Thyroid uptake of radioactive iodine and scintigraphy in mice.
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Animal Feed↗
Biomedical subjects
R Rocchi
Publications and source records attributed to R Rocchi.
Predictors of impaired blood pressure homeostasis during acute and sustained orthostasis in patients with type 2 diabetes.
AIM: Sympathetic failure with acute postural hypotension is a common feature of advanced autonomic neuropathy in type 2 diabetes. It is unknown, however, whether: a) the presence of sympathetic autonomic neuropathy is also a powerful predictor of postural blood pressure changes during sustained orthostasis and b) other factors affecting baroreceptor and neuro-hormonal control might play a role. METHODS: Systolic blood pressure (SBP) was measured during supine rest and after 2, 5, and 20 min of active orthostasis in 45 males with type 2 diabetes (age 56.4+/-8.2 years, mean+/-SD) and different degrees of autonomic neuropathy (absence of neuropathy, n=26, parasympathetic neuropathy, n=9, and sympathetic neuropathy, n=10). Eight healthy subjects (50.1+/-11.6 years) served as controls. A multiple backward regression analysis was performed to identify independent predictors of SBP changes during orthostasis. The regression model included presence/absence of sympathetic autonomic neuropathy, age, diabetes duration, presence/absence of hypertension, baseline SBP and neuro-hormonal parameters (plasma adrenaline, noradrenaline, plasma renin activity, and aldosterone). RESULTS: Sympathetic autonomic neuropathy (P=0.005), baseline SBP (P=0.001), and adrenaline (P=0.003) independently predicted SBP changes after 2 min (R2=0.64); sympathetic autonomic neuropathy (P<0.001), baseline adrenaline (P=0.008), and plasma renin activity (P=0.006) predicted SBP changes after 5 min (R2=0.58); whereas sympathetic autonomic neuropathy (P<0.001) and baseline SBP (P<0.001) predicted SBP changes after 20 min orthostasis (R2=0.65). CONCLUSIONS: The presence of sympathetic autonomic neuropathy and higher supine SBP values remain strong and independent predictors of SBP fall not only during the acute transition from supine to standing position but also during sustained orthostasis in type 2 diabetes. Lower baseline plasma adrenaline concentrations and plasma renin activity are also involved, though to a lesser extent, in the genesis of this haemodynamic response.
Blood Pressure↗
Novel aspects of immunosuppressive and radiotherapy management of Graves' ophthalmopathy.
Treatment of severe Graves' ophthalmopathy (GO) is a complex therapeutic challenge and, in spite of any efforts, about one third of patients are disappointed with the outcome of treatment. Glucocorticoids (GC), orbital radiotherapy (RT), or a combination of both, are most frequently used for their immunosuppressive effects. Novel immunosuppressive treatment procedures (or novel modalities of established treatments) are reviewed in the present article. GC has recently been used by the i.v. route and this treatment modality has been shown to be more effective and better tolerated than the oral route. Promising preliminary results have been reported by some authors with somatostatin analogs, octreotide and lanreotide. The number of patients treated so far is limited, most of the results have been obtained in nonrandomized or uncontrolled studies, and comparison with other validated methods of treatment is also needed. Because of the pathogenic role of cytokines, cytokine antagonists, currently evaluated in other autoimmune diseases, have been tested with positive results also in a small series of GO patients. The use of antioxidants might also be envisioned in the future, since in vitro studies have shown that oxygen free radicals might be involved in GO. Based on the shared antigen(s) theory, total thyroid ablation, by removing the bulk of shared antigens(s), might be beneficial for the course of GO. New data on recently performed placebo-controlled studies on orbital radiotherapy are discussed, together with studies on long-term safety of orbital radiotherapy.
Antioxidants↗
Floppy eyelid syndrome associated with obstructive sleep apnoea.
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Blepharoptosis↗
Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD.
Both dopamine agonists and levodopa may induce episodes termed "sleep attacks" in patients with PD. These episodes are well detailed behaviorally, but little is known about their neurophysiologic characterization. The authors performed a 24-hour polysomnography (PSG) in a PD patient taking pergolide in combination with levodopa, in which four of these diurnal sleep episodes occurred. PSG findings were followed up after pergolide withdrawal. Sleep episodes shared with narcolepsy both behavioral and EEG findings. However, pergolide partly restored a more physiologic sleep architecture, which was disrupted during therapy with levodopa alone.
Adult↗
Synthesis, conformation and biological activity of linear and cyclic Thr6-bradykinin analogues containing N-benzylglycine in place of phenylalanine.
Three linear Thr6-bradykinin analogues in which either one or both the two phenylalanine residues in the peptide sequence have been substituted by N-benzylglycine (BzlGly) and their head-to-tail cyclic analogues were synthesized and tested on an isolated rat duodenum preparation. The linear (BzlGly5,Thr6-BK, BzlGly8,Thr6-BK and BzlGly(5,8),Thr6-BK) and the cyclic (cyclo BzlGly5,Thr6-BK, cyclo BzlGly8,Thr6-BK and cyclo BzlGly(5,8),Thr6-BK) peptoid-like analogues were characterized by amino acid analysis, optical rotation, analytical HPLC and MALDI-TOF mass spectroscopy. The conformational features of both the linear and cyclic derivatives were investigated by FT-IR and CD measurements. Preliminary molecular mechanics calculations were also performed on some synthetic peptides. Pharmacological screening using the relaxation of the isolated rat duodenum preparation showed that incorporation of N-benzylglycine at positions 5 and/or 8 in the linear Thr6-BK causes a substantial decrease in potency. Comparable incorporation in cyclo Thr6-BK, at position 8, or 5 and 8, resulted in nearly inactive analogues. However, cyclo BzlGly5,Thr6-BK showed a potency which is of the same order of magnitude as for cyclo-BK and cyclo Thr6-BK.
Bradykinin↗
Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study.
Eighty-two consecutive patients with moderate-to-severe and active Graves' ophthalmopathy were randomly treated with orbital radiotherapy combined with either oral (prednisone; starting dose, 100 mg/d; withdrawal after 5 months) or iv (methylprednisolone; 15 mg/kg for four cycles and then 7.5 mg/kg for four cycles; each cycle consisted of two infusions on alternate days at 2-wk intervals) glucocorticoids. The two groups did not differ for age, gender, duration of hyperthyroidism and ophthalmopathy, prevalence of smokers, thyroid volume, and pretreatment ocular conditions. Both groups of patients received radioiodine therapy shortly before treatment for Graves' ophthalmopathy. Follow-up lasted for 12 months. A significant reduction in proptosis (from 23.2 +/- 3.0 to 21.6 +/- 1.2 mm in the iv glucocorticoid group, P < 0.0001; and from 23 +/- 1.8 to 21.7 +/- 1.8 mm in oral glucocorticoid group, P < 0.0001) and in lid width (from 13.3 +/- 2.5 to 11.8 +/- 2.2 mm, and from 13.6 +/- 2.0 to 11.5 +/- 1.9 mm, respectively; P < 0.001 in both cases) occurred, with no difference between the two groups. Diplopia significantly improved in both groups: it disappeared in 13 of 27 (48.1%) iv glucocorticoid patients (P < 0.005) and in 12 of 33 (36.4%) oral glucocorticoid patients (P < 0.03). The degree of amelioration of diplopia did not significantly differ between the two groups (P = 0.82). Optic neuropathy improved in 11 of 14 iv glucocorticoid (P < 0.01) and only in 3 of 9 oral glucocorticoid (P = 0.57) patients, with no significant difference in these outcomes. The Clinical Activity Score decreased from 4.5 +/- 1.2 to 1.7 +/- 1.0 (P < 0.0001) in the iv glucocorticoid group and from 4.2 +/- 1.1 to 2.2 +/- 1.2 (P < 0.0001) in the oral glucocorticoid group; final Clinical Activity Score was significantly lower in iv glucocorticoid than in oral glucocorticoid patients (P < 0.01). By self-assessment evaluation, 35 (85.3%) iv glucocorticoid and 30 (73.2%) oral glucocorticoid patients reported an improvement of ocular conditions (P = 0.27). Overall, both treatments produced favorable effects in most patients, but responders in the iv glucocorticoid group (36 of 41, 87.8%) were more than in the oral glucocorticoid group (26 of 41, 63.4%) (P < 0.02). Moreover, iv glucocorticoid treatment was better tolerated than oral glucocorticoid treatment. Side effects occurred in 23 (56.1%) iv glucocorticoid and 35 (85.4%) oral glucocorticoid patients (P < 0.01); in particular, cushingoid features developed in 5 of the former and 35 of the latter patients. One iv glucocorticoid patient had severe hepatitis of undetermined origin at the end of glucocorticoid treatment, followed by spontaneous recovery. In conclusion, high-dose iv glucocorticoid and oral glucocorticoid (associated with orbital radiotherapy) are effective in the management of severe Graves' ophthalmopathy, but the iv route seems to be more effective and better tolerated than the oral route and associated with a lower rate of side effects.
Administration, Oral↗
Soluble interleukin-1 receptor antagonist concentration in patients with Graves' ophthalmopathy is neither related to cigarette smoking nor predictive of subsequent response to glucocorticoids.
OBJECTIVE: The aim of the present study was to evaluate serum soluble interleukin-1 receptor antagonist (sIL-1RA) concentration and its relationship with the degree of cigarette smoking in patients with Graves' ophthalmopathy (GO). DESIGN AND SUBJECTS: Twenty-two consecutive GO patients (20 women, two men; age range 25-68 years, mean 48 years; 12 smokers, 10 non-smokers) submitted to IV glucocorticoid pulses over a 3-month period. MEASUREMENTS: sIL-1RA levels were measured by an immunoenzymatic assay (sensitivity, 4 ng/l; normal range, 50-290 ng/l) before glucocorticoid treatment, after two months of therapy, and 3 months after drug withdrawal. RESULTS: Thirteen patients responded to treatment (59%; five smokers and eight non-smokers), nine were non-responders (41%; seven smokers and two non-smokers). Baseline median sIL-1RA concentration did not differ in smokers and non-smokers (222 and 173 ng/l, respectively; P = 0.69). Likewise, no significant differences were found between the two groups during treatment (537 and 389 ng/l, respectively; P = 0.28); sIL-1RA concentration after treatment was higher in smokers (258 vs. 94 ng/l; P = 0.02). There was no correlation between basal sIL-1RA levels and the degree of cigarette smoking. Likewise, there was no difference in sIL-1RA levels in responders and non-responders, either at baseline (186 vs. 216 ng/l; P = 0.83), during or after treatment. CONCLUSION: Our study suggests that circulating soluble interleukin-1 receptor antagonist levels, both at baseline and during glucocorticoid treatment, are neither influenced by cigarette smoking nor predictive of subsequent response to glucocorticoid treatment.
Adult↗
A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.
OBJECTIVE: To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia. BACKGROUND: CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19. METHODS: The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE). RESULTS: Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia. CONCLUSIONS: The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.
Acetazolamide↗
Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration.
In the present paper we describe the synthesis of some dermorphin and deltorphin analogues beta-O- and alpha-C-glycosylated on the C-terminal amino acid residue and report their opioid receptor affinity and selectivity as well as their analgesic potency after subcutaneous injection in mice.
Amino Acid Sequence↗
Radioiodine is an effective, inexpensive, and safe treatment for Graves' hyperthyroidism, its immunological effects must be taken into account.
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Autoimmunity↗
Chromogenic and fluorogenic glycosylated and acetylglycosylated peptides as substrates for serine, thiol and aspartyl proteases.
We synthesized short chromogenic peptidyl-Arg-p-nitroanilides containing either (Galbeta)Ser or (Glcalpha,beta)Tyr at P2 or P3 sites as well as O-acetylated sugar moieties and studied their hydrolysis by bovine trypsin, papain, human tissue kallikrein and rat tonin. For comparison, the susceptibility to these enzymes of Acetyl-X-Arg-pNa and Acetyl-X-Phe-Arg-pNa series, in which X was Ala, Phe, Gln and Asn were examined. We also synthesized internally quenched fluorescent peptides with the amino acid sequence Phe8-His-Leu-Val-Ile-His-Asn14 of human angiotensinogen, in which [GlcNAcbeta]Asn was introduced before Phe8 and/or after His13 and ortho-aminobenzoic acid (Abz) and N-[2-, 4-dinitrophenyl]-ethylenediamine (EDDnp) were attached at N- and C-terminal ends as a donor/receptor fluorescent pair. These peptides were examined as substrates for human renin, human cathepsin D and porcine pepsin. The chromogenic substrates with hydrophilic sugar moiety increased their susceptibility to trypsin, tissue kallikrein and rat tonin. For papain, the effect of sugar depends on its position in the substrate, namely, at P3 it is unfavorable, in contrast to the P2 position that resulted in increasing affinity, as demonstrated by the higher inhibitory activity of Ac-(Gal3)Ser-Arg-pNa in comparison to Ac-Ser-Arg-pNa, and by the hydrolysis of Ac-(Glcalpha,beta)Tyr-Arg-pNa. On the other hand, the acetylation of sugar hydroxyl groups improved hydrolysis of the susceptible peptides to all enzymes, except tonin. The P'4 glycosylated peptide [Abz-F-H-L-V-I-H-(GIcNAcbeta)N-E-EDDnp], that corresponds to one of the natural glycosylation sites of angiotensinogen, was shown to be the only glycosylated substrate susceptible to human renin, and was hydrolysed with lower K(m) and higher k(cat) values than the same peptide without the sugar moiety. Human cathepsin D and porcine pepsin are more tolerant to substrate glycosylation, hydrolysing both the P'4 and P4 glycosylated substrates.
Angiotensinogen↗
Graves' ophthalmopathy and 131I therapy.
Graves' ophthalmopathy is an autoimmune process initiated and maintained by antigen(s) shared by the thyroid and the orbit. A matter of argument concerns the choice of the method of treatment for Graves' hyperthyroidism when clinically evident ophthalmopathy is present. Restoration of euthyroidism appears to be beneficial for ophthalmopathy. On the other hand the continuing disease activity associated with the recurrence of hyperthyroidism appears to adversely affect the course of ophthalmopathy. For these reasons it is our opinion that in patients with Graves' hyperthyroidism and ophthalmopathy the permanent control of thyroid hyperfunction by ablation of thyroid tissue should be obtained by radioiodine therapy or thyroidectomy. The rationale for an ablative strategy is the following: i) permanent control of hyperthyroidism avoids exacerbations of eye disease associated with recurrence of hyperthyroidism; ii) hypothyroidism, which follows thyroid tissue ablation, should be regarded as a therapeutic end point rather than as an undesirable result; iii) ablation of thyroid tissue may result in the removal of both the thyroid-orbit cross-reacting antigen(s) and the major source of thyroid-autoreactive lymphocytes. The relationship between radioiodine therapy and the course of GO is a matter of controversy, and some authors have suggested that radioiodine administration may be associated with a worsening of preexisting ophthalmopathy. This was not observed when radioiodine treatment was associated with a 3-month oral course of prednisone. The development or progression of GO after radioiodine therapy might be due to the release of thyroid antigens following radiation injury and to subsequent exacerbations of autoimmune reactions directed towards antigens shared by the thyroid and the orbit. The view that radioiodine therapy may be associated with a progression of ophthalmopathy is not shared by some authors who claim that the apparent link between progression of ophthalmopathy and radioiodine therapy might simply be coincidental, reflecting the natural history of the disease. The radioiodine-associated exacerbation of eye disease might be used as an argument against the use of radioiodine therapy in patients with ophthalmopathy. We do not share this view, since the outward effects of radioiodine on eye disease can easily be prevented by concomitant administration of glucocorticoids. Glucocorticoid treatment should be limited, in our opinion, to patients with clinically evident eye disease and to those without ophthalmopathy but with other known risk factors, such as smoking.
Graves Disease↗
Conformational investigations on glycosylated threonine-oligopeptides of increasing chain length.
Stepwise solution syntheses are described of the homo-oligomers Z-(Thr)n-NHCH3 (n=1-4, I1-4), Z-¿[Gal(Ac)4beta]Thr¿n-NHCH3(n=1-5, II1-5) and Z-[(Galbeta)Thr]n-NHCH3 (n=1-5, III1-5). Members of the III1-5 series were obtained by de-acetylation of the corresponding oligomers of the II1-5 series. The conformational preferences of the terminally protected homo-peptides of the three series were investigated by FT-IR absorption spectroscopy both in the solid state and in CDCl3 solution, at various concentrations. Proton NMR measurements in CDCl3 and in DMSO-d6 were also carried out and the effect of temperature variation on the chemical shifts of amide protons was determined in DMSO-d6 (range 298-335 K) and in CDCl3 (range 298-320K). CD spectra were recorded in water and in TFE. Solubility problems prevented measurements in CDCl3 solution for Z-(Thr)4-NHCH3 and for the entire III1-5 series. The existence of unordered structures in the carbohydrate-free oligomers and of more or less extended, organized structures in the glycosylated derivatives is indicated by the NMR and IR measurements. The sugar moieties apparently show a structure-inducing effect on the peptide chain.
Glycosylation↗
Comparison of the immunogenicity of wasp venom peptides with or without carbohydrate moieties.
Three synthetic vespulakinin analogues either with or without carbohydrate moieties and mastoparan B isolated from Vespa basalis venom were investigated for their immunogenic activity and solution conformation. Mice immunized with these wasp venom peptides, with the exception of (Gal alpha)Thr3, (Gal alpha)Thr4-vespulakinin 1, showed positive antibody responses. However, the response elicited by mastoparan B was much higher than those induced by vespulakinin analogues. The class of antibody induced by these peptides was identified as an IgG1 isotype with kappa-light chain, suggesting stimulation of a T-cell-dependent immune response by these peptides. According to the circular dichroism spectra of these peptides, the structures of the vespulakinin analogues in solution were largely unordered, while mastoparan B exhibited a conformation rich in alpha-helices. The presence of carbohydrate moieties and the rather random structure in vespulakinins may interfere with T-cell recognition of the peptides, leading to lower immune responses.
Allergens↗
Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood-brain barrier penetration.
1. In order to improve the in vivo stability of the opioid peptide dermorphin we synthesized O-betaglucosylated analogs ([Ser7-O-betaGlc]dermorphin and [Ser7-O-betaGlc(Ac)4]-dermorphin) and C-alphagalactosylated analogs ([Ala7-C-alphaGal]dermorphin and [Ala7-C-alphaGal(Ac)4]-dermorphin). 2. O- and C-glycosylation of dermorphin halved the peptide affinity for brain mu-opioid receptors and the biological potency in guinea-pig ileum assay (GPI). Despite their lower opioid receptor affinity, when administered intracerebroventricularly (i.c.v., 8-40 pmol) and subcutaneously (s.c., 0.5-3 micromol kg(-1)) in rats, glycosylated analogs were two times more potent than dermorphin in reducing the nociceptive response to radiant heat. Acetylation of sugar hydroxyl groups reduces 5-10 times both biological activity on GPI and mu-receptor affinity, whereas the antinociceptive potency was equal to (i.c.v.) or only two-three times lower (s.c.) than dermorphin potency. 3. Blood-Brain Barrier Permeability Index (BBB-PI) of the glycodermorphins was significantly higher than that of dermorphin, indicating a facilitated entry into the brain: O-beta-linked glucoconiugates are expected to enter CNS by the glucose transporter GLUT-1 of the endothelial barrier. However the calculated BBB-PI for the C-alphagalactoside was about two times higher than that of the O-betaglucoside, excluding the implication of GLUT-1 that is known to be selective for O-beta-links and preferring for the exose glucose. 4. The enhanced brain permeability with the subsequent decrease in peripheral dosage of these opioid peptides did not result in lowering constipation.
Amino Acid Sequence↗
Orbital radiotherapy for Graves' ophthalmopathy.
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Graves Disease↗
Outcome of thyroid function in Graves' patients treated with radioiodine: role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage.
UNLABELLED: We investigated the interrelationship and the influence of thyroid-stimulating antibodies (TSAb), TSH-blocking antibodies (TSHBAb), and of radioiodine (131I)-induced thyroid damage in the early (within 1 yr) outcome of thyroid function in hyperthyroid patients with Graves' disease (GD) treated with 131I. TSAb, TSHBAb, and ultrasound thyroid volume (as an index of thyroid damage) were simultaneously measured before and at 1, 3, 6, and 12 months after 131I in 31 GD patients. One year after radioiodine, 9.7% of patients were hyperthyroid (Hyper-group), requiring methimazole; 12.9% were euthyroid (Eu-group); and 77.4% were hypothyroid (Hypo-group). Pretreatment thyroid volume in the Eu-group and Hyper-group was significantly greater (P = 0.009) than in the Hypo-group. Pre-131I TSAb levels were higher in the Hyper-group vs. the Hypo-group (P = 0.01) or the Eu-group (P = 0.03). A significant post-131I increase in TSAb levels occurred in 66% of patients developing hypothyroidism but not in those remaining hyperthyroid. After 131I, TSHBAb appeared in 7 patients, in all but one associated with high levels of TSAb. One year after radioiodine: 1) the mean percent reduction in thyroid volume was greater in the Hypo-group (80.7%) or the Eu-group (83.5%) than in the Hyper-group (35.7%) (P = 0.007 and 0.0033 respectively); 2) hypothyroid patients had smaller (P = 0.0058) post-131I thyroids than hyperthyroid patients; and 3) TSAb were still elevated in 75% hypothyroid patients, but all of them had a thyroid volume < or = 8 mL, indicating major postradioiodine gland damage. IN CONCLUSION: 1) the early outcome of thyroid function after 131I for GD is mainly related to pretreatment thyroid volume and to the degree of its reduction after therapy; 2) high TSAb levels before 131I are associated with a relative resistance to therapy; 3) a postradioiodine increase in TSAb levels is related to the development of hypothyroidism; and 4) the concomitant appearance of TSHBAb and disappearance of TSAb are not frequent after 131I and play a role in the development of early postradioiodine hypothyroidism only in a minority of patients.
Adult↗