High urinary excretion of uric acid combined with high excretion of calcium links kidney stone disease to familial hypertension.

BACKGROUND: Past studies identified an association between kidney stone disease (KSD) and hypertension. We recently reported a high occurrence of hypertension in families of patients with hyperuricosuric KSD. As hypercalciura frequently coexists with hyperuricosuria and high urinary excretion of calcium is found in patients with hypertension, we hypothesized that hyperuricosuria that is accompanied by hypercalciuria better describes the familial association between KSD and hypertension. METHODS: Four hundred and eighty-six KSD patients, aged 18-50 years, attending a lithotripsy unit collected a 24-h urine sample for metabolic analysis and provided information on family history of hypertension. The familial occurrence of hypertension was compared among four groups of patients: those who had combined elevation of both urinary calcium and uric acid excretions ("combined" abnormality, n=56), those who had hyperuricosuria without concomitant hypercalciuria ("pure" hyperuricosuria, n=67), those who had hypercalciuria without concomitant hyperuricosuira ("pure" hypercalciuria, n=52), and a control KSD patient group ("other" abnormality, n=311). The prevalence of treated hypertension in patients from the four groups was 16%, 12%, 2%, 10%, respectively. RESULTS: Thirty-four per cent of the patients with the "combined" abnormality had a positive family history of hypertension, defined as two or more first-degree relatives with treated hypertension, that was significantly higher than in patients with either "pure" hyperuricosuira (15%, P<0.02), "pure" hypercalciuria (8%, P<0.001), or patients with "other" abnormality (10%, P<0.001). The adjusted OR for positive family history of hypertension in the "combined" abnormality group compared to the control KSD patient group was 5.6 (2.39-13.30). The prevalence of hypertension in siblings of patients with the "combined" abnormality (13%) was significantly higher than in siblings of patients with either "pure" hyperuricosuria (3%, P<0.001), "pure" hypercalciuria (1%, P<0.001), or siblings of control patients with "other" abnormality (4%, P<0.001). The adjusted OR for hypertension in siblings of a patient with "combined" abnormality compared to a control KSD patient was 3.4 (1.97-5.91). Patients in the "combined" abnormality group were also characterized by significantly elevated urinary sodium, phosphorus, citrate and potassium excretions. CONCLUSIONS: Our data suggest that there is a strong, independent association between familial occurrence of hypertension and the phenotype characterized by combined elevation of both urinary uric acid and calcium excretions. The association is not present in those with "pure" hyperuricosuria or "pure" hypercalciuria. Ascertainment of patients based on this phenotype may identify more homogeneous populations for genetic analysis of hypertension.     

Clearance and disposition of indometacin in chronically instrumented fetal lambs following a 3-day continuous intravenous infusion

Indometacin is used in pregnancy for the treatment of premature labour, but there are limited data on the disposition of the drug in the fetus. In order to elucidate fetal indometacin pharmacokinetics at plasma levels and duration comparable with those occurring with use of the drug for tocolysis in humans, indometacin was administered at doses of 1.9 (low dose, LD; n = 5) or 7.5 (high dose, HD; n = 9) microg min(-1) to steady state over a 3-day period in chronically instrumented fetal lambs. Indometacin concentrations in biological fluid samples were analysed by a sensitive capillary gas chromatography-electron capture detection method. The mean steady-state fetal arterial plasma indometacin concentrations were 68.6+/-16.5 ng mL(-1) in the LD infusion and 230.3+/-28.8 ng mL(-1) in the HD infusion. Indometacin concentrations in amniotic fluid were approximately 10% of those in fetal plasma, and below assay detection limits in tracheal fluid. Total body clearance (TBC) in the LD and HD infusions were not different and the overall mean was 11.3+/-1.2 mL min(-1) kg(-1). In the 11 experiments where paired fetal arterial and umbilical venous samples were collected, the extraction of indometacin across the placenta averaged only 5.2+/-1.1%, indicating low placental permeability to the drug in sheep. However, fetal placental clearance (CLpl) of indometacin (10.0+/-2.5 mL min(-1) kg(-1), n = 10) averaged 115.1+/-41.2% of TBC in these animals and the calculated value for fetal non-placental clearance (0.6+/-2.8 mL min(-1) kg(-1)) was not significantly different from zero. Fetal renal clearance of intact indometacin (3.8+/-1.1 microL min(-1) kg(-1); n = 12) was also very low. However, treatment of fetal urine with glucuronidase indicated the presence of glucuronide conjugates and these comprised 69.9+/-8.2% of the total drug concentration (i.e. intact+conjugated) in urine. Thus, the fetal lamb appears to be able to glucuronidate indometacin, but the contribution of this and other non-placental routes to overall fetal elimination of the drug appear minimal. CLpl of the drug is also low owing to the physicochemical properties of indometacin (high polarity) and the permeability characteristics of the sheep placenta.     

Experimental stereotactic gamma knife radiosurgery. Vascular contractility studies of the rat middle cerebral artery after chronic survival

In vitro isometric small vessel myograph experiments and pathological investigations were performed on rat middle cerebral arteries. Thirty-four animals provided 68 normal vessels, six further rats had the endothelial layer mechanically removed from their 12 arteries. Eighteen animals received gamma knife irradiation to the middle cerebral arteries. Fifteen of these received 50 Gray, and three 25 Gray dose to the 50% isodose and the contralateral vessels offered 20 Gray and 15 Gray irradiated specimens. Survival times varied from 12 weeks to 18 months. In the acute stage, abolition of potassium-induced relaxation occurred as early as 24 h after irradiation whilst in one year this reaction seemed to recover and remained active to 18 months. The contraction response to prostaglandin F2 alpha was diminished at six weeks in the 50 Gray-irradiated vessels. However, from one year further reduction was seen and by 18 months this response was totally abolished. We demonstrated reduction of contractile capability of the irradiated normal vessels while the vessels remained patent. When using low irradiation dose there were no pathological changes even at 18 months, but marked physiological changes could be demonstrated. Different vessel wall functions appear to have different radiosensitivity, time course and capability for regeneration.     

Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury

Intraspinal transplantation of olfactory glial cells (OGC) has produced well-defined beneficial effects in experimental rodent models of spinal cord injury (SCI) and therefore has considerable promise as a treatment for severe SCI in human patients. In this study, we used clinical canine cases of severe SCI to determine whether derivation and transplantation of OGC from an autologous source was feasible. From the nerve fiber layer of a single olfactory bulb, we were able to generate 5 x 10(6) cells from each patient within 3 weeks. Of this population, 72% were p75(+) OGC, 20% were meningeal cells, and the remainder mainly astrocytes. Intraspinal transplantation was not associated with any observable long- or short-term complications.     

Donor hematopoietic cells from transgenic mice that express GFP are immunogenic in immunocompetent recipients

OBJECTIVE: To study the immunogenicity of hematopoietic cells marked with green fluorescence protein (GFP) while avoiding the potentially confounding effects of viral gene transduction, marked cells from GFP+ transgenic mice were tracked after transplantation into unconditioned immunocompetent recipients. MATERIALS AND METHODS: Marrow was harvested from GFP+ transgenic mice that had been crossed onto a BALB/cByJ background. Unconditioned marrow transplantation involved infusion of sex-matched or sex-mismatched cells into female BALB/cByJ hosts. Engraftment and contribution to circulating nucleated blood cells were compared to recipients of donor cells that were not GFP-marked. Donor cells were detected by flow cytometry (GFP) and fluorescence in situ hybridization (FISH) for Y-chromosome sequences. RESULTS: Donor cells from mice of the same genetic background that did not express GFP were detected for more than four-weeks in unconditioned recipients. In contrast, GFP-marked cells in the blood peaked at one-week, declined to undetectable levels by two-weeks and were not detected in the marrow at sacrifice. In sex-mismatched studies, detection of male GFP+ donor cells by FISH yielded levels similar to those observed by flow cytometry, in contrast to the levels detected for many weeks in mice infused with male cells that did not express GFP. In immunocompetent recipients immunized with irradiated GFP-expressing cells, rechallenge with GFP+ cells resulted in the accelerated loss of donor cells. CONCLUSION: Donor marrow cells from GFP+ transgenic mice were lost after infusion into unconditioned immunocompetent mice and sensitization studies infer an immunologic mechanism. These results are similar to studies of virally transduced cells. Thus, infusion of cells with optimum engraftment potential could not compensate for the loss of donor cells due to immunogenicity.     

Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus

Activation, proliferation, or programmed cell death of T lymphocytes are dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta Psi(m)) also plays a decisive role in cell survival by controlling activity of redox-sensitive caspases. T lymphocytes of patients with systemic lupus erythematosus (SLE) exhibit mitochondrial hyperpolarization, increased ROI production, diminished intracellular glutathione levels, cytoplasmic alkalinization, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. These redox and metabolic checkpoints represent novel targets for pharmacological intervention in SLE.