The genetics of geometry

Although much progress has been made in understanding how gene expression patterns are established during development, much less is known about how these patterns are related to the growth of biological shapes. Here we describe conceptual and experimental approaches to bridging this gap, with particular reference to plant development where lack of cell movement simplifies matters. Growth and shape change in plants can be fully described with four types of regional parameter: growth rate, anisotropy, direction, and rotation. A key requirement is to understand how these parameters both influence and respond to the action of genes. This can be addressed by using mechanistic models that capture interactions among three components: regional identities, regionalizing morphogens, and polarizing morphogens. By incorporating these interactions within a growing framework, it is possible to generate shape changes and associated gene expression patterns according to particular hypotheses. The results can be compared with experimental observations of growth of normal and mutant forms, allowing further hypotheses and experiments to be formulated. We illustrate these principles with a study of snapdragon petal growth.     

Effect of 12-month therapy with omega-3 polyunsaturated acids on glomerular filtration response to dopamine in IgA nephropathy

BACKGROUND: Omega-3 polyunsaturated acids therapy is efficient in primary IgA nephropathy. It is unknown whether doses of omega-3 smaller than those given previously are still effective. The aim of the study was to examine the effect of omega-3 therapy on renal vascular function in relation to proteinuria and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). METHODS: 20 IgA patients aged 36.5 +/- 10.77 with creatinine clearance (Cr(cl)) 105.71 +/- 27.3 ml/min and proteinuria 3.31 +/- 2.01 g/24 h were given orally 810 mg EPA and 540 mg DHA daily for 12 months. Before and at the end of the study, 24-hour proteinuria, serum homocysteine, and Cr(cl) were measured. At the same time, renal vascular function was estimated as dopamine-induced glomerular filtration response (DIR). DIR was measured as: two 120-min lasting Cr(cl) (before and during 2 microg/kg b.w./min i.v. dopamine). RESULTS: The results obtained during follow-up were as follows (baseline vs. after therapy): DIR 14.9 +/- 16.4 vs. 30.3 +/- 14.3% (p < 0.01); urine protein 2.31 +/- 2.01 vs. 1.31 +/- 1.37 g/24 h (p < 0.01); (Cr(cl)) 105.71 +/- 27.3 vs. 103.9 +/- 20.9 ml/min (n.s.); NAG 8.3 +/- 1.8 vs. 6.0 +/- 1.2 U/g(creat) (p < 0.01), and homocysteine 16.2 +/- 3.15 vs. 13.8 +/- 2.6 micromol/l (p < 0.05). The only correlation found was linear correlation between basal DIR and DIR change (r = -0.570; p < 0.010) and basal NAG (r = -0.460; p < 0.50). CONCLUSIONS: Omega-3 supplementation is associated with the improvement of both renal vascular function and tubule function.     

Disturbances of purine nucleotide metabolism in uremia

The increased concentration of adenosine triphosphate (ATP) in erythrocytes from patients with chronic renal failure (CRF) has been observed in many studies but the mechanism leading to these abnormalities still is controversial. It is believed that hyperphosphatemia and metabolic acidosis triggering enhanced reutilization of purine bases are the factors responsible for changes in erythrocyte nucleotide concentration. During the past decade we have performed several studies. A summary of the obtained results is presented. A high-performance liquid chromatography technique was used for the determination of plasma and intraerythrocyte nucleotide concentrations. Labeled adenine and adenosine were used for measuring adenine incorporation. In CRF patients treated conservatively increased concentrations of ATP levels and other nucleotides such as adenosine diphosphate were found. Adenosine monophosphate and hypoxanthine levels were lower than in controls. In hemodialyzed patients both ATP and adenosine monophosphate intraerythrocyte concentrations were higher than in controls. At the same time, adenosine monophosphate and hypoxantine level were comparable with levels in healthy people. The main pattern of nucleotides during hemodialysis remained unchanged, independent from the mode of therapy. The only exception was a decreased level of hypoxantine. Results of a consecutive study have suggested that the increased rate of adenine incorporation into the adenine nucleotide pool could be partially responsible for the increased ATP concentration in uremic erythrocytes. Last but not least, trying to elucidate the pathomechanism of adenine nucleotide disturbances in uremia, we have found that the concentration of N-methyl-2-pyridone-5-carboxamide (2PY), one of the end products of nicotinamide-adenine dinucleotide degradation, were enhanced in CRF patients to values that are potentially toxic. Our findings suggest that 2PY could be a novel uremic toxin. Disturbances of nucleotide metabolism are one of the important components of uremic syndrome.     

Combination of paclitaxel and nitric oxide as a novel treatment for the reduction of restenosis

The combination of a nitric oxide (NO) donor and a paclitaxel-NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7-position to give compound 7. An adamantane-based NO donor 14 was synthesized and combined with 7 to provide a burst of NO in the first few critical hours following injury to the vessel wall. Both 7 and 14 demonstrated antiproliferative activity (IC(50) = 20 nM and 15 microM, respectively) and antiplatelet activity (IC(50) = 10 and 1 microM, respectively). Stents were coated with a layer of a polymer containing test compounds. The total amount of NO eluted from the stents after a 6 h implantation in the rabbit iliac artery was 35%, 95%, and 69% of the original content for the stents coated with 7, 14, and the combination of 7 and 14, respectively. The antistenotic activity of 7 and 14 was determined in a 28-day rabbit model with two control groups (uncoated stents and polymer-coated stents) and two study groups (paclitaxel-coated stents and stents coated with the combination of 7 and 14). Polymer-coated stents caused inflammation and increased stenosis by 39% when compared to the uncoated stents. The stents coated with 7 plus 14 were as good as the uncoated stents, 41% better than the polymer-coated stents and 34% better than the paclitaxel-coated stents. These data indicate a beneficial effect of adding NO to an antiproliferative agent (paclitaxel) and suggest a potential therapeutic combination for the treatment of stenotic vessel disease.     

Presence of spinal B7.2 (CD86) but not B7.1 (CD80) co-stimulatory molecules following peripheral nerve injury: role of nondestructive immunity in neuropathic pain

Previous work in our laboratory demonstrated spinal neuroimmune activation and leukocyte trafficking into the central nervous system (CNS) parenchyma in a rat model of neuropathic pain. Recent studies suggest that co-stimulatory molecules B7.1 (CD80) and B7.2 (CD86) play a differential role in the effect of beneficial versus deleterious CNS autoimmune responses. In the present study, we determined the lumbar spinal expression of the co-stimulatory molecules B7.1 and B7.2 in a rat model of neuropathy. We observed intense B7.2 microglial immunoreactivity in the lumbar spinal cord following the injury but no expression of B7.1. These data suggest a role of protective CNS autoimmunity following peripheral nerve injury.     

New score indicating placental vascular resistance

BACKGROUND: Umbilical artery Doppler velocimetry is a routine method for fetal surveillance in high-risk pregnancy. Uterine artery Doppler seems to give comparable information, but it can be difficult to interpret as there are two arteries, which might show notching and/or increased pulsatility index (PI) as signs of increased vascular impedance. Combining the information on vascular resistance on both sides in a new score might simplify and improve evaluation of placental circulation. METHODS: Uterine and umbilical artery Doppler velocimetry was evaluated in 633 high-risk pregnancies. The managing clinician was informed only about the umbilical artery flow. The umbilical artery flow spectrum was semiquantitatively divided into four blood flow classes (BFC), expressing signs of increasing vascular resistance. The uterine artery Doppler flow spectrum was divided into five uterine artery scores (UAS), taking into account presence/absence of notching and/or increase in PI. By adding UAS to BFC, a new placental score (PLS) was constructed with values ranging from 0 to 7, indicating general placental vascular resistance. The scores were related to three outcome variables: small-for-gestational age (SGA), premature delivery (<37 weeks), and cesarean section. RESULTS: All three score systems showed a significant relationship between signs of increasing vascular resistance and outcome. The new PLS showed the best association to adverse outcomes, with optimal cut-off at values exceeding score 3. CONCLUSION: Doppler velocimetry on both sides of the placenta showed a strong relationship to an adverse outcome of pregnancy. The new PLS showed a better relationship to adverse perinatal outcome than the BFC and the UAS. The PLS can simplify evaluation of uteroplacental and fetoplacental Doppler velocimetry.     

Cutaneous melanoma during pregnancy at the Cancer Center-Institute in Warsaw

Malignant melanoma is a neoplasm which frequency has been increasing rapidly in Poland. The paper describes five cases of patients with cutaneous melanoma coexisting with pregnancy, who have been recently treated in the Department of Soft Tissue/Bone Tumors of M. Sklodowska-Curie Memorial Cancer--Institute of Oncology, Warsaw. All patients presented clinically advanced primary lesions with poor prognosis. In paper recommendations for treatment of women with suspicious cutaneous lesions before or during pregnancy and patients with melanoma planning a pregnancy are presented. The suspicion of melanoma is indication for immediate excisional biopsy by local anesthesia. Further treatment should be performed in tertiary oncological centres. There is no evident clinical data that pregnancy has a significant impact on progression of melanoma. The most important factor influencing prognosis of melanoma is the stage of the disease at the diagnosis. There are no grounds for abortion in pregnant women with melanoma in I/II/III stages.