A systematic approach for doing an a priori identifiability study of dynamical nonlinear models.

This paper presents a method for investigating, through an automatic procedure, the (lack of) structural identifiability of dynamical models parameters. This method takes into account constraints on parameters and returns parameters whose estimations turn unidentifiable parameters into identifiable ones. It is based on (i) an equivalence between an extension of the notion of identifiability and the existence of solutions of algebraic systems, (ii) the use of symbolic computations for testing their existence. This method is described in details and is applied to two examples, the last one involving 12 parameters.

Geodemographics--a tool for health intelligence?

In recent years, social marketing principles and techniques have featured at the heart of government proposals for improving health and tackling health inequalities. This, in part, has led to a shift in the type of information and intelligence needed to support service planning at all levels. In particular, there has been increasing interest in the use of commercial geodemographic classification systems. Despite the amount of activity and associated investment in this area, there is evidence of a real lack of understanding among users about the tools themselves, and the added value they are providing in the National Health Service. This paper describes some of the potential applications of geodemographic tools in the health sector, and explores issues for consideration when selecting or using a system. This paper also describes a potentially cost-effective and sustainable model for utilizing geodemographic tools as part of a regional insight function within the health service.

Placental tissue interleukin-10 receptor distribution in pre-eclampsia.

PROBLEM: Reduced placental (trophoblast) cytokine interleukin-10 (IL-10) occurs in human pre-eclampsia. Along with an increase in inflammatory cytokines this may play an important role in the development of hypertension in pregnancy. It is not clear whether the changes in placental IL-10 are due to a change in the placental cell production of IL-10 or a result of changes in cytokine receptor status in adjacent tissues. This study is aimed at qualifying the presence and distribution of IL-10 receptors in women with a pre-eclamptic outcome compared to normal pregnancy and gestational hypertension. METHOD OF STUDY: Patients at the KGV Hospital, Sydney was selected for the study. Placentas were collected fresh and paraffin serial sections made. Sections were stained with IL-10 receptor antibody (10 microgram/mL) using avidin-biotin immunohistochemistry. Tissues of patients with pre-eclampsia (n=11) were compared with normal pregnancy (n=12). Pre-eclampsia was defined as a blood pressure >140/90 mmHg on two occasions and de nova proteinuria >300 mg per day which resolved post-partum. The fetal weights, gestational ages and maternal ages at delivery were compared (ANOVA) and the differences in staining of decidual and villous tissues were graded according to density. Statistical comparisons were made using the Kruskal-Wallis test. RESULTS: The groups were similar for maternal gestational age but delivered at earlier gestation and with lower fetal weight. There was significantly less villous cytotrophoblast staining for IL-10 receptor in all groups (P=0.012) compared to decidual trophoblast cells. There was equal intensity and density of extravillous straining observed in normal pregnancy (45 +/- 12%) positive cells compared to pre-eclampsia (27 +/- 12%). CONCLUSION: IL-10 receptors are present in greater concentration in the extravillous (decidual) trophoblast compared to villi. The decrease in IL-10 produced by trophoblast cells in pre-eclampsia is not explained by a difference in the IL-10 receptor distribution compared to normal pregnancy.

Placental endothelial nitric oxide synthase localization and expression in normal human pregnancy and pre-eclampsia.

1. The aim of the present study was to investigate whether pre-eclampisa, a state of placental hypoxia, is associated with placental abnormalities in the amount, distribution and expression of endothelial nitric oxide synthase (eNOS). 2. Localization and intensity of eNOS was determined by immunohistochemistry using an antibody specific for eNOS. The amount of eNOS mRNA expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and the densitometry of gel bands was expressed as a ratio of the band density of the housekeeping gene beta2-microglobulin. 3. Endothelial NOS staining was localized to syncytiotrophoblast cells within the villi and decidual trophoblast cells. It was not present in the endothelium of terminal villous vessels. There was no significant difference in eNOS villous or decidual staining intensity between normal pregnancy (NP; n = 12), pre-eclampsia (n = 14), or gestational hypertension (GH; n = 4). Staining for eNOS was not significantly different in the decidua compared with the villi in NP, GH or pre-eclampsia. Within the decidua, the depth of eNOS staining was similar in NP, pre-eclampisa and GH. 4. There was no significant difference in eNOS mRNA expression between NP (0.70 +/- 0.11), pre-eclampsia (0.5 +/- 0.07) or GH (0.69 +/- 0.26). 5. These findings suggest that the amount of eNOS in the placenta is not deficient in pre-eclampsia, excluding a possible pathogenic role for eNOS in this disease. Furthermore, placental hypoxia, which is associated with pre-eclampsia, did not induce an upregulation of eNOS

Transforming growth factor-beta 1 does not relate to hypertension in pre-eclampsia.

1. Pre-eclampsia is a human disease of pregnancy characterized by high blood pressure, proteinuria and end-organ damage, if severe. Pre-eclampsia is thought to be related to changes in early placental development, with the formation of a shallower than normal placental bed. 2. Transforming growth factor (TGF)-beta1 is a multifunctional fibrogenic growth factor involved in immune regulation that is elevated in some populations with a high risk of hypertensive end-organ disease related to increases in endothelin release. Transforming growth factor-beta1 is also an important factor in placental implantation. Alterations in TGF-beta1 may be related to abnormal placental development in early pregnancy and, thus, are a candidate for the development of hypertension in pre-eclampsia. 3. The aim of the present study was to examine the placental distribution and serum concentration of TGF-beta1 in patients with pre-eclampsia compared with normal pregnancy. 4. Patients with pre-eclampsia (n = 12) were compared with patients with normal pregnancy (n = 14). Transforming growth factor-beta1 was determined by TGF-beta1 Max ELISA (Promega, Madsion, WI, USA) after serum dilution (1/150) and acid activation. Placental distribution was determined by immunostaining with TGF-beta1 (Santa Cruz, Santa Cruz, CA, USA; 20 ng/mL) and the villi and decidual trophoblast were scored for intensity and extent of staining. 5. Patients with pre-eclampsia had a mean gestational age of 36 weeks, whereas those with a normal pregnancy had a mean gestational age of 39.0 +/- 0.4 weeks. There was no difference in TGF-beta1 concentration between the two groups (mean (+/-SEM) 27.1 +/- 1.0 vs 26.4 +/- 0.7 pg/mL for normal pregnancy and pre-eclampsia, respectively; P = 0.73, Mann-Whitney U-test). There was no correlation between systolic or diastolic blood pressure and TGF-beta1 concentration (regression analysis P = 0.4 and 0.2). Immunostaining was absent in the villous trophoblast cells and endovascular and extravillous trophoblast of term placentas. 6. Although TGF-beta1 is present in trophoblast cells in early pregnancy during placental development, TGF-beta1 concentrations were not increased in the placenta at term in pre-eclampsia and there was no correlation between blood pressure and serum TGF-beta1, suggesting that TGF-beta1 does not play a role in the development of late gestation pre-eclampsia and hypertension.

Cardiovascular effects of chronic nitric oxide synthase inhibition in genetically hypertensive rats.

1. The possible role of an endothelial defect in the hypertension of the New Zealand genetically hypertensive (GH) rat strain was assessed by examining cardiovascular responses to the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the endothelium-dependent depressor agent acetylcholine (ACh). The vascular sensitivity of the hindquarter to nitric oxide (NO) was examined using the NO donor sodium nitroprusside (SNP). 2. NG-Nitro-L-arginine methyl ester (10 mg/kg per day in drinking water) was given to GH and normotensive (N) rats from age 7-9 weeks, with GH and N untreated control groups. Systolic blood pressure (tail-cuff) was monitored weekly from age 5-9 weeks. At age 9 weeks, pressure responses to various vasoactive agents were measured in vivo and in the rat isolated hindquarter. Left ventricular (LV) mass was measured at the time of death. 3. NG-Nitro-L-arginine methyl ester induced a greater hypertensive effect in GH (P < 0.001) compared with N (P < 0.05) rats and caused a significant increase in hindquarter perfusion pressure in GH rats only (P < 0.01). 4. Genetically hypertensive rats had LV hypertrophy that was exacerbated by L-NAME (P < 0.01). Left ventricular hypertrophy was not induced by L-NAME in N rats. 5. The normalized response to ACh did not differ between GH and N control rats and was unaffected by L-NAME treatment in vivo and in vitro except at the highest ACh dose (3 micrograms/kg) in GH hindquarters (P < 0.01). The response to SNP was similar in GH and N hindquarters and enhanced by L-NAME in GH (0.1 microgram; P < 0.05) and N rats (0.01 microgram, P < 0.01; 0.01 microgram, P < 0.001). 6. These results suggest that the L-arginine/NO system is not deficient in GH rats and that endothelial function in the GH hindquarter is preserved. They confirm that NO is involved in mediating blood pressure in GH and N rats and raise the possibility that a non-NO-mediated mechanism may underlie ACh-induced vasodilation in GH and N.