Changes in proteinase 3 anti-neutrophil cytoplasm autoantibody levels in early systemic granulomatosis with polyangiitis (Wegener's) may reflect treatment rather than disease activity.

OBJECTIVES: To investigate the nature of the relationship between proteinase 3 anti-neutrophil cytoplasm autoantibody (PR3-ANCA) and relapse in patients with early systemic granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: Clinical data from 16 relapsing and 12 non-relapsing patients with early systemic GPA from a randomised clinical trial were correlated to monthly PR3-ANCA values over 18 months. Each sample was examined using 9 different enzyme-linked immunosorbent assays (ELISAs) to ensure reliability of ANCA results. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays in samples after remission. RESULTS: A PR3-ANCA peak was identified in all relapsing and non-relapsing patients and coincided with relapse in all 14 evaluable relapsing patients. The monthly increment before the peak, however, was similar in relapsing and non-relapsing patients in all assays. Increments from remission to peak were higher in relapsing patients in 2/9 assays. PR3-ANCA values at entry and peak PR3-ANCA values were higher in relapsing patients in 3/9 and 2/9 assays, respectively. However, large overlaps of PR3-ANCA values prevented a distinction between relapsing and non-relapsing patients. The median time to reach peak values was 14 months in relapsing and 12 months in non-relapsing patients with scheduled termination of treatment at 12 months. CONCLUSIONS: The predictive value for relapses of PR3-ANCA determinations confirm and extend previous reports. Although all relapses were related to PR3-ANCA increases, reduction or withdrawal of immunosuppression without relapse was also related to increases and may explain the lack of predictive value of sequential PR3-ANCA determinations.

Polymethylmethacrylate membrane and serum free light chain removal: enhancing adsorption properties.

INTRODUCTION: Polymethylmethacrylate (PMMA) membranes can adsorb a wide variety of uremic toxins including serum free light chains (sFLC). However, limited data are available regarding the clinical use of PMMA in multiple myeloma patients and its maximum adsorption capacity in this setting. AIM: This study aimed to measure the capacity of PMMA to adsorb sFLC and identify strategies to improve its efficiency in clinical practice. METHODS: Ten patients with dialysis-dependent renal failure and high levels of sFLC were included in the study. Five patients received standard PMMA hemodialysis (HD; n = 18), while in the other 5 patients a new technique called enhanced adsorption dialysis (EAD) was used, which involves PMMA dialyzer replacement after 2 h (n = 19). In all patients, sFLC were measured at the beginning and at the end of each dialysis session to calculate the difference between start and end of treatment and the percentage removal. RESULTS: PMMA membranes reduced sFLC in both the PMMA HD and EAD groups. PMMA HD showed similar efficiency on κ and λ percentage removal (22.3 and 21.0%, respectively, n.s.) but, in contrast, had a significantly greater effect on the delta of sFLC in κ [1,555 mg/l (-511 to +6,027)] versus λ [390 mg/l (120-650)] treatments (p = 0.007). EAD treatments only partially increased percentage removal of κ sFLC (22.3-31.0%, p = 0.38), while they had a significantly great effect on λ (21.0-53.1%, p = 0.003). A positive linear correlation was found between delta sFLC and pre-HD sFLC concentrations in PMMA HD κ treatments (r = 0.68, p < 0.02) but not for λ treatments (r = 0.54, p = 0.21), while the analysis of patients receiving EAD demonstrated a strong positive correlation for both κ and λ subtypes (r = 0.81 and r = 0.85, respectively, p < 0.008). In EAD sessions, a positive linear correlation was shown between blood flow during treatment and percentage removal of sFLC (r = 0.58, p = 0.02); however, with PMMA HD such a correlation was not observed (r = 0.28, p = 0.25). CONCLUSIONS: PMMA membranes can efficiently adsorb sFLC, but the process is limited by membrane saturation and is different between κ and λ sFLC. The new EAD technique can greatly improve λ removal but only partially act on κ sFLC. Therefore, EAD should be considered a valid economic treatment option without side effects in particular subsets of patients for the removal of sFLC.

Natural course of temporomandibular disorders with low pain-related impairment: a 2-to-3-year follow-up study.

To describe the natural course of temporomandibular disorders (TMD) in patients with low levels of pain-related impairment, independently by the physical diagnoses they received. Amongst all patients who attended the TMD Clinic, University of Padova, Italy, during the year 2009, those who: (i) had Research Diagnostic Criteria for TMD (RDC/TMD) axis II Graded Chronic Pain Scale (GCPS) grade 0 or 1 scores, (ii) received counselling on their signs and symptoms at the time of their first visit and suggestions on how to self-manage their symptoms, (iii) did not attend the Clinic since the time of their last visit and (iv) were visited by the same resident, were recalled for a follow-up assessment during the period from September to December 2011. Sixty-nine patients (79% females; mean age 47.4 ± 11.3 years; range 26-77) of 86 who were potentially eligible accepted to enter the study. The time span since the first visit ranged from 23 to 36 months. At the follow-up assessment, the percentage of patients with muscle disorders decreased from 68.1% to 23.1%; disc displacement with reduction remained unchanged (52.1%), whilst the 5.7% of patients who had disc displacement without reduction with limited opening then showed absence of limitation; diagnoses related to other joint disorders decreased from 30.4% to 14.4% for arthralgia and from 27.5% to 24.6% for osteoarthritis/osteoarthrosis. In a sample of patients TMD with low pain-related impairment followed up with a single recall assessment at 2-to-3 years, the natural course of disease was generally favourable.

Association between silica exposure and necrotizing crescentic glomerulonephritis with p-ANCA and anti-MPO antibodies: a hospital-based case-control study.

A hospital-based case-control study was carried out to investigate the association between ANCA positive rapidly progressive glomerulonephritis (RPGN) and occupational exposure to silica dust. All ANCA positive male patients admitted to the Department of Nephrology of the University of Brescia between 1987 and 1992 were enrolled in the study as cases. The controls were pts of the same age, admitted at the Department immediately before or after the cases, affected by other renal diseases. Seven of the 16 cases and one of the 32 controls, had a positive history for jobs exposing to silica dust (relative risk 14; 95% C.I.: 1.7-113.8, p < 0.001). ANCA pattern was p-ANCA with anti-MPO antibodies in 6/7 of exposed pts. The review of renal histology showed a distinctive glomerular lesion consisting in peripheral nodular areas of glomerular sclerosis, in addition to the crescentic necrotizing glomerulonephritis, in 3/6 silica exposed pts, but in none of the unexposed pts.

Clinical manifestations in patients on chronic dialysis with high titres of ANCA.

Eight untreated patients with an apparent renal-limited disease continued to maintain high titres of ANCA long after the onset of the disease and the start of dialysis. In spite of the high ANCA titres, three of them remained for a long time free of symptoms related to the disease. Three pts developed, at various times from the beginning of the disease, fatal pulmonary hemorrhages.

[The heterotopic autograft of spleen fragments following splenectomy for trauma in the healthy subject]. / L'autotrapianto eterotopico di frammenti di milza dopo splenectomia per trauma, nel soggetto sano.

Authors report their experience on self-grafting of the spleen on 3 patients, among which a 9-year-old child. The surgical method is easy and quick and in their opinion it has given satisfactory results. In fact, basing themselves on the computation of the platelets values close to normality have been observed.

[Heparin-induced thrombocytopenia syndrome and thrombosis in patients undergoing periodic haemodialysis]. / La sindrome di trombocitopenia e trombosi indotte dall eparina (HIT) in emodialisi.

Heparin-induced thrombocytopenia (HIT) is the most important immunological drug reaction that patients face today. Being unfractionated heparin the standard anticoagulation used in haemodialysis, acute or chronic uremic patients starting haemodialysis are at risk of developing HIT. Through the accurate description of two patients, one with chronic and the other with acute uraemia, who developed this complication at the start of haemodialysis, we compare the distinct clinical problems of haemodialysis-related HIT with the general clinical features of HIT. We report the occurrence of repeated clotting of both dialysers and catheters, as well as thrombosis of the central veins where the catheters are placed and of the fistulas. We also report an accurate review of the literature on haemodialysis-related HIT. We have observed that HIT seems to be particularly rare in haemodialysis patients. Since newly treated haemodialysis patients are at risk of developing HIT, and most of the studies were made on long-term chronic haemodialysis patients, we assume that the syndrome is poorly documented. Our own experience on 37 haemodialysis patients who developed HIT is reported by focusing on both the clinical presentation of HIT as well as the long-term follow up of the patients. We present some considerations on the treatment options of acute HIT in uremic patients as well as on the problem of heparin re-exposure subsequent to the HIT episode, a very prominent problem in chronic haemodialysis patient.

Biological Effects of Cytokinin Antagonists 7-(Pentylamino) and 7-(Benzylamino)-3-Methylpyrazolo(4,3-d)Pyrimidines on Suspension-cultured Tobacco Cells.

We have studied the biological effects of two structural analogs of cytokinins, 3-methyl-7-(pentylamino)pyrazolo(4,3-d)pyrimidine and 3-methyl-7-(benzylamino)pyrazolo(4,3-d)pyrimidine, on tobacco cell suspension cultures. These two cytokinin analogs are highly inhibitory to cytokinin-autonomous and cytokinin-requiring tobacco cells. The growth inhibitory effect is markedly antagonized by benzyladenine, but not by adenine. Cell suspensions of tobacco cells of a cytokinin-autonomous strain become cytokinin-dependent in the presence of 0.1 micromolar 3-methyl-7-(benzylamino)pyrazolo(4,3-d)pyrimidine. It is also demonstrated that growth inhibition of cell suspension cultures is accompanied by cell death and that only dividing cells are sensitive to this cytotoxic effect.

Pressor responsiveness in pseudopregnant and pregnant rats: role of maternal factors.

During pregnancy the pressor response to vasoconstrictor substances such as angiotensin II (ANG II) is diminished, and renal, uterine, and vascular prostaglandin (PG) production may increase. However, little is known about the factors that alter vascular reactivity or stimulate PG synthesis during pregnancy. To ascertain whether these factors are of maternal or fetal-placental origin, we studied vascular reactivity and urinary PGE excretion in pseudopregnant rats. Pseudopregnant rats had plasma progesterone and weight gain similar to that observed in pregnant rats. Urinary PG excretion in nonpregnant rats was approximately 70 ng/24 h and remained constant during a 12-day observation. In contrast, urinary PG excretion in both pregnant and in pseudopregnant rats rose to levels approximately twice control within 4-6 days. The pressor response to ANG II was diminished in pseudopregnant rats compared with nonpregnant rats. When the PG synthesis inhibitor meclofenamate was given there was no change in the pressor response to ANG II in nonpregnant animals, but in pseudopregnant animals meclofenamate produced a significant increase in the pressor response to ANG II. The pressor response to norepinephrine and arginine vasopressin (AVP) was not diminished in pseudopregnant animals, and meclofenamate did not increase the pressor response to these agents. Therefore, a developing fetus and placenta is not necessary for the decrease in pressor response to ANG II nor for the early increase in urinary PGE excretion. Like in pregnancy, the pressor response to ANG II was increased after meclofenamate in pseudopregnancy. Increased PG production may, therefore, be partly responsible for the decrease in pressor responsiveness to ANG II. However, pseudopregnancy, unlike pregnancy, did not affect pressor responsiveness to norepinephrine or AVP. Both maternal and fetal-placental factors seem required for the reduction in responsiveness to norepinephrine and AVP in pregnancy.

Testosterone-induced hyperprolactinaemia in a patient with a disturbance of hypothalamo-pituitary regulation.

A case of a patient with hypopituitarism due to a disturbance of hypothalamo-pituitary regulation is presented, who developed high-grade hyperprolactinaemia after the initiation of substitutive therapy with testosterone esthers. The increase in serum Prl was strictly related to testosterone aromatization to oestradiol, since anti-oestrogen compounds were effective in reducing (clomiphene) or abolishing (tamoxifen) the enhanced Prl secretion. The oestrogen effect in raising Prl release was not attributable to a reduction in the dopamine inhibition of Prl-secreting cells, as the dopamine-antagonist domperidone failed to increase Prl serum levels in the same patient. This suggests that, in man, the oestrogen effect in enhancing Prl release is mainly enacted directly on the pituitary lactotrophs rather than exerted through a reduction in the hypothalamic dopamine activity.

Catecholamines and pituitary function. III. Restoration of the prolactin response to thyrotropin-releasing hormone by low-dose dopamine infusion in women with pathological hyperprolactinemia.

Previous studies in Rhesus monkeys have demonstrated that a dopamine (DA) infusion rate of 0.1 microgram/kg X min induces peripheral DA levels similar to those measured in hypophysial stalk blood and normalizes serum prolactin (PRL) levels in stalk-transected animals. We therefore examined the effect of such DA infusion rate on basal and thyrotropin-releasing hormone (TRH)-stimulated PRL secretion in both normal cycling women and women with pathological hyperprolactinemia. 0.1 microgram/kg X min DA infusion fully normalized PRL serum levels in 8 normal cycling women whose endogenous catecholamine synthesis had been inhibited by alpha-methyl-p-tyrosine (AMPT) pretreatment. Furthermore, DA significantly reduced, but did not abolish, the rise in serum PRL concentrations induced by both acute 500 mg AMPT administration and 200 micrograms intravenous TRH injection in normal women. A significant reduction in serum PRL levels in response to 0.1 microgram/kg X min DA, similar to that observed in normal cycling women when expressed as a percentage of baseline PRL, was documented in 13 amenorrheic patients with TRH-unresponsive pathological hyperprolactinemia. However, a marked rise was observed in the serum PRL of the same patients when TRH was administered during the course of a 0.1-microgram/kg X min DA infusion. The PRL response to TRH was significantly higher during DA than in basal conditions in hyperprolactinemic patients, irrespective of whether this was expressed as an absolute increase (delta PRL 94.4 +/- 14.2 vs. 17.8 +/- 14.1 ng/ml, p less than 0.002) or a percent increase (delta% PRL 155.4 +/- 18.9 vs. 17.9 +/- 7.1, p less than 0.0005), and there was a significant linear correlation between the PRL decrements induced by DA and the subsequent PRL responses to TRH. These data would seem to show that the 0.1-microgram/kg X min DA infusion rate reduces basal PRL secretion and blunts, but does not abolish, the PRL response to both TRH and acute AMPT administration. The strong reduction in PRL secretion and the restoration of the PRL response to TRH by 0.1 microgram/kg X min DA infusion in high majority of hyperprolactinemic patients, seem to indicate that both PRL hypersecretion and abnormal PRL response to TRH in women with pathological hyperprolactinemia are due to a relative DA deficiency at the DA receptor site of the pituitary lactotrophs.

Catecholamines and pituitary function. I. Effects of catecholamine synthesis inhibition and subsequent catecholamine infusion on gonadotropin and prolactin serum levels in normal cycling women and in women with hyperprolactinemic amenorrhea.

To investigate the role of catecholamines in the control of gonadotropin and prolactin release, we examined the effects of a catecholamine synthesis inhibitor (alpha-methyl-p-tyrosine, AMPT) administration and those of dopamine (DA) or epinephrine (EPI) infusion after endogenous catecholamine synthesis inhibition, on FSH, LH and PRL serum levels, in regularly cycling women and in patients with hyperprolactinemic amenorrhea. AMPT administration was followed by a prompt increase in serum PRL in regularly cycling women, but not in women with hyperprolactinemia either due to a PRL-secreting pituitary microadenoma or 'idiopathic'. Gonadotropin serum levels did not show any significant variation after AMPT in both normal and hyperprolactinemic women. DA infusion after endogenous catecholamine synthesis inhibition by AMPT, induced an appreciable decline in PRL levels in both normal and hyperprolactinemic subjects. Although the net decrements were higher in the hyperprolactinemic group, the PRL fall was similar in the two groups when expressed as a percentage of preinfusion PRL concentrations. LH serum levels similarly fell during DA infusion in normal women and in hyperprolactinemic patients, while FSH concentrations did not show any significant change. EPI infusion after analogous AMPT pretreatment was followed by an evident decrease in serum PRL in both normal and hyperprolactinemic subjects. No significant changes in FSH and LH serum concentrations were observed during EPI administration. These data, while confirming the existence of a functional derangement in the neural inhibitory control of PRL secretion in hyperprolactinemia either due to a PRL-secreting pituitary microadenoma or so-called 'idiopathic', do not agree with the hypothesis that tubero-infundibular DA hyperactivity inhibits gonadotropin secretion in hyperprolactinemic patients. The inhibitory action of exogenously administered DA might represent rather a pharmacological effect than express a physiological inhibitory role of hypothalamic DA pathway on gonadotropin secretion in humans.

Catecholamines and pituitary function. 2. Prolactin response to different dopamine doses in normal cycling women and patients with prolactin-secreting pituitary tumors, both before and after endogenous catecholamine synthesis inhibition.

The inhibitory effect of various doses of dopamine on serum PRL levels was assessed in both normal cycling women and patients with tumoral hyperprolactinemia before and after endogenous catecholamine synthesis inhibition by alpha-methyl-p-tyrosine, a strong and specific tyrosine-hydroxylase inhibitor. Dopamine infusion induced a significant decrease in the serum PRL levels in both normal cycling and hyperprolactinemic subjects. The mean percent inhibition of baseline PRL induced by the various dopamine infusion rates (0.1, 0.5, 1.0 and 2.0 micrograms/kg/min) was similar in regularly cycling women and in patients with tumoral hyperprolactinemia both before and after endogenous catecholamine synthesis inhibition by alpha-methyl-p-tyrosine. Alpha-methyl-p-tyrosine pretreatment significantly increased serum PRL concentrations in normal women and enhanced their responsiveness to the exogenously administered dopamine. Hyperprolactinemic patients, on the contrary, did not show any significant variation in either basal PRL release or the PRL sensitivity to dopamine infusion after endogenous catecholamine synthesis inhibition. These data indicate that reduced dopamine delivery to the adenomatous lactotroph, either due to a primary hypothalamic abnormality or to a deranged vascular pituitary arrangement, rather than a reduced PRL sensitivity to dopamine inhibition, is the main event accounting for PRL hypersecretion in women with PRL-secreting pituitary tumors.