MPO antibody-positive vasculitis in a patient with psoriatic arthritis and gold-induced membranous glomerulonephritis.
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Antibodies, Antineutrophil Cytoplasmic↗
Biomedical subjects
R Rossi
Publications and source records attributed to R Rossi.
An Escherichia coli expression assay and screen for human immunodeficiency virus protease variants with decreased susceptibility to indinavir.
We have developed a recombinant Escherichia coli screening system for the rapid detection and identification of amino acid substitutions in the human immunodeficiency virus (HIV) protease associated with decreased susceptibility to the protease inhibitor indinavir (MK-639; Merck & Co.). The assay depends upon the correct processing of a segment of the HIV-1 HXB2 gag-pol polyprotein followed by detection of HIV reverse transcriptase activity by a highly sensitive, colorimetric enzyme-linked immunosorbent assay. The highly sensitive system detects the contributions of single substitutions such as I84V, L90M, and L63P. The combination of single substitutions further decreases the sensitivity to indinavir. We constructed a library of HIV protease variant genes containing dispersed mutations and, using the E. coli recombinant system, screened for mutants with decreased indinavir sensitivity. The discovered HIV protease variants contain amino acid substitutions commonly associated with indinavir resistance in clinical isolates, including the substitutions L90M, L63P, I64V, V82A, L24I, and I54T. One substitution, W6R, is also frequently found by the screen and has not been reported elsewhere. Of a total of 12,000 isolates that were screened, 12 protease variants with decreased sensitivity to indinavir were found. The L63P substitution, which is also associated with indinavir resistance, increases the stability of the isolated protease relative to that of the native HXB2 protease. The rapidity, sensitivity, and accuracy of this screen also make it useful for screening for novel inhibitors. We have found the approach described here to be useful for the detection of amino acid substitutions in HIV protease that have been associated with drug resistance as well as for the screening of novel compounds for inhibitory activity.
Amino Acid Substitution↗
Anorectic effect of amylin is not transmitted by capsaicin-sensitive nerve fibers.
Abdominal vagal and splanchnic afferents play an important role in the control of food intake in that they transmit various satiety signals to the central nervous system. Inasmuch as previous studies have shown that the anorectic effect of intraperitoneally injected amylin was not abolished by subdiaphragmatic vagotomy, the aim of the present study was to elucidate the role of splanchnic afferents in mediating amylin's anorectic effect after intraperitoneal injection. Rats were pretreated intraperitoneally with the neurotoxin capsaicin, which destroys primary sensory (vagal and splanchnic) afferents. Sham-treated rats served as control. Capsaicin-pretreatment had no influence on the anorectic effects of amylin (5 microg/kg) and the related peptide, calcitonin gene-related peptide (CGRP; 5 microg/kg), in 24-h food-deprived rats. Abolition of cholecystokinin's (3 microg/kg) anorectic effect agrees with previous studies and confirmed the effectiveness of the capsaicin pretreatment. In conclusion, the anorectic effects of intraperitoneally injected amylin and CGRP are not mediated by capsaicin-sensitive primary sensory neurons. Both anorectic peptides are, therefore, most likely to act within the central nervous system. Previous studies suggest that the relevant receptors might be located in neurons of the area postrema-nucleus of the solitary tract region.
Afferent Pathways↗
Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison's disease.
To test the hypothesis that levels of adrenal autoantibodies correlate with the degree of adrenal dysfunction, we followed up adrenal cortex autoantibody (ACA) titers and 21-hydroxylase (21OH) autoantibody (21OHAb) levels in 19 ACA-positive subjects with preclinical Addison's disease. On enrollment, all the 19 ACA-positive subjects were positive for 21OHAb. At follow-up, the concordance rate for simultaneous presence/absence of both ACA and 21OHAb was as high as 91% and a strong, positive correlation between 21OHAb levels and ACA titers was observed (P < 0.0001). The levels of adrenal autoantibodies were positively associated with the severity of adrenal dysfunction (ANOVA, P < 0.0001 for both 21OHAb and ACA): the 21OH index was significantly lower at stage 0 or 1 than at stage 2+3 (corrected P < 0.001 andP < 0.05) or stage 4 (corrected P < 0.001 and <0.01). Similarly, ACA titer at stage 4 was significantly higher than stage 0 (P < 0.001), stage 1 (P < 0.001), and stage 2+3 (P < 0.05); and ACA titer at stage 2+3 was higher than stage 0 (P < 0.001) and stage 1 (P < 0.05). In subjects with progression of adrenal dysfunction (n = 14), levels of 21OHAb and ACA increased significantly (P = 0.041 and P = 0.002) during the follow-up period. In 5 subjects, the remission of biochemical signs of adrenal dysfunction was associated with the disappearance of both ACA and 21OHAb. Our study shows that the levels of adrenal autoantibodies correlate with the degree of adrenal dysfunction, and this suggests that production of high-level 21OHAb strongly signals the destructive phase of the autoimmune disease process.
Addison Disease↗
Antiphospholipid syndrome, adrenal failure, dilated cardiomyopathy and chronic hepatitis: an unusual manifestation of multiorgan autoimmune injury?
The antiphospholipid syndrome is characterized by clinical evidence of arterial or venous thrombosis, thrombocytopaenia, recurrent fetal loss and repeated positivity of antiphospholipid autoantibodies. The association of antiphospholipid syndrome with the development of adrenal failure has been reported in more than 40 patients in the last 20 years, mostly due to bilateral cortical haemorrhage or thrombosis of adrenal vessels. The presence of antibodies against adrenal cortex was never documented in these patients. Here we report a case of recurrent thrombophlebitis, acute adrenal failure, and chronic hepatitis occurring in a young man found to have antiphospholipid antibodies and lupus anticoagulant. Autoantibodies against adrenal cortex were detected and abdominal ultrasonography showed morphologically normal adrenals. Mild thrombocytopaenia, Coomb's positive anaemia, increase in alanine- and aspartate-aminotransferases and increase in urinary protein excretion were found. Autoantibodies against liver/kidney microsomes were positive and liver biopsy was compatible with autoimmune hepatitis. The patient was treated with cortisone acetate, fludrocortisone and warfarin. Dilated cardiomyopathy was revealed one year later and coronarography did not document any occlusive coronary disease. Three years later, titres of autoantibodies, including those directed towards the adrenal cortex, were increased and others, previously absent, were detected. Nevertheless, the patient's clinical conditions seemed unchanged. At this time, an abdominal CT scan showed adrenal dysmorphisms with bilateral annular calcifications and central hypodensities suggesting previous bilateral adrenal haematomas. The hypercoagulable state that occurs in antiphospholipid syndrome can induce a localized inflammatory response generated by tissue injury, with a consequent release of intracellular antigens and antibodies production. Consequently, tissue-specific autoantibodies positivity may persist until the cells involved in antigen production are completely destroyed.
Adrenal Insufficiency↗
Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells.
Evidence for the expression of the canonic androgen receptor (AR) in human adrenal cortex has not been provided so far. The aim of the present study was to demonstrate the expression of the AR gene in normal and neoplastic adrenocortical human tissues and in the human adrenocortical cancer cell line, NCI-H295, and then to evaluate the effect of dihydrotestosterone (DHT) on human adrenocortical cell growth. An AR cDNA fragment with the expected size of 262 bp was detected by using reverse transcription (RT)-PCR in normal and neoplastic adrenocortical human tissues and in the neoplastic cell line, demonstrating that the gene for AR is indeed expressed in human adrenal cells. In the human adrenocortical cancer cell line NCI-H295, DHT at physiological concentrations produced a significant reduction in cell proliferation and inhibition of colony formation in soft agar. The inhibitory effect on adrenocortical cell growth was evident after both 24 and 48 h of treatment. The antiandrogens, cyproterone acetate and hydroxyflutamide, were capable of reversing the effects exerted by DHT. The androgen-induced growth inhibitory effect was also detected in primary culture of three non-functioning adrenocortical adenomas. These findings show that the canonic AR is present in human adrenocortical cells and that androgens may have a role in the adrenal cortex by reducing cell proliferation.
Adrenal Cortex↗
Effects of histamine H1 receptors on the feeding and drinking patterns in pygmy goats.
The goal of these experiments was to determine which histamine receptors are involved in the relationship between drinking and feeding in ruminants. To this end, the effects of the histamine receptor antagonists dexbrompheniramine (H1 receptor antagonist), cimetidine (H2 receptor antagonist), and terfenadine (H1 receptor antagonist) on feeding and drinking patterns of pygmy goats were investigated. Two experiments using dexbrompheniramine [1 and 2 mg/kg of body weight (BW)0.75], two experiments using cimetidine (16 and 32 mg/kg of BW0.75), and two experiments using terfenadine (5 and 11.5 mg/kg of BW0.75) were performed to assess the type and location (periphery or central nervous system) of the histamine receptors involved in the mediation of prandial drinking by pygmy goats. The H1 receptor antagonists dexbrompheniramine (2 mg/kg of BW0.75) and terfenadine (11.5 mg/kg of BW0.75) significantly reduced water intake, but cumulative feed intake did not change. Consequently, the ratio of water intake to feed intake decreased. In contrast, the H2 receptor antagonist did not affect either water or feed intake. Dexbrompheniramine at 2 mg/kg of BW0.75 and terfenadine at 11.5 mg/kg of BW0.75 also decreased draft frequency and decreased the water intake associated with meals. Results showed that blockage of peripheral H1 histamine receptors attenuates the association between water and feed intake in pygmy goats. Therefore, the stimulating effect of feed intake on water intake appears to depend on activation of peripheral H1 histamine receptors.
Animals↗
Current role of venography in the diagnosis of deep-vein thrombosis.
The clinical diagnosis of deep vein thrombosis (DVT) is barely sensitive and specific. Thus, the clinical suspicion of DVT needs to be confirmed by objective testing. Venography has been for a long time the only reliable technique to confirm or rule-out the clinical suspicion of DVT. Furthermore, venography served as "gold standard" for the validation of non-invasive diagnostic methods for DVT. Among these methods, compressive real-time B-mode ultrasonography (CUS) has substantially reduced the need of performing venography, mainly in outpatients with clinical suspicion of DVT. However, indications for venography still remain in the three DVT patient categories. CUS is highly specific in patients with a first episode of clinically suspected DVT, so that positive patients can be treated with anticoagulants without any further testing. In CUS negative patients three options are available in order to rule-out clinically significant DVT: a) to repeat CUS at day 2 and 8; b) to associate D-dimer to CUS to rule-out DVT (negative D-dimer) or to reinforce surveillance (positive D-dimer); c) to perform venography on the same day. This last approach has been proposed in patients with negative CUS and high pretest clinical probability. CUS is highly specific in high risk patients with asymptomatic DVT and thus it could be used to make treatment decision in positive patients. However, CUS is less sensitive in asymptomatic than in symptomatic patients. Thus, venography remains the only available diagnostic technique to rule-out DVT in asymptomatic patients. In clinical practice, venography should be used on individual basis. In clinical research on DVT prophylaxis, venography should be used in the assessment of the end-point. However, three recent clinical trials on the prevention of post-discharge DVT has generated some uncertainty on the clinical relevance of asymptomatic venography detected DVT. Four to six weeks after discharge a high prevalence of venography detected DVT was observed, a finding disagreeing with the low incidence of clinically overt thromboembolic events at long-term follow-up. Two strategies are available in patients with recurrent symptomatic DVT: to follow-up patients with serial impedance plethysmograph and CUS after the first episode in order to pick-up a positive test in patients previously turned negative or to perform venography, a new intraluminal filling defect suggesting DVT recurrence.
Female↗
[Gastrointestinal hemorrhage].
Acute digestive system haemorrhage is a recurrent cause of hospitalization. As to the upper segment of the digestive system, ulcerous peptic disease is often the cause of this pathology, above all in Western Countries. As to the lower segment, colic diverticula and angiodysplasy represent the most common cause. Bleeding usually clears up spontaneously or with hemodynamic pharmacological help. In some cases, the situation does not improve because of bleeding persistence, so more complex diagnostic and therapeutic techniques are necessary. Instrumental diagnostics is based on endoscopy (once with flexible optical fibre instruments, now with videoendoscopy) whose diagnostic effectiveness is inversely proportional to the latency since the haemorrhagic occurrence. Success is evident in 90-95% of the cases within the first twelve hours. Mesenteric angiography and scintigraphy with marked erythrocytes can solve difficult diagnosis and topographic location on some serious occasions. In every case the risk of complication and death is closely related to the haemorrhagic consistency, the flow of the bleeding, the basic disease, the age and the presence of chronic diseases. The authors examine a personal survey taken from the hospitalization in their own ward during a period of a year.
Adult↗
Excretion kinetics of ifosfamide side-chain metabolites in children on continuous and short-term infusion.
Ifosfamide (IFO) requires metabolic activation by hydroxylation of the ring system to exert cytotoxic activity. A second metabolic pathway produces the cytostatically inactive metabolites 2-dechloroethyl-ifosfamide (2-D-IFO) and 3-dechloroethyl-ifosfamide (3-D-IFO) under release of chloroacetaldehyde. This side-chain metabolism has been suggested to be involved in CNS- and renal toxicity. The total urinary excretion of ifosfamide and its metabolites was investigated during 23 cycles in 22 children at doses ranging from 400 mg/m2 to 3 g/m2. The kinetics of the excretion were compared following short-term and continuous ifosfamide infusion at a dosage of 3 g/m2. IFO and side-chain metabolites were analyzed by gas chromatography, the active metabolites by indirect determination of acrolein (ACR) and IFO mustard (IFO-M) with the NBP test. 59+/-15% of the applied dose could be recovered in the urine, 23+/-9% as unmetabolized IFO. The main metabolite was 3-D-IFO (14+/-4%) followed by isophosphoramide mustard (IFO-M) (13+/-4%) and 2-D-IFO (8+/-3%). Neither the total amount recovered nor the excretion kinetics of ifosfamide and side-chain metabolites showed obvious schedule dependency. The excretion kinetics of side-chain metabolites as well as unmetabolized IFO were nearly superimposable on short-term and continuous infusion. Even after 1-hour infusion there was a lag of 3 - 6 hours until dechloroethylation became relevant. Therefore, differences in toxicity and efficacy cannot be explained by an influence of the application time on the metabolic profile of ifosfamide.
Acetaldehyde↗
Short-term results of transdermal estrogen replacement therapy in cardiovascular disease-free postmenopausal females with and without hypertension.
BACKGROUND: Many studies have shown that estrogen replacement with oral micronized 17 beta-estradiol reduces the risk of cardiovascular disease. The aim of the present study was to evaluate the efficacy of transdermal estrogen replacement therapy in improving the risk profile of cardiovascular disease in postmenopausal women. METHODS: Two hundred and fifty postmenopausal women were enrolled from the "Bene Essere Donna" Center and grouped according to the absence (Group I, n = 175; mean age 54.6 +/- 3.5) or presence of mild to moderate hypertension (Group II, n = 75; mean age 54.1 +/- 4.5). Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose and fibrinogen levels were tested in all women. The total study population was treated with estrogen replacement therapy for 12 months: hysterectomized women received 17 beta-estradiol (0.05 mg/die), while non-hysterectomized women received 17 beta-estradiol 0.05 mg/die plus 5 mg/die of medroxyprogesterone acetate for 12 days during every 28-day cycle. After 12 months, blood pressure and blood chemistry were measured as baseline. RESULTS: Total cholesterol, LDL cholesterol and glucose levels decreased in both groups. HDL cholesterol levels increased significantly only in the sub-group of Group II treated with estrogen plus progesterone. Triglycerides glucose and fibrinogen blood levels decreased in both groups. No cardiovascular events were recorded during the first year of follow-up. CONCLUSION: Transdermal estrogen replacement therapy should be considered as a therapeutic support in order to contrast the elevated cardiovascular risk in postmenopausal women.
Antihypertensive Agents↗
Pain associated with venous ulcers in injecting drug users.
Pain is a concern among people with venous ulcers. Although the prevalence is unknown, venous ulcers occur in those who have a history of illicit injecting drug use. The purpose of this study was to (a) examine the relationship between venous ulcer characteristics and pain severity, (b) ascertain factors that cause pain, (c) determine methods to alleviate pain, and (d) explore beliefs about pain medications among people with a history of injection drug use. Thirty-two patients answered pain and demographic questionnaires and had their venous ulcers traced onto plastic to identify wound area. Greater current pain, worse pain in 24 hours, and higher levels of pain relief from medications were significantly related to larger wound areas. Ibuprofen, compression dressing Unna's boot, and heroin ranked highest in decreasing pain. The most painful activities were working, walking outside, standing, and stair climbing. Many patients (41%) did not like to bother others with their complaints of pain. Participants were generally satisfied with pain treatments and the response of care providers to their pain. People who have used injected drugs and have venous ulcers do have pain. Therefore, research must continue to evaluate this pain as well as the best ways to treat it.
Adult↗
A method to study kinetics of transnitrosation with nitrosoglutathione: reactions with hemoglobin and other thiols.
The rate of protein S-nitrosylation, a reversible process by which S-nitroso thiol (RS-NO) compounds exchange the NO+ moiety with protein SH groups, is essentially governed by two factors, the pK alpha and the accessibility of the protein sulfhydryl. A useful method of following transnitrosation kinetics of various protein and nonprotein SH compounds with GS-NO is described. When the reaction is carried out in the presence of 1-chloro-2,4-dinitrobenzene and glutathione transferases, the rate of RS-NO formation (RSH + GS-NO-->RS-NO + GSH) can be monitored by spectrophotometry at 340 nm in terms of the enzymatic conversion of GSH to a GS conjugate. Unlike methods based on NO release from the S-NO bond, this procedure is rapid and accurate and requires relatively small amounts of thiols. The second order rate constants of S-nitrosylation of human and rat oxy- and deoxyhemoglobin of BSA and other thiols were calculated by this method which confirmed previous results reported in the literature.
Animals↗
Short atrioventricular delay reduces the degree of mitral regurgitation in patients with a sequential dual-chamber pacemaker.
This study was performed in a population of sequential dual-chamber pacemaker-patients with isolated mitral regurgitation (MR) to identify the "ideal atrioventricular (AV) delay" and to determine the effect of sequential pacing with the ideal AV delay on MR degree. Twenty consecutive patients (age 69 +/- 7 years; 45% men) hospitalized at our institution for symptomatic III degree AV block and isolated MR were studied. All received a dual-chamber pacemaker programmed in DDD at a rate of 70 pulses/minute. The ideal AV delay was selected using echo-color Doppler parameters; it was defined as that resulting in a lower degree of MR and in the highest cardiac output. The mean "optimal short" AV delay resulted in 98 +/- 7 ms. At short AV delay we observed a significant reduction in MR severity (regurgitant fraction from 48 +/- 12% to 25 +/- 10% and jet area from 15 +/- 2 to 9 +/- 2 cm2; p <0.0001) together with an increase in stroke volume (68 +/- 16 vs 88 +/- 15 ml; p = 0.007) and mitral early-to-late peak velocity ratio (0.79 +/- 0.33 vs 1.38 +/- 0.37; p <0.0001). In conclusion, a short AV delay may be used to improve cardiac output in sequential paced patients with pure, isolated MR.
Aged↗
Evidence for a physiological role of central calcitonin gene-related peptide (CGRP) receptors in the control of food intake in rats.
In the present study, we investigated the role of central calcitonin gene-related peptide (CGRP) and amylin receptors in mediating the anorectic effects of CGRP and amylin in rats chronically cannulated in the lateral brain ventricle. Intracerebroventricular (ICV) injection of the CGRP and amylin receptor antagonist CGRP(8-37) failed to influence the anorectic effects of peripherally injected CGRP and amylin. CGRP(8-37) alone, however, increased food intake in food deprived rats when administered 2 h before food presentation. Under the same experimental conditions, the more specific amylin receptor antagonists amylin(8-37) or AC 187 did not affect food intake. We therefore conclude, that CGRP is a physiological regulator of food intake within the central nervous system, acting at central CGRP receptors. Peripheral receptors, however, are likely to mediate the anorectic effects of peripherally administered amylin and CGRP.
Amyloid↗
Functional characterization of the T4 DNA ligase: a new insight into the mechanism of action.
ATP-dependent DNA ligases are essential enzymes in both DNA replication and DNA repair processes. Here we report a functional characterization of the T4 DNA ligase. One N-terminal and two C-terminal deletion mutants were expressed in Escherichia coli as histidine- tagged proteins. An additional mutant bore a substitution of Lys159 in the active site that abolished ATP binding. All the proteins were tested in biochemical assays for ATP-dependent self-adenylation, DNA binding, nick joining, blunt-end ligation and AMP- dependent DNA relaxation. From this analysis we conclude that binding to DNA is mediated by sequences at both protein ends and plays a key role in the reaction. The enzyme establishes two different complexes with DNA: (i) a transient complex (T.complex) involving the adenylated enzyme; (ii) a stable complex (S.complex) requiring the deadenylated T4 DNA ligase. The formation of an S. complex seems to be relevant during both blunt-end ligation and DNA relaxation. Moreover the inactive His-K159L substitution mutant, although unable to self-adenylate, still possesses AMP-dependent DNA nicking activity.
Adenosine Monophosphate↗
Effect of antiorthostatic hypokinetic/hypodynamia on urinary endothelin-1 and N-acetyl-beta-D-glucosaminidase excretion in rats.
In an experimental model with rats in head-down suspension, plasma levels and urinary excretion of endothelin-1 (ET-1) and urinary excretion of N-acetyl-beta-D-glucosaminidase (EC 3.2.1.30; NAG) were determined. Significant variations in time in the effective plasma ET-1 levels in the superior and inferior cava vessel blood of animals maintained for 6 days in hypogravity with respect to controls were observed. We not only found a transient increase in urinary NAG activity but also that the levels of U-ET-1 increased during head-down suspension. The simultaneous evaluation at urinary level of these two parameters could be an indication that there are different sites of renal parenchymal involvement or injury during antiorthostatic hypokinesis.
Acetylglucosaminidase↗
Possible involvement of neuropeptidergic sensory nerves in alopecia areata.
Alopecia areata (AA) is a dermatosis involving the sudden occurrence of bald patches on the scalp. Although the aetiology is unknown, experimental data indicate that cutaneous microcirculation plays an important role. The skin is richly innervated by neuropeptidergic sensory nerves that help regulate microvascular circulation. This study shows a reduction of cutaneous levels of substance P and calcitonin gene-related peptide (CGRP) but not of vasoactive intestinal polypeptide in scalp biopsies from patients with AA. Laser-Doppler flowmetry was used to study microcirculation of the scalp. Results indicate that patients with AA have lower basal blood flow and greater vasodilatation following intradermal CGRP injection than control subjects. A vascular hyper-reactivity to vasodilatatory substances such as neuropeptides, probably because of the lack of these substances, is hypothesized.
Adolescent↗