Temporal gene expression profiles of target-ablated olfactory epithelium in mice with disrupted expression of scavenger receptor A: impact on macrophages.

Target ablation [removal of the olfactory bulb (OBX)] induces apoptotic death of olfactory sensory neurons (OSNs) and an immune response in which activation and recruitment of macrophages (ms) into the olfactory epithelium (OE) occupy a central role. Ms phagocytose apoptotic neurons and secrete cytokines/growth factors that regulate subsequent progenitor cell proliferation and neurogenesis. Scavenger receptor A (SR-A) is a pattern recognition receptor that mediates binding of ms to apoptotic cells and other relevant immune response functions. The aim of this study was to determine the impact of the absence of SR-A on the immune response to OBX. The immune response to OBX was evaluated in mice in which functional expression of the m scavenger receptor (MSR) was eliminated by gene disruption (MSR-/-) and wild-type (wt) mice of the same genetic background. OBX induced significant apoptotic death of mature OSNs in the two strains. However, subsequent m infiltration and activation and progenitor cell proliferation were significantly reduced in MSR-/- vs. wt mice. Gene expression profiling at short intervals after OBX demonstrated significant differences in temporal patterns of expression of several gene categories, including immune response genes. Many immune response genes that showed different temporal patterns of expression are related to m function, including cytokine and chemokine secretion, phagocytosis, and m maturation and activation. These studies suggest that impairment of the immune response to OBX in the OE of MSR-/- mice most likely resulted from decreased m adhesion and subsequent reduced infiltration and activation, with a resultant decrease in neurogenesis.

Effect of parathyroid hormone levels on carotid intima-media thickness after renal transplantation.

BACKGROUND: The present study aimed to investigate the intact parathyroid hormone (iPTH)-dependent evolution of common carotid intima-media thickness (CC IMT) in renal transplant recipients (RTR) within a 12-month follow-up, ie, before (E0) and 3 months (E3), 6 months (E6), and 12 months after renal transplantation (RTX). METHODS: A total of 55 normotensive patients, aged 47 +/- 1.7 years, underwent a RTX. The graft function was stable (clearanceCockroft >60 mL/min and S-creatinine <2.5 mg/dL) in all patients throughout the follow-up. RESULTS: In 67% of the RTR, the iPTH levels were classified as high at E0 (E6: 63%; E6: 49%; E12: 67%). The plasma iPTH levels decreased after RTX (P < .01). The arterial blood pressure remained stable. The CC IMT was positively and independently correlated with age (P < .01), gender (P < .01), and iPTH levels (P < .01). CONCLUSIONS: Normalization of iPTH levels is associated with a significant intima-media thickness (IMT) reduction. The increased IMT in renal transplant recipients may contribute to the high cardiovascular morbidity and mortality in patients with end-stage renal failure.

Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation.

Various factors, including the orphan nuclear receptor Nurr1, have been implicated in dopamine biosynthesis, but many of the specific events involved in this process have to be determined. Using genetic manipulations in mice, the obligatory role for Nurr1 in dopamine (DA) biosynthesis has been documented; however, the mechanism remains unclear. DA biosynthetic enzymes, transporters and receptors are absent in the substantia nigra (SN) and the ventral tegmental area (VTA) of Nurr1-null neonates. The current study establishes that the loss of Nurr1 function does not affect the normal ventralization of neuroepithelial cells to the ventral midbrain, their differentiation into neurons, and their topographical pattern in the SN and VTA. Futhermore, the absence of Nurr1 does not affect the survival of these DA precursor cells in the ventral midbrain, as determined by quantitative analysis of cells, expressing the general neuronal nuclear marker (NeuN) and the TUNEL assay for apoptosis. These neurons express cholecystokinin (CCK), a co-transmitter of dopaminergic neurons in this area. The untranslated exon 1-2 of the Nurr1 gene, which remains intact after homologous recombination, revealed the presence of dopaminergic precursors in the ventral midbrain of the Nurr1-null mice. In addition, these neurons establish their nigrostriatal projections, as shown by axonal transport of a fluorescent tracer, DiI. These results provide evidence that Nurr1 is essential for terminal differentiation of the dopaminergic neurons in the ventral midbrain but does not affect the early steps of their neurogenesis, migration, survival and striatal projections. Our findings suggest that activation of Nurr1 might be therapeutically useful in Parkinson's disease.

Vessel wall alterations in patients with renal failure.

Cardiovascular complications are a major cause of morbidity and mortality in patients with renal failure. Death due to myocardial infarction and to stroke is more frequent in hemodialysis patients than in the total population. These cardiovascular diseases are mainly the consequence of atherosclerosis and cause decreased life expectancy in patients with renal failure. Ultrasound techniques now make it possible to measure atherosclerotic lesions in big and medium-sized arteries. Thickening of the intima-media-complex is an early sign of atherosclerosis in these vessels. It reduces the distensibility of the arteries during systole. The distensibility of big and medium-sized arteries can be determined using ultrasound-doppler-techniques. In our studies, the intima-media-thickness of the carotid artery was significantly (p< 0.01) increased in patients with chronic renal failure (1.32+/-0.49 mm, n=28) as compared with aged-matched healthy control subjects (0.75 +/- 0.20, n= 29). The distensibility coefficient was higher (p< 0.05) in healthy controls (26 +/- 1.8 10(-3)/kPa, n= 12) than in patients with renal insufficiency (19 +/- 1.7 10(-3)/kPa, n = 12). This demonstrates increased stiffness of the vessel wall resulting in loss of Windkessel function and increased work load of the heart.

Effect of homocysteine on carotid intima-media thickness after renal transplantation.

The common carotid intima-media thickness (CC IMT) is a strong predictor for cardiovascular disease in patients with end-stage renal failure. However, little is known about possible associations between potential cardiovascular risk factors such as serum total homocysteine concentrations (tHcy) and the CC IMT. Thus, we investigated (a) the course of tHcy levels after renal transplantation (RTX) and (b) the relationship between CC IMT and tHcy in 53 renal allograft recipients with chronic renal failure before transplantation and 3, 6, and 12 months after transplantation. Exclusion criteria were volume overload, symptomatic coronary artery disease, symptomatic cerebrovascular disease, peripheral artery disease, heart failure, valvular heart disease, diabetes mellitus, severe hypercholesterolemia, and blood pressure above 159/89 mmHg at the time of the investigation. In all renal allograft recipients, a carotid high-resolution B-mode ultrasound measurement of the CC IMT was performed. Eighteen patients had normal ( < 20 micromol/L) pre-transplant (U0) tHcy, 25 had moderately elevated (20-40 micromol/L) pre-transplant (U0) tHcy, and 10 had severely elevated (> 40 micromol/L) pre-transplant (U0) tHcy. After 12 months of follow-up time (U12), no statistically significant differences concerning the tHcy levels could be detected between the groups (average serum tHcy 16.4 micromol/L +/- 1.1 micromol/L). The CC IMT did not differ significantly between the three tHcy groups at any time within the present follow-up. This was also true for the 'wall-to-lumen ratio'. A multiple forward stepwise regression analysis showed that the reduction of the CC IMT was positively correlated with gender (p < 0.01), glucose levels at U12 (p < 0.05; r2 = 0.96), systolic arterial blood pressure at U12 (p < 0.05; r2 = 0.97), and with the intact parathyroid hormone levels at U0 (p < 0.01; r2 = 0.98). In conclusion, (a) tHcy decreases significantly after RTX, but (b) does not influence the CC IMT thickness independently.

Studies on structural changes of the carotid arteries and the heart in asymptomatic renal transplant recipients.

BACKGROUND: The present study was designed to characterize early structural changes of large arteries in renal transplant recipients with no clinical evidence of cardiovascular disease and normal blood pressure values, and to analyse the relationship between arterial alterations and those of the heart. METHODS: Intima media thickness and atherosclerotic plaques of the carotid arteries as well as left ventricular geometry and function were examined in 35 asymtomatic renal transplant recipients and 29 age- and sex-matched healthy controls by high resolution B-mode ultrasound and by echocardiography. RESULTS: Intima-media thickness of the carotid arteries was significantly higher in renal transplant recipients (1.21+/-0.08 mm) than in healthy controls (0.74+/-0.04 mm) (P<0.001). Atherosclerotic plaques were found in the majority of renal transplant recipients (71% vs 14% in healthy controls, P<0.001). Left ventricular mass index was significantly increased in the group of renal transplant recipients (264+/-13 g, 146+/-7 g/m2) when compared with healthy controls (155+/-8 g, 83+/-4 g/m2) (P<0.001). Multiple regression analysis in renal transplant recipients showed that intima media thickness of the carotid arteries was significantly related to left ventricular mass index (P<0.02), but not to age, blood pressure, body mass index, serum creatinine, cholesterol and lipoprotein (a) levels. In the group of healthy controls, intima-media thickness of the carotid artery was related to age (P<0.002), but not to left ventricular mass index or the other independent variables. CONCLUSIONS: The present study documents pronounced intima-media thickening in asymptomatic renal transplant recipients. Atherosclerotic lesions are present in most renal transplant recipients with no clinical evidence of cardiovascular disease. We observed a parallelism between arterial wall thickening and left ventricular hypertrophy, although blood pressure levels were normal during haemodialysis therapy and after renal transplantation.

Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene.

To ascertain the function of an orphan nuclear receptor Nurr1, a transcription factor belonging to a large gene family that includes receptors for steroids, retinoids, and thyroid hormone, we generated Nurr1-null mice by homologous recombination. Mice, heterozygous for a single mutated Nurr1 allele, appear normal, whereas mice homozygous for the null allele die within 24 h after birth. Dopamine (DA) was absent in the substantia nigra (SN) and ventral tegmental area (VTA) of Nurr1-null mice, consistent with absent tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase, and other DA neuron markers. TH immunoreactivity and mRNA expression in hypothalamic, olfactory, and lower brain stem regions were unaffected. L-Dihydroxyphenylalanine treatments, whether given to the pregnant dams or to the newborns, failed to rescue the Nurr1-null mice. We were unable to discern differences between null and wild-type mice in the cellularity, presence of neurons, or axonal projections to the SN and VTA. These findings provide evidence for a new mechanism of DA depletion in vivo and suggest a unique role for Nurr1 in fetal development and/or postnatal survival.

Elemental mercurial poisoning.

A 39-year-old man injected 40 mL of elemental mercury in an attempted suicide 3 years before coming to our facility. No specific treatment regimen had been done since then. Chest x-ray films showed mercury deposits in the lungs, as well as around the injection site. The mercury concentration in his blood was at 96.3 micrograms (0.480 nmol/L), thus significantly elevated (given a reference range of up to 2 micrograms Hg/L), as was the renal mercury elimination. Despite mercurial deposits within the pulmonary circulation, the pulmonary function showed normal values, with no reduction of the diffusion capacity. There were signs of polyneuropathy. The patient was given sodium dimercaptopropanesulfate (Dimaval) for mercury complexation. This case report outlines the diagnosis and therapy for mercurial poisoning through metallic mercury.

Reduced distensibility of the common carotid artery in patients treated with ergotamine.

To investigate the effect of vascular smooth muscle contraction on mechanical vessel wall properties of proximal "elastic" arteries, we investigated the effect of the vasoconstrictor ergotamine on the distensibility of the common carotid artery in 10 migraine patients with ergotamine intake, in 10 control patients with migraine headache but no prior ergotamine intake, and in 10 healthy control subjects. The patients and control subjects were matched for age, blood pressure, and sex. In the ergotamine group, 2.2 +/- 1.4 mg ergotamine tartrate (0.25 to 6 mg) was taken within 12 hours before investigation. Differences in mean 24-hour blood pressure between the study groups were excluded by 24-hour blood pressure recording and differences in arterial wall thickness by high-resolution and differences in arterial wall thickness by high-resolution B-mode ultrasound. A multigate Doppler system was used for measurement of vessel wall movements by M-mode Doppler analysis. Blood pressure was determined by sphygmomanometry. The end-diastolic diameter of the common carotid artery was insignificantly reduced in the ergotamine group compared with the healthy control subjects and control patients (healthy control subjects, 6.6 +/- 0.4 mm; control patients, 6.7 +/- 0.5 mm; patients with ergotamine intake, 6.3 +/- 0.4 mm; P = NS). Arterial distensibility was significantly lower in the patients with ergotamine intake (17.4 +/- 4.0 10(-3)/kPa) than in the healthy control subjects (22.3 +/- 5.1 10(-3)/kPa) and control patients (22.8 +/- 3.6 10(-3)/kPa) (one-way ANOVA, P = .014). The results show that ergotamine reduces the distensibility of the common carotid artery. The data suggest that vascular smooth muscle contraction can modulate the buffering function of the arterial system independently of blood pressure changes.