Scrutinizing the cut-off for "pathological" meniscal body extrusion on knee MRI.

OBJECTIVES: Medial meniscal body extrusion ≥ 3 mm on MRI is often considered "pathologic." The aims of this study were to (1) assess the adequacy of 3 mm as cut-off for "pathological" extrusion and (2) find an optimal cut-off for meniscal extrusion cross-sectionally associated with radiographic knee osteoarthritis, bone marrow lesions (BMLs), and cartilage damage. METHODS: Nine hundred fifty-eight persons, aged 50-90 years from Framingham, MA, USA, had readable 1.5 T MRI scans of the right knee for meniscal body extrusion (measured in mm). BMLs and cartilage damage were read using the whole organ magnetic resonance imaging score (WORMS). Knee X-rays were read according to the Kellgren and Lawrence (KL) scale. We evaluated the performance of the 3-mm cut-off with respect to the three outcomes and estimated a new cut-off maximizing the sum of sensitivity and specificity. RESULTS: The study persons had mean age of 62.2 years, 57.0% were women and the mean body mass index was 28.5 kg/m2. Knees with radiographic osteoarthritis, BMLs, and cartilage damage had overall more meniscal extrusion than knees without. The 3-mm cut-off had moderate sensitivity and low specificity for all three outcomes (sensitivity between 0.68 [95% CI 0.63-0.73] and 0.81 [0.73-0.87], specificity between 0.49 [0.45-0.52] and 0.54 [0.49-0.58]). Using 4 mm maximized the sum of sensitivity and specificity and improved the percentage of correctly classified subjects (from between 54 and 61% to between 64 and 79%). CONCLUSIONS: The 4-mm cut-off may be used as an alternative cut-off for denoting pathological meniscal extrusion. KEY POINTS: • Medial meniscal body extrusion is strongly associated with osteoarthritis. • The 3-mm cut-off for medial meniscal body extrusion has high sensitivity but low specificity with respect to bone marrow lesions, cartilage damage, and radiographic osteoarthritis. • The 4-mm cut-off maximizes the sensitivity and specificity with respect to all three osteoarthritis features.

Risk factors for meniscal body extrusion on MRI in subjects free of radiographic knee osteoarthritis: longitudinal data from the Osteoarthritis Initiative.

OBJECTIVE: To determine risk factors associated with increased meniscal body extrusion on knee magnetic resonance (MR) images in subjects free of radiographic osteoarthritis (OA). METHODS: We selected 340 subjects (aged 45-55 years, mean [SD] body mass index 26.7 [4.4], 51% women) with Kellgren-Lawrence grade 0 in both knees and bilateral knee MR images available at the baseline, 24 months, 48 months, and 72 month exam from the Osteoarthritis Initiative (OAI). We assessed mid-coronal 3-T MR images from baseline through the 72-month exam. One observer measured widths of the tibia plateau and medial or lateral meniscal body extrusion for baseline and 72 months follow-up. Another observer assessed meniscal integrity at all four time points. We calculated an extrusion ratio ([meniscal body extrusion]/[tibia width] × 100) to account for knee size. We evaluated risk factors for increased meniscal body extrusion ratio from baseline to 72 months by a multivariable linear regression mixed model for medial and lateral compartment, respectively. RESULTS: In the medial compartment female sex (ß = 0.35; 95% confidence interval [CI] 0.16-0.53), incident meniscal tear (ß = 0.29; 95% CI 0.22-0.55), and the baseline value of the extrusion ratio (ß = 0.63; 95% CI 0.56-0.70) were associated with increased extrusion ratio by 72 months. Results were similar for the lateral compartment. CONCLUSIONS: Only female sex, incident meniscal tear, and higher baseline value of extrusion are risk factors for increased meniscal body extrusion in subjects free of radiographic OA. The results suggest that meniscal extrusion may contribute to and mediate the well-known increase in knee OA incidence in middle-aged women.

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this two-stage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P<0.08) between patients and controls. After additional genotyping in stage two, two genes--each containing at least three significantly (P<0.05) associated SNPs--conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis--and, by extension, derangement of immune homeostasis--influence the risk of MS.

CGP 48664, a potent and specific S-adenosylmethionine decarboxylase inhibitor: effects on regulation and stability of the enzyme.

Mammalian S-adenosylmethionine decarboxylase (AdoMetDC) catalyses a regulatory important step in the biosynthesis of polyamines and is a potential target for therapeutic agents against various parasitic diseases and proliferative disorders. In the present study we examined the effects of a newly synthesized AdoMetDC inhibitor. 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664), on polyamine metabolism in the mouse leukaemia cell line L1210. Treatment of the cells with 2 microM CGP 48664 led to a depletion of cellular spermidine and spermine. The putrescine content, in contrast, was markedly increased. Cells seeded in the presence of the inhibitor showed a significant decrease in growth rate, which was fully reversed by the addition of 2 microM spermidine or 1 microM spermine. The syntheses of ornithine decarboxylase and AdoMetDC were greatly increased in cells treated with CGP 48664. These increases were not correlated with similar changes in the mRNA levels, indicating the involvement of a translational mechanism. CGP 48664 was demonstrated to be a very poor competitor of spermidine uptake in the L1210 cells. L1210 cells deficient in polyamine transport were as sensitive to the antiproliferative effect of the inhibitor as were the parental cells, indicating that CGP 48664 did not enter the cells by the polyamine transport system. In addition to inhibiting AdoMetDC, CGP 48664 stabilized the enzyme against degradation. In the present study we also demonstrated that aminoguanidine (AMG), which is frequently used in cellular systems to inhibit any action of serum polyamine oxidase, apparently inhibits AdoMetDC by an irreversible mechanism that markedly stabilizes the enzyme against proteolytic degradation. CGP 48664 and the parental compound methylglyoxal bis(guanylhydrazone), which is also a potent inhibitor of AdoMetDC, contain one or two AMG-like moieties; the importance of these residues in the inhibition of AdoMetDC is discussed.

Cloning of a trypanosomatid gene coding for an ornithine decarboxylase that is metabolically unstable even though it lacks the C-terminal degradation domain.

Mammalian ornithine decarboxylase (ODC) is among the most labile of cellular proteins, with a half-life of usually less than an hour. Like other short-lived proteins ODC is degraded by the 26S proteasome. Its degradation is not triggered by ubiquitination, but is stimulated by the binding of an inducible protein, antizyme. Truncations and mutations in the C terminus of mammalian ODC have been shown to prevent the rapid turnover of the enzyme, demonstrating the presence of a degradation signal in this region. Moreover, ODCs from the trypanosomatid parasites Trypanosoma brucei and Leishmania donovani, which lack this C-terminal domain, are metabolically stable, and recombination of T. brucei ODC with the C terminus of mammalian ODC confers a short half-life to the fusion protein when expressed in mammalian cells. In the present study we have cloned and sequenced the ODC gene from the trypanosomatid Crithidia fasciculata. To our knowledge, this is the first protozoan shown to have an ODC with a rapid turnover. The sequence analysis revealed a high homology between C. fasciculata ODC and L. donovani ODC, despite the difference in stability. We demonstrate that C. fasciculata ODC has a very rapid turnover even when expressed in mammalian cells. Moreover, ODC from C. fasciculata is shown to lack the C-terminal degradation domain of mammalian ODC. Our findings indicate that C. fasciculata ODC contains unique signals, targeting the enzyme for rapid degradation not only in the parasite but also in mammalian cells.

Regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase in a polyamine auxotrophic cell line.

In the present study we have examined the regulation of the polyamine biosynthetic pathway in a cell line deficient in ornithine decarboxylase (ODC) activity. These cells were unable to grow unless polyamines were provided in their growth medium. Seeding the cells in the absence of polyamines rapidly resulted in a cellular depletion of putrescine and spermidine. Although the cells were devoid of ODC activity they were demonstrated to express an inactive ODC which was feedback regulated by polyamines in a normal manner. Cells seeded in the absence of polyamines exhibited a marked increase in ODC synthesis rate which was not correlated with an equal change in the ODC mRNA level. The synthesis of S-adenosylmethionine decarboxylase (AdoMetDC) was also increased in the cells seeded in the absence of polyamines. However, this increase was essentially explained by a change in the amount of AdoMetDC mRNA. The addition of putrescine to the growth medium appeared to stimulate the conversion of AdoMetDC proenzyme into its two subunits, indicating a physiological role of putrescine in the regulation of AdoMetDC expression.

Regulation of mammalian S-adenosylmethionine decarboxylase as studied in a transient expression system.

Mammalian S-adenosylmethionine decarboxylase (AdoMetDC), which catalyzes a key step in the biosynthesis of polyamines, is regulated by a multitude of mechanisms. The polyamines exert a strong feedback control of the enzyme. In the present study we have used a transient expression system to study the regulation of mammalian AdoMetDC. COS cells were transfected with a SV 40-based expression vector containing a 5'- and 3'-truncated human AdoMetDC cDNA (pSDC:16). The cells were shown to contain high levels of AdoMetDC activity 2 days after expression. This was partly due to an increase in the synthesis of the enzyme. However a marked stabilization of the enzyme against degradation did also contribute to the high AdoMetDC activity seen in the COS cells after the transfection with pSDC:16. The high expression of AdoMetDC was reflected in a marked change in intracellular polyamine levels. The cells were almost depleted of their putrescine, and their spermidine content was decreased to about 35% of that found in the mock-transfected cells. The spermine content, on the other hand, was increased. This change in polyamine levels was most likely attributable to the pSDC:16-induced increase in decarboxylated S-adenosylmethinine, which favors the accumulation of spermine at the expenses of putrescine and spermidine. The effects on the expression of AdoMetDC of polyamine synthesis inhibitors varied dependent on whether the COS cells were transfected with control vector or pSDC:16, in spite of similar effects on cellular polyamine levels, indicating a difference in feedback regulation of 'native' and recombinant AdoMetDC. The construct used in the present study gave rise to an AdoMetDC mRNA without a 5' and devoid of most of the 3' untranslated regions. However, whether these parts of the mRNA are involved in the polyamine-mediated translational control of the enzyme remains to be confirmed.

Diethylglyoxal bis(guanylhydrazone), a potent inhibitor of mammalian S-adenosylmethionine decarboxylase. Effects on cell proliferation and polyamine metabolism in L1210 leukemia cells.

The polyamines are cell constituents essential for growth and differentiation. S-Adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in the polyamine biosynthetic pathway. Methylglyoxal bis(guanylhydrazone) (MGBG) is an anti-leukemic agent with a strong inhibitory effect against AdoMetDC. However, the lack of specificity limits the usefulness of MGBG. In the present report we have used an analog of MGBG, diethylglyoxal bis(guanylhydrazone) (DEGBG), with a much greater specificity and potency against AdoMetDC, to investigate the effects of AdoMetDC inhibition on cell proliferation and polyamine metabolism in mouse L1210 leukemia cells. DEGBG was shown to effectively inhibit AdoMetDC activity in exponentially growing L1210 cells. The inhibition of AdoMetDC was reflected in a marked decrease in the cellular concentrations of spermidine and spermine. The concentration of putrescine, on the other hand, was greatly increased. Treatment with DEGBG resulted in a compensatory increase in the synthesis of AdoMetDC demonstrating an efficient feedback control. Cells seeded in the presence of DEGBG ceased to grow after a lag period of 1-2 days, indicating that the cells contained an excess of polyamines which were sufficient for one or two cell cycles in the absence of polyamine synthesis. The present results indicate that analogs of MGBG, having a greater specificity against AdoMetDC, might be valuable for studies concerning polyamines and cell proliferation.

Social networks and longevity. A 14 year follow-up study among elderly in Denmark.

The hypothesis of the study was that social contacts to close friends and relatives and perceived social integration was able to delay mortality in general and cardiovascular mortality in particular. Altogether 1752 males and females, aged 70-100 years were interviewed by trained nurses in 1972 to 1974. The study group was based upon a random sample of all elderly in the town of Odense, Denmark. More than 80% participated in the survey which included data collection on social networks and health at the time of interviewing. By means of linking the study group to national registries on mortality and causes of mortality practically all in the cohort were traced until 1987. During follow-up 1501 persons died. Most of the association between social networks and mortality were weak and statistically insignificant but had the expected sign. After adjusting for initial health status only the interviewer's assessment of the quality of the network was statistically significant associated with longevity. A feeling of loneliness was found to be associated with cardiovascular mortality, especially for males.

Prevention of relocation of the aged in nursing homes.

In the period 1972-76 a descriptive and experimental socio-geriatric longitudinal investigation was carried out in the municipality of Odense. The aim of the experimental aspect was prevention of relocation of the aged in nursing homes. The practical work consisted in casefinding and social medical intervention by nurses experienced in geriatrics and in close contact with interdisciplinary groups. Emphasis was placed on familiarity with the structure of the social and health services, the provisions available, and with problem areas and deciding channels. Contact with the aged focused on gaining an overall impression of their situation, establishing mutual trust and cooperation. Aspects of the practical work that were emphasized were introduction to services, advice to the aged and personnel, coordination and follow-up for assessment of results. Twenty-three per cent of the age group 70-79 years and 51 per cent of the 80-years-olds and over were drawn randomly from the national person-register. In all, 4,128 persons were picked. They were then randomly divided into an intervention group and a control group. On December 31st, 1976, 154 persons from the intervention group and 189 from the control group had been relocated in nursing homes. The difference concerned mainly women over 80 years of age who had a statistically significant low relocation risk in the intervention group. Fewer elderly in the intervention group were relocated in nursing homes compared to controls after mid 74. Findings showed that on March 1st, 1983, duration of residence (survival) in nursing homes for the 343 persons who had taken up residency, was rather similar for both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of mental disorders in old age. Examples of comparability of epidemiological investigations in relation to utility in planning.

Due to the increase in the number of old people, diseases of old age have acquired more and more importance. In estimating the need for psychiatric hospitals and nursing homes, epidemiological investigations are necessary. Only relatively few population investigations of the old-age population have been carried out, and most of these have been carried out in countries in Northern Europe, which are closely related culturally and socially. In the present paper nine investigations are described in relation to certain central factors which include the purpose of the investigation, description of the population, selection of probands, and statistical concepts used, the collection of data, and the main results. Seven of the investigations give results in the form of prevalence, two investigations calculate incidence and morbidity risk. It is concluded that comparison of the various results is difficult as most of the authors have not intended their investigations for mutual comparison. It is clear that there are many dissimilarities in the milieus involved, in the methods used, in the prerequisites of the interviewers and assessors, and in the classification of the results. The investigations presented have been used for evaluation of prognosis and planning of care for the old-age population. It must be said that an investigation is an expression of local truth and as such often usable in local planning, but on the other hand it is not often possible to utilize results from investigations carried out in outside regions for more than a rough basis for local prognosis and local planning. It must therefore be stressed that in future investigations more standardized methods and better correlated descriptions are necessary.