within subjects , although insufficiently studied, has generally been poor. ES₂ was investigated in 30 healthy subjects, using a computerized technique of recording, rectifying and averaging the EMG signals. Hour to hour and week to week variations of ES₂ durations were calculated, and the influence of pain during a cold pressor test and of sustained muscle contraction on ES₂ durations was investigated. The intra-individual variation of ES₂ durations was 16.0% from hour to hour and 20.7% from week to week. The inter-individual variation was 36.7%. The present method for analysis of ES₂ periods proved to be reliable, as the intra-observer variation was 4.2% and the inter-observer variation 4.6%. ES₂ periods were significantly shorter on the first compared to the second day of examination ( p = 0.006) and during experimental pain ( p = 0.0005). We recommend the use of the computerized averaging technique in future studies and caution against the dependence of results upon factors such as conditioning and pain.     

Knee arthroplasty in rheumatoid arthritis: A report from the Swedish Knee Arthroplasty Register on 4, 381 primary operations 1985-1995

The Swedish Knee Arthroplasty Register has data on 4, 381 primary operations performed 1985-1995 for rheumatoid arthritis. Of these, 192 were performed with unicompartmental prostheses and 4143 with tricompartmental. 77% were women and the mean age was 66 years. There were 126 first, 20 second, and 1 third revision in tricompartmental arthroplasties, mainly for loosening, infection and patellar problems. There were 38 first, 3 second, and 1 third revision in unicompartmental arthroplasties, mainly for progression of RA and loosening .

Cumulative revision rates (Kaplan-Meier) were calculated. Tricompartmental knees had a 10-year cumulative revision rate of 5% and uni-knees 25%. Patients treated before 1990, men and patients younger than 55 had higher revision rates than patients treated after 1990, women and older patients, respectively. Cemented tibial components resulted in lower revision rates than uncemented ones. There was no significant difference in revision rates between patellar replaced and unreplaced knees or between the 9 commonest implant types.     

Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.