Relationship between anti-neutrophil cytoplasmic antibody determined with conventional binding and the capture assay, and long-term clinical course in vasculitis.

OBJECTIVES: To evaluate the relationship between anti-neutrophil cytoplasmic antibody (ANCA) measured with two different methods and long-term clinical course in vasculitis. DESIGN: Retrospective determination of ANCA with two different assays for detection of PR3-ANCA, conventional direct binding ELISA and capture ELISA using monoclonal antibodies against PR3. The 245 ANCA determinations were performed from frozen blood samples collected three to four times a year in each patient. SETTING: Department of Nephrology at a Swedish University Hospital. SUBJECTS: A total of 10 ANCA-positive patients with vasculitis caused by Wegener's granulomatosis (WG) or microscopic polyarteritis (MPA) and a very long follow-up time (mean 9 years, range 5-15.5 years). RESULTS: The total number of episodes with active vasculitis was 29 and all of them (100%) were detected by the capture technique whilst the conventional technique detected 23 (79%). The mean number of episodes with active disease requiring treatment with steroids and cytotoxic drugs was three per patient (range 1-6). At the time of clinical relapse of the vasculitis disease, the ANCA titre using the capture technique was either increasing or showed a very high value in all cases. The pattern of capture ANCA response could be subdivided into three categories: a close (four patients), an intermediate (three patients), and no (three patients) relationship between capture ANCA level and long-term clinical course. CONCLUSION: Detection of PR3-ANCA by the capture ELISA showed a higher sensitivity than that obtained by the direct ELISA in diagnosing relapse during follow-up of patients with vasculitis. The specificity of the capture ANCA was, however, low, as high levels occurred in patients without clinical disease activity.

Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome.

BACKGROUND: The association between malignant midgut carcinoid tumours and right-sided cardiac lesions is well known, but the pathogenetic link between tumour secretion and valvular disease is still obscure. The purpose of this investigation was to describe the morphological and functional changes of valvular heart disease in a large patient series and to correlate these findings with hormonal secretion and prognosis. METHODS: Of 64 consecutive patients with the midgut carcinoid syndrome followed between 1985 and 1998, valvular heart disease was evaluated in 52 patients by two-dimensional echocardiography, Doppler estimation of valvular regurgitation and flow profiles. A majority was also evaluated with exercise electrocardiography and spirometry. RESULTS: Structural and functional abnormalities of the tricuspid valve were found in 65 per cent of patients, while only 19 per cent had pulmonary valve regurgitation. Long-term survival was related to excessive urinary excretion of 5-hydroxyindole acetic acid of over 500 micromol in 24 h, but the main predictor of prognosis was the presence of severe structural and functional abnormalities of the tricuspid valve. Although advanced tricuspid abnormalities were prevalent in this series, only one patient died from right ventricular heart failure. CONCLUSION: Tricuspid valvular disease is a common manifestation of the midgut carcinoid syndrome and advanced changes are associated with poor long-term survival. Active surgical and medical therapy of the tumour disease reduced the hormonal secretion and, combined with cardiological surveillance, made right ventricular heart failure a rare cause of death in these patients.

Cadmium, mercury, and lead in kidney cortex of the general Swedish population: a study of biopsies from living kidney donors.

Cadmium, mercury, and lead concentrations were determined in deep-frozen kidney cortex biopsies taken from 36 living, healthy Swedish kidney donors (18 males and 18 females), who were 30-71 (mean 53) years of age. Information about occupation, smoking, the presence of dental amalgam, and fish consumption could be obtained for 27 of the donors. The samples (median dry weight 0.74 mg) were analyzed using inductively coupled plasma mass spectrometry, and the results were transformed to wet-weight concentrations. The median kidney Cd was 17 micrograms/g (95% confidence interval, 14-23 micrograms/g), which was similar in males and females. In 10 active smokers, the median kidney Cd was 24 micrograms/g, and in 12 who never smoked, it was 17 micrograms/g. The median kidney Hg was 0.29 micrograms/g, with higher levels in females (median 0.54 micrograms/g) than in males (median 0.16 micrograms/g). Subjects with amalgam fillings had higher kidney Hg (median 0.47 micrograms/g, n = 20) than those without dental amalgam (median 0.15 micrograms;g/g, n = 6), but kidney Hg was below the detection limit in some samples. Nearly half of the samples had kidney Pb below the detection limit. The median kidney Pb was estimated as 0. 14 micrograms/g. This is the first study of heavy metals in kidney cortex of living, healthy subjects, and the results are relatively similar to those of a few previous autopsy studies, indicating that results from autopsy cases are not seriously biased in relation to kidney metal concentrations in the general population. Cd concentrations in those who never smoked were relatively high, indicating considerable Cd intake from the diet in Sweden. The effect of dental amalgam on kidney Hg was as expected, although the reason for the difference in Hg levels between males and females is unclear.

Rhabdomyolysis and acute renal failure associated with influenza virus type A.

Two patients with rhabdomyolysis-induced acute renal failure due to influenza A virus infection are presented. Both had influenza symptoms, with high fever and severe muscular pain leading to walking problems. In addition, they were dehydrated due to vomiting and diarrhoea. Both had evidence of an ongoing influenza infection according to serological tests. Muscle injury due to the viral infection gave rise to rhabdomyolysis with efflux of myoglobin from the muscles, causing renal failure. In conclusion, influenza A virus infection can cause rhabdomyolysis accompanied by reversible acute renal failure.

The arginine-nitric oxide pathway in thrombotic microangiopathy.

Eleven patients with thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS) were investigated with respect to plasma concentrations of L-arginine, a substrate for nitric oxide (NO) and asymmetrical dimethyl arginine (ADMA), during active disease and after recovery. Plasma concentration of NO3-, the degradation product of NO, was also analyzed. The patients were treated with fresh-frozen plasma and plasmapheresis. One of the patients had experienced relapses of TTP five times during the preceding year. After treatment with p.o. arginine hydrochloride 1.5 g x 3 was started, no relapse has occurred during a 12-month period. During the active phase the plasma concentration of arginine was low and that of NO3- was very high, indicating a high NO-synthesis rate. The arginine concentration normalized on recovery. Plasma levels of ADMA, was twice normal during active disease, and did not return to normal on recovery. In conclusion, patients with TTP/HUS exhibit signs of activation of the NO-synthesis.

Secretory patterns of tryptophan metabolites in midgut carcinoid tumor cells.

Hormonal overproduction is a significant problem in patients with disseminated midgut carcinoid tumors. Serotonin (5-HT) is one major product secreted from such tumors and the urinary excretion of its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) serves as an important tumor marker. The present study aimed at elucidating mechanisms of tryptophan metabolite secretion to facilitate the treatment of the carcinoid syndrome. When midgut carcinoid tumors were studied in primary cell cultures, several similarities with adrenergic neurons could be demonstrated. A marked dose-dependent depletion of intracellular 5-HT could be induced by reserpine, and monoamine oxidase-activity was revealed both in functional studies and by immunocytochemistry. Differences between tumors in the ratios of tryptophan metabolites released indicated that enzymes for synthesis and degradation of 5-HT were individually expressed. Treatment with the somatostatin analogue octreotide or with dexamethasone decreased the extracellular levels of tryptophan metabolites, but the mechanisms were partly different. In some tumors octreotide also decreased the synthesis of 5-HT, while dexamethasone markedly increased the intracellular 5-HIAA levels. It is of clinical interest to further elucidate these mechanisms, since the two drugs may have complementary actions in carotid crisis reactions.

Effects of chemical stimulation of masseter muscle nociceptors on trigeminal motoneuron and interneuron activities during fictive mastication in the rabbit.

An electrophysiological study was carried out in sixteen decerebrate and paralyzed New Zealand rabbits to determine how a bolus injection of a nociceptor stimulant (hypertonic saline, 5%) into the masseter muscle influences the activity of the trigeminal motor circuitry during fictive jaw movements. Hypodermic needles connected to a syringe held in a computer-controlled infusion pump were inserted into the anterior deep layer of either the right or the left masseter. Twenty-three infusions of 50, 70 or 80 microl saline were made in fourteen animals at constant rates over 1 min. Eight control infusions of normal saline (0.9%) were made in a subpopulation of five animals in an identical manner. Fictive jaw movements were evoked before and after the infusions by repetitive electrical stimulation of the corticobulbar tract. Effects were assessed by extracellular microelectrode recordings made from the digastric motoneuron pool and from putative last-order interneurons in the oral subnucleus of the spinal trigeminal tract and adjacent structures. In comparison with pre-infusion control cycles, nociceptor stimulation caused significant slowing of the rhythm and a reduction of the area of the digastric motoneuron bursts in the majority of the animals (12/14). The decrease in cycle frequency was due almost entirely to a lengthening of the time between the digastric bursts. Changes usually began 1-2 min after the infusion and returned to pre-infusion values within 10-15 min. No significant effects were seen when isotonic saline was applied. Recordings were obtained from nine interneurons, eight of which had low threshold mechanosensitive receptive fields. One neuron was, in addition, excited by pinch. Eight were not active in the absence of motor activity and this did not change when hypertonic saline was applied. However, once fictive movements began, all started to fire rhythmic bursts of spikes. In five cases, there was a significant post-infusion increase in spike frequency, and three showed decreases. Seven showed significant post-infusion changes in mean phase and/or concentration of their firing within the movement cycle. Changes in the preferred phase of interneuronal firing were significantly correlated to changes in the phase of offset of the digastric burst. The present results provide evidence that the stimulation of nociceptors in a muscle slows the frequency of rhythmical movements in the absence of sensory feedback. They confirm that infusions into one muscle affect the output of its antagonist. The results also suggest that neurons in the oral subnucleus of the spinal trigeminal tract and adjacent reticular formation appear to participate in programming these changes in motor output.

Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction.

Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 +/- 79 micromol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow-up, the mean 5-HIAA levels were still normal after 69.0 +/- 6. 2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 +/- 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5-year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival.

Treatment of liver metastases of carcinoid tumors.

Liver metastases imply a major problem in patients with carcinoid tumors. Patients with localized disease should always undergo resection for cure. Patients with distant metastatic disease can also undergo resection for potential cure or symptom palliation because of the slow growth rate of many carcinoid tumors. In patients with the midgut carcinoid syndrome and bilobar hepatic disease we have performed primary surgery to relieve such symptoms as intestinal obstruction and ischemia, followed by successive embolizations of the hepatic arteries to reduce functional tumor burden in the liver. For optimal palliation, all patients with residual tumor were treated by octreotide. In a consecutive series of 64 patients with the midgut carcinoid syndrome we thus attained a 5-year survival rate of 70%. Fourteen of the patients underwent intentionally curative surgery (e.g., primary surgery followed by liver surgery). Of these patients, none died from their tumor disease during the period of study. The value of adjunctive interferon therapy is currently under evaluation.

Pathophysiology of the vascular wall: the role of nitric oxide in renal disease.

Nitric oxide (NO) is formed in the endothelium by the constitutive enzyme NO synthase from the substrate amino acid L-arginine. As an endogenous vasodilator it contributes to renal arteriolar tone and modulates relaxation of the mesangium, thus contributing to regulation of glomerular microcirculation. NO also plays a role in regulating renal sodium excretion and renin release. It has antiplatelet and antithrombogenic effects and thus helps prevent thrombosis within the glomerular capillaries. In sepsis and sepsis-related syndromes, NO has a renoprotective role in that it aids in maintaining renal vasodilation and inhibiting platelet adhesion and aggregation. More knowledge of these effects may lead to the design of therapeutic interventions for preventing glomerular injury.

Renal hemodynamic effects of dietary protein in the rat: role of nitric oxide.

The biologic mediator(s) of the renal hemodynamic effects of a high dietary protein intake (hyperfiltration and renal vasodilation) are unknown. The endogenous nitrovasodilator nitric oxide (NO) derives from the amino acid L-arginine, and NO has been demonstrated to mediate the hyperfiltration and vasodilation observed during amino acid infusion in rats. We therefore hypothesized that NO may also mediate the long-term renal hemodynamic effects of variations in dietary protein intake. We studied rats maintained with low protein (6%) and high-protein (50%) diets for 2 weeks. An additional group of rats receiving a high-protein diet was also treated with the NO synthase inhibitor, L-nitro-arginine-methyl ester (NAME, 100 mg per liter of drinking water). After 2 weeks a high-protein diet was associated with a significant increase in glomerular filtration rate (GFR) (50% protein group vs 6% protein group, 1.01 +/- 0.03 vs 0.61 +/- 0.03 ml/min; p < 0.05) and renal vasodilation (renal vascular resistance: 50% protein group vs 6% protein group, 11.70 +/- 0.88 vs 17.65 +/- 1.55 mm Hg/min/ml; p < 0.05) compared with a low-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between current smoking, leanness, and physical inactivity in the prediction of hip fracture.

To study the association between smoking habits and the incidence of hip fracture, adjusted for leanness and physical inactivity, a cohort study with 3 years follow-up was conducted. Subjects were 34,856 adults aged 50 years or older who attended a health screening in Nord-Trøndelag County in Norway in 1984-1986 (91% of eligible subjects in 1986, n = 38,356). Of these, 421 suffered a hip fracture during the years 1986-1989. Using Cox regression models, the relative risk (with 95% confidence interval) of suffering a hip fracture for female smokers versus nonsmokers was 1.5 (1.0-2.4). These results refer to females when the female body mass index (BMI) was set at 25 kg/m2 in the female model (the mean BMI for the smoking female population in this study). Among thinner females, however, smoking had a much stronger effect. For instance, if the female BMI was set at 20 kg/m2, the relative risk was 3.0 (1.8-5.0). The relative risk of hip fracture for male smokers versus nonsmokers was 1.8 (1.2-2.9) irrespective of BMI. Smoking is associated with incidence of hip fracture in both sexes and also after adjusting for body mass index and physical inactivity (the effect of physical inactivity was adjusted for self-reported ill health because ill health was included in the model). For lean females, the association with current smoking was large, as large as if they added 10 years to their age.

Exogenous nitric oxide prevents endotoxin-induced glomerular thrombosis in rats.

Nitric oxide (NO) synthesized from L-arginine is an endogenous vasodilator and inhibitor of platelet adhesion and aggregation. Gram-negative lipopolysaccharide (LPS) can induce NO synthesis, which may mediate the pathophysiologic effects of endotoxemia. In addition, our previous studies suggested that LPS-induced NO may protect against thrombosis in rats. In the present study, male Sprague-Dawley rats given LPS (0.1 mg/kg) i.p. increased their urinary excretion of NO2 + NO3 (stable end-products of NO) by 4.3-fold. Rats given 10 micrograms/kg/hr i.v. of nitroglycerin (GTN), an exogenous NO donor, showed a similar increase. L-NAME, an inhibitor of NO synthesis, abrogated the increase in urinary NO2 + NO3 in LPS-treated rats but not in rats given GTN. Glomerular thrombosis developed in rats given LPS + L-NAME (thrombosis score = 3.02 +/- 0.4), while those given LPS + L-NAME + GTN were largely protected (thrombosis score = 1.37 +/- 0.5, P < 0.05). Atrial natriuretic peptide (ANP), an NO-independent vasodilator, neither increased urinary NO2 + NO3 nor prevented glomerular thrombosis (thrombosis score = 2.68 +/- 0.5, NS). Hydralazine, another vasodilator without effects on NO or platelets, also failed to prevent glomerular thrombosis in rats given LPS + L-NAME. We conclude that in endotoxemia, the antithrombogenic properties of endogenously synthesized NO are important in preventing alomerular thrombosis. The exogenously NO donor, GTN, can substitute for the antithrombogenic effect of endogenous NO. Clinically, administration of NO synthesis inhibitors to treat endotoxic shock may need to be combined with concomitant administration of exogenous NO donors to prevent microvascular thrombosis.