Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM.

Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids. Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G>C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options.

Survival and its predictors from age 75 to 85 in men and women belonging to cohorts with marked survival differences to age 75: a comparative study in three Nordic populations.

BACKGROUND AND AIMS: While predictors of survival in older people have been examined in depth in a large number of studies, a literature search revealed no cross-national comparative prospective cohort studies on this issue. This study investigated survival and its predictors from age 75 to 85 among three local Nordic populations using survival data on national cohorts as background information. METHODS: The data were derived from national registers and from samples of 75-year old living in Denmark, Sweden, and Finland. The subjects were invited to take part in interviews and examinations focusing on different domains of health, functional capacity, and physical and social activities. RESULTS: The proportion of survivors to age 75 was markedly smaller among the Finnish men and women than Danish or Swedish subjects. In the local population no marked differences in survival from age 75 to 85 were observed between the groups of men, while women survived longer than men and longer in Göteborg than in Glostrup or Jyväskylä. Univariate models revealed 12 predictors of survival. In the multivariate models, the significant predictors among men related to physical fitness, whereas among women they pertained to social activities and morbidity. CONCLUSIONS: Despite great differences in the proportions of survivors to age 75, and excepting the survival advantage of women, only minor differences were present in the subjects' further survival to age 85. In the univariate analyses, many of the factors predictive of survival from age 75 to 85 were the same in the examined populations, whereas in the multivariate analyses differences between the sexes emerged.

Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults.

BACKGROUND AND AIMS: Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. METHODS AND RESULTS: LTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = -0.238; p = 0.032), waist circumference (r = -0.256; p = 0.02), triglycerides (r = -0.218; p = 0.049), PAI-1 (r = -0.288; p = 0.009) and directly correlated with HDL-cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62). CONCLUSION: LTL is independently associated to CV risk factors also in healthy young adults.

Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration.

A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

Different tyrosine autophosphorylation requirements in fibroblast growth factor receptor-1 mediate urokinase-type plasminogen activator induction and mitogenesis.

Among the seven tyrosine autophosphorylation sites identified in the intracellular domain of tyrosine kinase fibroblast growth factor receptor-1 (FGFR1), five of them are dispensable for FGFR1-mediated mitogenic signaling. The possibility of dissociating the mitogenic activity of basic FGF (FGF2) from its urokinase-type plasminogen activator (uPA)-inducing capacity both at pharmacological and structural levels prompted us to evaluate the role of these autophosphorylation sites in transducing FGF2-mediated uPA upregulation. To this purpose, L6 myoblasts transfected with either wild-type (wt) or various FGFR1 mutants were evaluated for the capacity to upregulate uPA production by FGF2. uPA was induced in cells transfected with wt-FGFR1, FGFR1-Y463F, -Y585F, -Y730F, -Y766F, or -Y583/585F mutants. In contrast, uPA upregulation was prevented in L6 cells transfected with FGFR1-Y463/583/585/730F mutant (FGFR1-4F) or with FGFR1-Y463/583/585/730/766F mutant (FGFR1-5F) that retained instead a full mitogenic response to FGF2; however, preservation of residue Y730 in FGFR1-Y463/583/585F mutant (FGFR1-3F) and FGFR1-Y463/583/585/766F mutant (FGFR1-4Fbis) allows the receptor to transduce uPA upregulation. Wild-type FGFR1, FGFR1-3F, and FGFR1-4F similarly bind to a 90-kDa tyrosine-phosphorylated protein and activate Shc, extracellular signal-regulated kinase (ERK)2, and JunD after stimulation with FGF2. These data, together with the capacity of the ERK kinase inhibitor PD 098059 to prevent ERK2 activation and uPA upregulation in wt-FGFR1 cells, suggest that signaling through the Ras/Raf-1/ERK kinase/ERK/JunD pathway is necessary but not sufficient for uPA induction in L6 transfectants. Accordingly, FGF2 was able to stimulate ERK1/2 phosphorylation and cell proliferation, but not uPA upregulation, in L6 cells transfected with the FGFR1-Y463/730F mutant, whereas the FGFR1-Y583/585/730F mutant was fully active. We conclude that different tyrosine autophosphorylation requirements in FGFR1 mediate cell proliferation and uPA upregulation induced by FGF2 in L6 cells. In particular, phosphorylation of either Y463 or Y730, dispensable for mitogenic signaling, represents an absolute requirement for FGF2-mediated uPA induction.

alphavbeta3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells.

Fibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture plastic promotes adhesion and spreading of bovine and human endothelial cells that are inhibited by anti-FGF-2 antibody. Heat-inactivated FGF-2 retains its cell-adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors or to cell-surface heparan sulfate proteoglycans. Recombinant glutathione-S-transferase-FGF-2 chimeras and synthetic FGF-2 fragments identify two cell-adhesive domains in FGF-2 corresponding to amino acid sequences 38-61 and 82-101. Both regions are distinct from the FGF-receptor-binding domain of FGF-2 and contain a DGR sequence that is the inverse of the RGD cell-recognition sequence. Calcium deprivation, RGD-containing eptapeptides, soluble vitronectin (VN), but not fibronectin (FN), inhibit cell adhesion to FGF-2. Conversely, soluble FGF-2 prevents cell adhesion to VN but not FN, thus implicating VN receptor in the cell-adhesive activity of FGF-2. Accordingly, monoclonal and polyclonal anti-alphavbeta3 antibodies prevent cell adhesion to FGF-2. Also, purified human alphavbeta3 binds to immobilized FGF-2 in a cation-dependent manner, and this interaction is competed by soluble VN but not by soluble FN. Finally, anti-alphavbeta3 monoclonal and polyclonal antibodies specifically inhibit mitogenesis and urokinase-type plasminogen activator (uPA) up-regulation induced by free FGF-2 in endothelial cells adherent to tissue culture plastic. These data demonstrate that FGF-2 interacts with alphavbeta3 integrin and that this interaction mediates the capacity of the angiogenic growth factor to induce cell adhesion, mitogenesis, and uPA up-regulation in endothelial cells.

A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

Basic fibroblast growth factor (FGF-2) induces cell proliferation and urokinase-type plasminogen activator (uPA) production in fetal bovine aortic endothelial GM 7373 cells. In the present paper we investigated the role of the interaction of FGF-2 with tyrosine-kinase (TK) FGF receptors (FGFRs) in mediating uPA up-regulation in these cells. The results show that FGF-2 antagonists suramin, protamine, heparin, the synthetic peptide FGF-2(112-155), and a soluble form of FGFR-1 do not inhibit FGF-2-mediated uPA up-regulation at concentrations that affect growth factor binding to cell surface receptors and mitogenic activity. In contrast, tyrosine phosphorylation inhibitors and overexpression of a dominant negative TK- mutant of FGFR-1 abolish the uPA-inducing activity of FGF-2, indicating that FGFR and its TK activity are essential in mediating uPA induction. Accordingly, FGF-2 induces uPA up-regulation in Chinese hamster ovary cells transfected with wild-type FGFR-1, -2, -3, or -4 but not with TK- FGFR-1 mutant. Small unilamellar phosphatidyl choline:cholesterol vesicles loaded with FGF-2 increased uPA production in GM 7373 cells in the absence of a mitogenic response. Liposome-encapsulated FGF-2 showed a limited but significant capacity, relative to free FGF-2, to interact with FGFR both at 4 degrees C and 37 degrees C and to be internalized within the cell. uPA up-regulation by liposome-encapsulated FGF-2 was quenched by neutralizing anti-FGF-2 antibodies, indicating that the activity of liposome-delivered FGF-2 is mediated by an extracellular action of the growth factor. Taken together, the data indicate that a distinct interaction of FGF-2 with FGFR, quantitatively and/or qualitatively different from the one that leads to mitogenicity, is responsible for the uPA-inducing activity of the growth factor.

Paracrine and autocrine effects of fibroblast growth factor-4 in endothelial cells.

Recombinant Fibroblast Growth Factor-4 (FGF4) and FGF2 induce extracellular signal-regulated kinase-1/2 activation and DNA synthesis in murine aortic endothelial (MAE) cells. These cells co-express the IIIc/Ig-3 loops and the novel glycosaminoglycan-modified IIIc/Ig-2 loops isoforms of FGF receptor-2 (FGFR2). The affinity of FGF4/FGFR2 interaction is 20-30 times lower than that of FGF2 and is enhanced by heparin. Overexpression of FGF2 or FGF4 cDNA in MAE cells results in a transformed phenotype and increased proliferative capacity, more evident for FGF2 than FGF4 transfectants. Both transfectants induce angiogenesis when applied on the top of the chick embryo chorioallantoic membrane. However, in contrast with FGF2-transfected cells, FGF4 transfectants show a limited capacity to growth under anchorage-independent conditions and lack the ability to invade 3D fibrin gel and to undergo morphogenesis in vitro. Also, they fail to induce hemangiomas when injected into the allantoic sac of the chick embryo. In conclusion, although exogenous FGF2 and FGF4 exert a similar response in MAE cells, significant differences are observed in the biological behavior of FGF4 versus FGF2 transfectants, indicating that the expression of the various members of the FGF family can differently affect the behavior of endothelial cells and, possibly, of other cell types, including tumor cells.

Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations.

The t(4;14)(p16.3;q32) chromosomal translocation occurs in approximately 20% of multiple myelomas (MM) and leads to the apparent deregulation of two genes located on 4p16.3: the fibroblast growth factor receptor 3 (FGFR3) and the putative transcription factor WHSC1/MMSET. Interestingly, FGFR3 mutations known to be associated with autosomal dominant human skeletal disorders have also been found in some MM cell lines with t(4;14) but their pathogenetic role in MM is still controversial. Since cell lines may represent useful models for investigating the effects of deregulated FGFR3 mutants in MM, we analysed the expression, activation, signaling pathways and oncogenic potential of three mutants identified so far: the Y373C and K650E in the KMS-11 and OPM-2 cell lines respectively, and the novel G384D mutation here identified in the KMS-18 cell line. All of the cell lines present a heterozygous FGFR3 gene mutation and transcribe the mutated allele; unlike KMS-11 and OPM-2 (which express the IIIc isoform), the KMS-18 cell line expresses prevalently the isoform IIIb. We demonstrated that, under serum-starved conditions, KMS-11 and OPM-2 cells express appreciable levels of phosphorylated FGFR3 mutants indicating a constitutive activation of the Y373C and K650E receptors; the addition of the aFGF ligand further increased the level of receptor phosphorylation. Conversely, the FGFR3 mutant in KMS-18 does not seem to be constitutively activated since it was phosphorylated only in the presence of the ligand. In all three MM cell lines, ligand-stimulated FGFR3 mutants activated the MAP kinase signaling pathway but did not apparently involve either the STAT1 or STAT3 cascades. However, when transfected in 293T cells, G384D, like Y373C and K650E, was capable of activating MAPK, STAT1 and STAT3 under serum-starved condition. Finally, a focus formation assay of NIH3T3 cells transfected with FGFR3-expressing plasmid vectors showed that Y373C and K650E (albeit at different levels) but not G384D or the wild-type receptor, can induce transformed foci. Overall, our results support the idea that FGFR3 mutations are graded in terms of their activation capability, thus suggesting that they may play a critical role in the tumor progression of MM patients with t(4;14).

Physical activity and the changes in maximal isometric strength in men and women from the age of 75 to 80 years.

OBJECTIVE: To research the natural changes in maximal isometric strength, over a period of 5 years, in men and women aged 75 at baseline, and to study the effect of everyday physical activity on strength alterations. DESIGN: A 5-year longitudinal study. SETTING: Exercise laboratory. PARTICIPANTS: The target group in 1989 was the total 75-year-old population of Jyväskylä. One hundred one men (81%) and 186 women (75%) participated in baseline strength tests, and after 5 years, 55 men and 111 women (70% and 72% of the survivors) took part in the follow-up measurements. METHODS: Maximal isometric hand grip, arm flexion, knee extension, trunk flexion, and trunk extension forces were measured using dynamometers. Self-rated physical activity was recorded using a scale by Grimby (1986). Strength changes were compared between groups based on the amount of everyday physical activity: (1) remained active (AA, 24 men, 24 women); (2) remained sedentary (SS, 11 men, 43 women); (3) decreased activity (AS, 11 women); and (4) increased activity (SA, 32 women). AS and SA could be formed for women only because of the small number of men. All analyses were stratified by gender. MAIN RESULTS: The average percentage change in strength over 5 years among survivors varied from a 4% increase in knee extension strength observed in men and women to a 16% decrease in grip strength in women. The grip strength decrease was greater in women than men. The AA men maintained their trunk extension strength at a higher level than the SS men. Time by group interactions in men were not significant. In women, the rate of decline in AS was 32% in grip and 27% in elbow flexion strength, which was greater than in the other activity groups. The AA women retained their knee extension strength at a higher level than the other groups. Those who died before follow-up tests exhibited poorer strength test results at baseline. Physical activity decreased over follow-up. CONCLUSIONS: Strength alterations with age differed between muscle groups. Undertaking everyday physical activities such as household work, walking, and gardening, which are also the most common physically demanding activities of older people, may play an important role in maintaining strength at an adequate level for independent living.

Postural balance and self-reported functional ability in 75-year-old men and women: a cross-national comparative study.

OBJECTIVE: To study postural balance in relation to self-reported functional ability (mobility and ADL) and general physical activity in elderly men and women living in three different Nordic environments. PARTICIPANTS: A random sample of 448 men and 556 women from among the 75-year-old residents in Glostrup, Denmark, and Göteborg, Sweden, and all the residents of relevant age (127 men and 261 women) in Jyväskylä, Finland. MEASUREMENTS: Assessment of postural balance with eyes open and closed using a piezoelectric force platform. A structured interview on self-reported functional ability and physical activity. An in-laboratory medical examination. RESULTS: In spite of some differences in balance between the groups studied (better results in women compared with men and, to some extent, better results in the participants from Denmark and Finland than in those from Sweden), the performance in the balance tests was similarly associated with functional ability within all groups. The subjects reporting no need of help in performing the ADL and mobility functions performed significantly better in the balance tests. These differences were seen more clearly in the control of anteroposterior movement of center of forces than in the mediolateral direction. The performance in the balance tests was also significantly better among the subjects reporting a higher level of general physical activity than in their less active counterparts. Physical activity and than in their less active counterparts. Physical activity and certain long standing illnesses modified significantly the relationship between postural balance and ADL-performance. When these factors were analyzed simultaneously, the role of balance as a predictor of ADL-performance largely disappeared. CONCLUSIONS: The results suggest that good balance is one of the prerequisites of performance without difficulty in mobility and ADL functions. Physical exercise may help to maintain balancing abilities in old age; good balance, in turn, may also enable a physically active way of life. The associations of balance with functional ability and physical activity were independent of sex and locality. The results also support the validity of static stabilometry as a tool for evaluating threats to functional limitations in older subjects.

Postural balance and its sensory-motor correlates in 75-year-old men and women: a cross-national comparative study.

BACKGROUND: There are no earlier cross-national comparative studies analyzing the functions of the posture control mechanisms and its sensory-motor correlates in elderly subjects. We investigated whether there are differences in balance between elderly subjects living in different geographical areas, and analyzed the sensory-motor associates of balance in men and women separately. METHOD: Using a force platform method, the functioning of the posture control system under three standardized conditions (normal standing, eyes open; normal standing, eyes closed; and tandem standing, eyes open) was studied among samples of 75-year-old residents in three Nordic localities, namely Glostrup in Denmark, Göteborg in Sweden, and Jyväskylä in Finland. The associations of the variables describing performance in each test with other sensory and motor functions were studied using correlation analyses and multivariate regression models. RESULTS: Differences between the populations were observed in both tests with visual control, favoring the participants from Glostrup and Jyväskylä compared with those from Göteborg. However, only minor differences between the subjects from different localities were observed in the test performed with the eyes closed. In all localities there was a primary sex difference in favor of the women which, however, mainly disappeared when body height was taken into the analyses as a covariate. A good performance in the balance tests (body height-adjusted values) was associated with good visual acuity, low vibrotactile thresholds, and high psychomotor speed. Also, isometric muscle strength, especially hand grip and body extension, was positively associated with good performance in the balance tests. Among the women, a poorer balance was observed in women with a smaller body mass. The results of the multivariate analyses showed that among the men, the most important predictors of good performance in the balance tests were low vibrotactile threshold on the foot, high isometric hand grip strength, and low body stature. Among the women, the most important predictors were low body stature, high body mass, high isometric body extension strength, and high psychomotor speed. However, only a small proportion of the variance in balance (about 13% in the men and 11% in the women) could be explained by the help of these factors. CONCLUSIONS: As the same procedure was applied to the analysis of postural balance, some differences between the populations living in different localities could be detected in some of the tests. The better performance of the women in the balance tests may partly be explained by anthropometric factors, especially differences in body height. There may also be differences in sensory-motor associates of balance in elderly men and women. On the basis of the associations observed, it is difficult to explain the differences in balance between the sexes or subjects living in different localities. Within the sexes, only a small proportion (10-13%) of the variation in balance during normal standing with eyes open could be explained by the factors included in the study.

Differential expression of fibroblast growth factor receptors by human neurones, astrocytes and microglia.

Expression of fibroblast-growth factor receptors (FGFRs) was studied in human fetal neurones, astrocytes and microglia in culture. Northern blot analysis showed that neurones and microglia expressed the mRNAs for FGFR-1, FGFR-2, FGFR-3, FGFR-4 at different levels, whereas astrocytes expressed only FGFR-1 and FGFR-4 mRNAs. Immunocytochemical localization of FGFR-1 revealed that this receptor was predominantly localized on the axon hillock membrane in neurones, and was associated with the plasma membrane of ameboid, activated microglia and of glial-fibrillar acidic protein positive astrocytes. The expression of various members of the FGFR family in all the cell types investigated implicates FGFs in human brain development and functions.

Expression of basic fibroblast growth factor and its receptors in human fetal microglia cells.

The presence of basic fibroblast growth factor (bFGF) and FGF receptors was investigated in microglia cells derived from human fetal brain long-term cultures. Production of bFGF was suggested through the capability of microglial extracts to stimulate plasminogen activator (PA) synthesis in endothelial cells. The identity of PA-stimulating activity with bFGF was confirmed by its high affinity for heparin and its cross-reactivity with polyclonal antibodies to human recombinant bFGF. These antibodies recognized a cell-associated M(r) 18,000 protein as well as trace amounts of the M(r) 24,000 bFGF isoform in Western blot. All microglial cells showed bFGF immunoreactivity in the cytoplasm and, sometimes, in the nucleus. Scatchard plot analysis of 125I-bFGF binding data revealed the presence of low affinity heparansulphate proteoglycans (380,000 +/- 60,000 sites/cell; Kd = 730 +/- 200 nM) and of high affinity tyrosine-kinase receptors (10,300 + 2500 sites/cell; Kd = 30 +/- 9 pM). Immunocytochemistry confirmed the presence of FGF receptor (1/flg) on the cell surface of some, but not all microglial cells, with prevalent association to ameboid microglia. Transcripts for FGF receptors 1, 2, 3 and 4 were found in microglia by Northern blot analysis. Co-expression of bFGF and its receptors in human fetal microglia suggests an autocrine role of bFGF in these cells.

Postural stability and skilled performance--a study on top-level and naive rifle shooters.

Posture control during aiming over a period of 7.5 s preceding the shot was studied among national top-level rifle shooters as well as among national level shooters and amateurs familiar with rifle shooting. Movement of the center of forces (COF) was analyzed in terms of the speed and amplitude of the movement. These calculations were carried out in 1.5 s windows, the first window beginning 7.5 s and ending at 6.0 s prior the shot. The last window ended at the trigger pull. Posture control data differentiated the studied groups according to their level in competitive shooting. The male top-level shooters could stabilize their posture significantly better than female top-level or male national level shooters, who were, in turn, much more stable than naive shooters. The experienced shooters were able to stabilize their posture even better during the last seconds preceding the shot, whereas in naive shooters there were no significant differences when the successive windows were compared with each other. When a comparison was made between the best and worst 20 shots of each subject, a significant difference in balance parameters was only observed among the naive shooters, who showed more pronounced movement of the COF in the less successful trials. Among the highly trained top-level shooters a miss in whole-body posture stabilization apparently seldom is a reason for a poor result.

Body composition of 80-years old men and women and its relation to muscle strength, physical activity and functional ability.

OBJECTIVE: To measure body composition and analyse the relation to muscle strength, physical activity and functional ability in healthy, old subjects, and to relate the results to an optimal BMI level for the elderly. SETTING: Subjects aged 80 years living at home from the 1914-population in Glostrup, Denmark. SUBJECTS AND METHOD: 121 men and 113 women had their height and weight measured. Body fat mass and fat-free mass were assessed by bioelectrical impedance. Muscle strength was measured as handgrip, elbow flexion, knee extension, body flexion and body extension. Physical activity was self reported and functional ability was assessed by the Physical Performance Test (PPT) and self reported mobility including information about tiredness and help. RESULTS: After dividing BMI into three groups: BMI < 24, BMI 24-29 and BMI > 29 no relationship was seen between a BMI interval of 24-29 kg/m2, and physical activity and functional ability. BMI was related to body fat mass, and FFM was related to muscle strength. Muscle strength was related to mobility and PPT. Mobility and PPT were mutually related and were related to physical activity. CONCLUSION: Our cross sectional study did not support newly proposed guidelines for the elderly of an optimal BMI interval of 24-29 kg/m2. We found relations between body composition, muscle strength, physical activity and functional ability.

Examining new models for the study of autocrine and paracrine mechanisms of angiogenesis through FGF2-transfected endothelial and tumour cells.

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumour neovascularization. Several growth factors and cytokines have been shown to stimulate endothelial cell proliferation in vitro and in vivo and among them FGF2 was one of the first to be characterised. FGF2 is a Mr 18,000 heparin-binding cationic polypeptide that induces proliferation, migration, and protease production in endothelial cells in culture and neovascularization in vivo. FGF2 interacts with endothelial cells through two distinct classes of receptors, the high affinity tyrosine-kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix. Besides experimental evidence for paracrine mode of action for FGF2, some observations raise the hypothesis that FGF2 may also play an autocrine role in endothelial cells. FGF2 may therefore represent a target for anti-angiogenic therapies. In order to assess the angiostatic potential of different classes of compounds, novel experimental models have been developed based on the autocrine and/or the paracrine capacity of FGF2.

Reaction and movement times in men of different ages: a population study.

Tests of psychomotor and motor speed at different levels of complexity were studied in random samples of men aged 31 to 35, 51 to 55, and 71 to 75 yr. The study was performed as a part of a larger research project on health and functional aging. Analyses indicated significantly slower responses among older men at all levels of test complexity (maximal knee extension velocity, tapping rate, simple and choice reaction and movement times). There were marked differences both between the youngest and the middle-aged groups and between the middle-aged and the oldest groups. Within the age groups high psychomotor and motor speed were associated with a favourable functioning of certain senses (vibration sensitivity and postural balance), with a high isometric muscular force, and with a high directly assessed aerobic capacity. The most important covariants of the speed functions within the age groups were, however, cognitive performance, length of education, and perceived health.

[Physical fitness of Danish men and women aged 50 to 80 years]. / Danske maend og kvinders fysiske arbejdsevne fra 50- til 80-års-alderen.

Maximal power in sustained work in originally randomly selected men and women, born in 1914, was studied five times between the ages of 50 and 80 years in a longitudinal design. Of the originally 514 men and 461 women in 1964 living in the Western suburbs of Copenhagen, 23 men and 18 women performed a bicycle test at age 50, 60, 70, 75 and 80. The mean annual decline in body mass adjusted maximal power in sustained work (W/kg) was 1.43% in the 18 men and 1.64% in the 23 women. Based on "cross-sectional" comparisons of all subjects tested at any age, the mean annual decline in men was 1.56%; in women the corresponding figure was 1.80%. When the results of the "longitudinal" and "cross-sectional" analyses were compared with each other, a rather similar picture of the age-related decline in maximal power was obtained, especially in women. In the longitudinal data only moderate (women) or zero (men) correlations were observed between the submaximal test results at the ages of 50 and 60 years and the maximal test results at higher ages. The physical work load at the age of 50 years had no significant correlation with maximal power at that age or thereafter. There were only minor changes in mean body height, body mass and BMI during the follow-up.

Relationships between postural balance, rifle stability and shooting accuracy among novice rifle shooters.

The present study examined the relationships between shooting accuracy and shooters' behavioral performance, i.e., postural balance and gun barrel stability, among novice rifle shooters in intra- and inter-individual levels. Postural balance and rifle stability were assessed in terms of anteroposterior (VEL(AP)) and mediolateral (VEL(ML)) sway velocity of the movement of center of pressure, and horizontal (DEV(H)) and vertical (DEV(V)) deviation of the aiming point. The participants (n=58) performed 30 shots in the standing position at a distance of 10 m from the target. The data showed that shooting accuracy was related to postural balance and rifle stability, but only at the inter-individual level. The correlation coefficients between shooting score and behavioral performance variables ranged from -0.29 to -0.45. The stepwise multiple regression analysis revealed that the VEL(ML) and the DEV(H) as independent variables accounted for 26% of the variance in the shooting score. The results also suggested that postural balance is related to the shooting accuracy both directly and indirectly through rifle stability. As the role of postural balance appeared to be important in shooting performance, the use of additional balance training programs to improve a shooter's postural skills should be encouraged.