Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat

Mal II, a 19-residue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thrombospondin-1 (TSP-1), was inactive in angiogenesis assays. Yet the substitution of any one of three L-amino acids by their D-enantiomers conferred on this peptide a potent antiangiogenic activity approaching that of the intact 450-kDa TSP-1. Substituted peptides inhibited the migration of capillary endothelial cells with an ED50 of 8.5 nM for the D-Ile-15 substitution, 10 nM for the D-Ser-4 substitution, and 0.75 nM for the D-Ser-5 substitution. A peptide with D-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal II D-Ile derivative inhibited a broad range of angiogenic inducers, was selective for endothelial cells, and required CD36 receptor binding for activity. A variety of end modifications further improved peptide potency. An ethylamide-capped heptapeptide was also active systemically in that when injected i.p. it rendered mice unable to mount a corneal angiogenic response, suggesting the potential usefulness of such peptides as antiangiogenic therapeutics.     

The material basis for reduced mechanical properties in oim mice bones

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values. Collagen content was reduced by 20% in the oim/oim compared with +/+ bone and tended to be intermediate to these values for the oim/+. Mineral content was not significantly different between the oim/oim and +/+ bones. However, the oim/oim ash content was significantly reduced compared with that of the oim/+. Mineral carbonate content was reduced by 23% in the oim/oim bone compared with controls. Mineral crystallinity was reduced in the oim/oim and oim/+ bone compared with controls. Overall, for the majority of parameters examined (geometrical, mechanical, and material), the oim/+ values were intermediate to those of the oim/oim and +/+, a finding that parallels the phenotypes of the mice. This provides evidence that specific material properties, such as mineral crystallinity and collagen content, are indicative and possibly predictive of bone fragility in this mouse model, and by analogy in human OI.     

A combined approach of conventional and molecular cytogenetics for detailed karyotypic analysis of the small cell lung carcinoma cell line U2020

Until recently the ability to analyze complex karyotypic rearrangements was totally dependent upon light microscopy of G-banded chromosomes. Developments in the area of molecular cytogenetics have revolutionized such analysis, making it possible to determine the nature of complex rearrangements. An extensive analysis has been made of the small cell lung carcinoma (SCLC) cell line U2020, using a combined approach of conventional and molecular cytogenetics, enabling a highly detailed karyotype to be constructed revealing rearrangements previously undetected by G-banding alone. This approach offers the opportunity to reassess other tumor karyotypes, particularly those of high complexity found in solid tumors, for tumor-specific consistent rearrangements indecipherable by conventional karyotyping.     

Giant bladder diverticulum in Ehlers-Danlos syndrome type I causing outflow obstruction

A series of 33 patients with juvenile dermatomyositis was reviewed in terms of their prognosis in relation to their drug therapy. This retrospective study was intended to help clarify the use of various therapies in this rare, heterogeneous disease from our hospital's experience in the last 24 years. The results confirmed that oral corticosteroids should remain the undisputed first line of treatment. For more refractory, chronic patients, the results suggest that azathioprine should be the favored drug of first choice (in addition to corticosteroids). There may be a role for cyclosporine as a "rescue" treatment, but this needs to be further defined.     

Delayed cytogenetics effects of chronic irradiation of South Ural population

The aim of this study was to assess the referral pattern and the impact on long-term survival of postoperative radiotherapy in patients with adenocarcinoma of the endometrium stage I. This was a retrospective study performed in a regional cancer registry which covers a population of approximately 1,000,000 persons. All 724 patients registered between 1975 and 1992 in the Comprehensive Cancer Centre South, Eastern Section, The Netherlands, were analysed. All patients had received surgery as primary treatment which was performed in one of the seven community hospitals of the region. Radiotherapy was given in one regional department. All pathology reports were checked for data on tumour differentiation and myometrial invasion. Almost half the patients (45%) were referred for postoperative radiotherapy. The depth of myometrial invasion and the degree of tumour differentiation were the main factors (P < 0.0001) influencing referral for postoperative radiotherapy. The referral pattern varied between the different hospitals, but became more similar during 1985-1988, to diverge again in recent years. In patients younger than 60 years, the depth of myometrial invasion was significantly (P = 0.01) correlated with survival. In patients older than 60 years, tumour differentiation (P = 0.05) and age (P < 0.001) were correlated with survival, but not the depth of myometrial invasion. After adjustment for known prognostic factors, a survival benefit of postoperative radiotherapy could not be established. The studied group had an excess death rate over the normal Dutch female population. This excess death rate did not decrease during follow-up, as even after 10 years an excess death rate was found. A prospective randomised trial is ongoing in The Netherlands.     

Autonomic assessment of cardiovascular disease

Port wine stains (PWS) can lead to considerable emotional distress. The present study evaluated a) the coping with illness, the quality of life and the body image of patients with PWS and b) the effects of dye laser treatment on psychosocial parameters. Seventy PWS patients undergoing treatment with the flashlamp-pumped pulsed dye laser (FPDL) were assessed with questionnaires regarding coping with skin disease, quality of life and body image. Major clinical criterium was the lightening of PWS under treatment. PWS patients showed significant social phobia and avoidance similar to patient suffering from chronic skin diseases. The anxiety correlated with size and darkness of the PWS. In terms of helplessness and depressive mood, PWS patients were less affected than the comparison group. Also, PWS patients had reductions in quality of life and in body image. The coping strategies had a differential effect on the body image. Since there is a correlation between lightening of the PWS and reduction of emotional distress, FDPL therapy can be considered an effective treatment of PWS also in psychosocial terms.     

Effects of estrogen on tight junctional resistance in cultured human umbilical vein endothelial cells

OBJECTIVE: To study the effects of estrogen on transendothelial paracellular permeability in women. METHODS: Human umbilical vein endothelial cells (HUVEC) obtained from women were grown on filters. The paracellular permeability characteristics were determined in terms of changes in the permeability to the polar acid pyranine (Ppyr) and as changes in the transendothelial electrical resistance (RTE). Tight junctional resistance characteristics were assayed by lowering luminal NaCl and measuring the dilution potential, and were expressed as the ratio of monoion mobility uCl/uNa (cation selectivity). RESULTS: Low extracellular calcium and hyperosmolarity increased Ppyr and decreased RTE. The former but not the latter condition abolished the endothelium-specific cation selectivity. Treatment with 10 nM of estradiol-17 beta had no effect on RTE, but it increased the cation selectivity. The effect of estradiol required 1-6 hours' incubation with the hormone; it was dose dependent and saturable, with a median effective concentration of estradiol of 1 nM. Diethylstilbestrol, but not estriol, could mimic the effect of estradiol, and the estrogen receptor antagonist ICI-182, 780 blocked it. CONCLUSION: Cultured HUVEC cells form patent tight junctions. Estrogens increase the cation selectivity across HUVEC cultures. The effect of estrogen may be mediated by an estrogen receptor. These effects may be important for vasculoprotection in cases of sudden changes in ions levels across the capillary wall, such as ischemia or reperfusion.     

Central nervous system nitric oxide formation in cerebral systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an inflammatory disease in which up to two thirds of the patients present neurological symptoms. The diagnosis of the disease is based on clinical findings and the presence of autoantibodies, and the pathogenesis is unclear. The purpose of this study was to determine if the pathogenesis was partly mediated via nitric oxide (NO) formation. Cerebrospinal fluid (CSF) samples from 15 patients with cerebral SLE were analyzed for the NO metabolites nitrite and nitrate using capillary electrophoresis. The severity of neurological symptoms was scored by dividing the patients into two groups with either mild or moderate/severe CNS involvement. All patients with cerebral SLE showed increased levels of NO metabolites. In CSF, there was a relationship between signs of NO production and clinical results showing that increased levels of nitrite and nitrate were associated with more severe neurological symptoms. These findings may shed new light on the pathogenesis of cerebral SLE, and analysis of nitrate and nitrate may prove to be of value in monitoring the activity of the disease.     

Therapy of dislocated calcaneus joint fracture with the AO calcaneus plate

From August 1992 to March 1997, 66 patients with 71 displaced intraarticular calcaneal fractures were prospectively examined after an operative treatment using an extended lateral approach and the ASIF calcaneal plate followed by early functional postoperative treatment (mean follow-up 25 months, retrieval rate 96%). To classify the type of fracture and to verify the results of reduction and of retention CT scans in the coronal and transverse plane were performed pre- and postoperatively and on the day of assessment. The Zwipp Score was used for clinical evaluation. After fractures with 5 to 8 points according to the calcaneal fracture scale, 97% of the patients had an anatomical or near anatomical reduction of the posterior facet and the clinical outcome in 82% of the patients was graded as good or excellent. In 70% of patients with a fracture rated 9 to 10 points a good reduction was demonstrated and clinically there were 67% good or excellent results. But in the fractures with 11 to 12 points, despite 40% good reductions, the clinical outcome was graded as good in 10% of the patients only. However, if the post-operative displacement of the posterior facet was more than 2 mm no patient had a good result independent of the type of fracture. Due to restoration of the geometry of the most comminuted fracture types and the immediate partial weight bearing secondary soft tissue problems could be minimized without any loss of articular reduction. Anatomical reduction and stable internal fixation together with adequate physical therapy are apparently preconditions but not a guarantee for a good clinical result after displaced calcaneal fractures.     

Inputs to directionally selective simple cells in macaque striate cortex

It is clear that the initial analysis of visual motion takes place in the striate cortex, where directionally selective cells are found that respond to local motion in one direction but not in the opposite direction. Widely accepted motion models postulate as inputs to directional units two or more cells whose spatio-temporal receptive fields (RFs) are approximately 90 degrees out of phase (quadrature) in space and in time. Simple cells in macaque striate cortex differ in their spatial phases, but evidence is lacking for the varying time delays required for two inputs to be in temporal quadrature. We examined the space-time RF structure of cells in macaque striate cortex and found two subpopulations of (nondirectional) simple cells, some that show strongly biphasic temporal responses, and others that are weakly biphasic if at all. The temporal impulse responses of these two classes of cells are very close to 90 degrees apart, with the strongly biphasic cells having a shorter latency than the weakly biphasic cells. A principal component analysis of the spatio-temporal RFs of directionally selective simple cells shows that their RFs could be produced by a linear combination of two components; these two components correspond closely in their respective latencies and biphasic characters to those of strongly biphasic and weakly biphasic nondirectional simple cells, respectively. This finding suggests that the motion system might acquire the requisite temporal quadrature by combining inputs from these two classes of nondirectional cells (or from their respective lateral geniculate inputs, which appear to be from magno and parvo lateral geniculate cells, respectively).