Dysregulated innate lymphocytes in patients with primary antibody deficiency treated with intravenous immunoglobulin

No disponible

Prevalence of cerebral aneurysms in patients treated for left cardiac myxoma: a prospective study.

AIM: To estimate the prevalence of cerebral aneurysms in patients previously treated for left cardiac myxoma (LCM). MATERIALS AND METHODS: This prospective institutional review board-approved study included patients treated for LCM. All patients treated at our institution (IRCCS Policlinico San Donato, Italy) were telephoned and those enrolled underwent unenhanced brain magnetic resonance imaging (MRI) using sagittal T1-weighted turbo spin-echo (TSE); axial T2-weighted TSE; axial fluid-attenuated inversion-recovery; axial echo-planar diffusion-weighted; and three-dimensional time-of-flight angiographic sequences. RESULTS: Seventy-six patients were telephoned, and data regarding their clinical history since tumor resection were obtained for 49 patients (64%). Four of the 49 (8%) patients were deceased, one due to a cerebral hemorrhage from a ruptured cerebral aneurysm 8 years after tumor resection. One patient had a pacemaker preventing MRI. Of the remaining 44 patients, 31 refused MRI and 13 were enrolled (10 females; mean age 64 years). Three of the 13 (23%; two females; 59-78 years) were diagnosed with a cerebral aneurysm, from 2 mm to 4-5 mm in diameter, involving the right middle cerebral artery (n = 2) or the right internal carotid artery (n = 1). Including the deceased patient, the resulting prevalence was 4/14 (29%). CONCLUSION: From this preliminary study, one-third of patients treated for LCM may present with a cerebral aneurysm. Longitudinal large studies are needed to further clarify this matter.

Positive and negative regulation of cellular immune responses in physiologic conditions and diseases.

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

[Renal tubular transport and genetic hypotension]. / Trasporto renale tubulare e forme genetiche di ipotensione.

The progressive improvement of genetic research technologies has led to the identification of different genes involved in blood pressure regulation. Renal regulation systems of sodium homeostasis play a key role. Mutations capable of determining an increase or a decrease in carrier proteins function could cause not only hypotension or hypertension, but also the related metabolic symptoms and changes, and the possible response to pharmacologic treatment. Monogenic forms of hyper- or hypotension are rare, though they highlight the importance of sodium tubular transport in blood pressure adjustment.

[Genetics and arterial hypertension: monogenic forms]. / Genetica e ipertensione arteriosa: forme monogeniche.

Hypertension is a complex, multifactorial disease; genetic factors represent one third to half of the inter-individual variability of blood pressure values. The study of genes involved in rare forms of monogenic hypertension led to the identification of pivotal pathophysiological pathways of kidney sodium and water reabsorption that can influence blood pressure values when changed. Glucocorticoid-Remediable Aldosteronism (GRA) is characterised by normal to high aldosterone levels, despite plasma renin activity suppression, and by the fact that these alterations are corrected by exogenous glucocorticoid administration. Apparent Mineralocorticoid Excess (AME) is due to a mutation of the gene encoding the renal isoform of 11 â HSD enzyme; the non-conversion of cortisol to cortisone result in increasing cortisol levels that activate the mineralocorticoid receptor. Early onset hypertension exacerbating during pregnancy is caused by a mutation leading to a conformational change in the mineralocorticoid receptor. Therefore, substances that are normally inactive at this level, such as progesterone, become potent agonists of the mutated receptor. Liddle's syndrome (or type I pseudo-hyperaldosteronism (PHA1), is characterised by a constitutive activation of the epithelial sodium channels in the distal tubule, causing an increase in sodium and chloride reabsorption. Gordon syndrome (Type II pseudo-hyperaldosteronism, PHA2) differs from the other forms because of the presence, in addition to hypertension, of hyperkaliemia and hyperchloremic acidosis that can be normalized with thiazide diuretics. Finally, a large pedigree of Turkish origin has been described: these patients are affected by an uncertain form of monogenic hypertension associated with brachydactyly.

Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients.

This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300-400 mg/m2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC(0-12)) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 +/- 0.6 and 1.9 +/- 1.1 microg/mL (P < .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC(0-12) at 6 and 180 days after transplantation was 23.3 +/- 10.8 and 40 +/- 11.6 mg*h/L (P = .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r = 0.8 and 0.79; P < .001). The abbreviated MPA AUC (0-4 hours) correlated reasonably with the full AUC (r = 0.87; P < .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P < .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.

[After the 2001 European Society of Cardiology Guidelines: is it possible to reduce the number of patients with syncope to be hospitalized?]. / Dopo le Linee Guida 2001 della Società Europea di Cardiologia: è possibile ridurre il numero di pazienti con sincope da ospedalizzare?

AIM: The aim of this paper was to evaluate how many patients with syncope should be hospitalized according to the 2001 European Society of Cardiology (ESC) Guidelines on the management of syncope. METHODS: Starting from August 2002 we prompted a Syncope Unit (SU), as a multi-disciplinary functional structure including the Emergency Department. One of the main objectives of the SU was the implementation of the 2001 ESC Guidelines on Syncope and of the relevant criteria for hospitalization. All the clinical data concerning the patients presenting with syncope were prospectively collected and stored in a dedicated database. RESULTS: Between September 1, 2002 and April 30, 2003, 402 patients were observed for a syncope. Out of these, 19 had a cardiogenic syncope, 3 focal neurologic disorders, 25 a severe trauma, 4 severe orthostatic hypotension and 5 carotid syncope. Therefore, 56 patients out of 402 were found to have indication to therapeutical hospitalization. Among the remaining 346 patients, 83 patients were found to have a structural heart disease and/or an abnormal ECG, 1 had syncope during exercise, 3 presented a familial history of sudden death. Thirty-three were found to have severe comorbidities and further 14 had occasional indication to hospitalization. Thus, 190 out of the 402 patients with syncope (47.3%) presented at least 1 criterion for hospitalization according to the ESC Guidelines. CONCLUSION: The implementation of the ESC Guidelines on Syncope is technically feasible. Nevertheless, even when the Guidelines are strictly observed, a high percentage of patients with syncope has still to be hospitalized. Our data suggest that new criteria should be established for a safe Emergency Department discharge of the patients with syncope, particularly of those with structural heart disease or abnormal ECG.

Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase.

Rapamycin, a specific inhibitor of the serine/threonine mTOR kinase, markedly inhibited both cell growth and apoptosis in human B-cell lines. Besides arresting cells in G(1) by increasing p27(kip1), rapamycin tripled the cellular level of the BCL-2 protein. The activity was dose-dependent and specific for the p27(kip1) and BCL-2 proteins. Rapamycin did not affect bcl-2 mRNA although it increased cellular BCL-2 concentration by inhibiting phosphorylation, a mechanism initiating the decay process. To add new insight, we combined rapamycin treatment with treatment by taxol, which, by damaging microtubules, can phosphorylate BCL-2 and activate apoptosis. It was found that the mTOR kinase was activated in cells treated with taxol or with nocodazole although it was inhibited in cells pre-treated with rapamycin. BCL-2 phosphorylation, apoptosis and hyperdiploidy were also inhibited by rapamycin. In contrast, taxol-induced microtubule stabilization or metaphase synchronization were not inhibited by rapamycin. Taken together, these findings indicate that mTOR belongs to the enzymatic cascade that, starting from damaged microtubules, phosphorylates BCL-2. By regulating apoptosis, in addition to the control of a multitude of growth-related pathways, mTOR plays a nodal role in signaling G(1) and G(2)-M events.

Lactobacillus casei pneumonia and sepsis in a patient with AIDS. Case report and review of the literature.

Lactobacilli are ubiquitous gram-positive anaerobic rods present in the normal bacterial flora of the mouth, vagina and gastrointestinal tract. Although they are usually non pathogenic, serious infections have occasionally been described in transplant recipients or severely ill patients. Only 4 cases have been reported involving AIDS: one had predisposing conditions other than AIDS, and none of the others had pure growth of lactobacilli. We report a case of community-acquired Lactobacillus casei pneumonia in a CD4 lymphocyte-depleted AIDS patient. Lactobacillus was isolated in pure growth in repeated blood cultures in an outpatient with no preexisting lung diseases and no known risk factors for Lactobacillus infections (dental procedures, complicated deliveries, gastrointestinal diseases, cardiac prosthetic valves) or consumption of unusual dairy products. Although uncommon, lactobacilli are possible pathogens in HIV-infected patients with very low CD4 counts, and their isolation in clinical specimens must not be neglected. Susceptibility tests are essential because of the variable antibiotic-resistance patterns of these bacteria.

Detection and epitope mapping of immunoreactive human endothelin-1 using ELISA and a surface plasmon resonance-based biosensor.

A surface plasmon resonance-based biosensor (BIA technology) and enzyme-linked immunosorbent assays (ELISA) have been used for detecting and characterizing human endothelin (ET), a potent vasoactive 21 amino acid polypeptide. Antibodies produced against the isoform ET-1 and its C-terminal eptapeptide ET-1(15-21) have been characterized with respect to their binding capacity to the two isoforms ET-1 and ET-3, the non-secreted portion of the precursor molecule Big.ET-1(22-38), the C-terminal of ET-1, six analogues of ET-1(16-21) each containing a substitution with Ala of a single amino acid in positions 16-21, respectively, and three synthetic cyclic peptides mimicking the N-terminal portion of ET-1. Antibodies reacting with ET-1 also bound to ET-1(16-21) and, with less affinity, to ET-3 but did not cross-react with Big.ET-1(22-38). Ala substitution in positions 16, 17 and 19 of ET-1(16-21) hardly affected the antibody binding capacity of ET-1(16-21), whereas Ala substitution of Asp18, Ile20 and, in particular, Trp21, inhibited its immunoreactivity. The C-terminus thus represents an immunodominant epitope in ET-1 and is important for antibody binding. Epitope mapping using as antibody pairs polyclonal anti-ET-1 and monoclonal anti-ET-1(15-21) antibodies indicated the presence of another immunogenic domain in the N-terminal portion of the molecule. There was excellent agreement between the epitopes determined using ELISA and BIA analyses.

[Therapy of tuberculosis today: to prescribe is not enough. A case report]. / La terapia della tubercolosis oggi: prescrivere non è curare. Descrizione di un caso.

Tuberculosis is a re-emerging disease not only in developing but also in industrialized countries. The multidrug resistance of Mycobacterium tuberculosis is an increasing problem, mainly due to the poor compliance of the patients on drug regimens. The authors discuss the case of a 28-year-old male affected by pulmonary tuberculosis who did not improve after a 3-month period of oral tuberculosis treatment. The switch to intravenous therapy was rapidly followed by clinical and microbiological improvement. The patient subsequently admitted that he had not complied with oral treatment because after healing he would be sent back to prison. This case demonstrates that, even in the hospital setting, noncompliance to antitubercular therapy is not unfrequent, as demonstrated by other case reports. The authors discuss a great amount of literature that strongly supports the introduction of directly observed therapy for the treatment of all tuberculosis patients.

Binding of human GM-CSF to synthetic peptides of the alpha subunit of its receptor.

We have synthesized a series of peptides corresponding to portions of the extracellular domain of human granulocyte-macrophage colony stimulating factor receptor alpha subunit (hGM-CSFR alpha). The sequences were chosen according to the homology between hGM-CSFR alpha and the growth hormone receptor (GHR) and correspond to the regions reported to form the binding site of the latter receptor. The peptides were examined for their binding activity to hGM-CSF by affinity chromatography on resin-immobilized hGM-CSF and by a solid phase binding assay. For peptides endowed with hGM-CSF binding activity were identified and the postulated homology between the binding sites of hGM-CSFR alpha GHR was confirmed.

Investigation of newly synthesized peptides by capillary zone electrophoresis/electrospray mass spectrometry.

A series of newly synthesized peptides (M(r) = 1600-2250 Da), corresponding to portions of the extracellular domain of human granulocyte-macrophage colony stimulating factor receptor alpha subunit have been examined by capillary zone electrophoresis/electrospray-mass spectrometry (CZE/ES-MS). The separation efficiency of CZE combined with the specificity of mass spectrometry allowed rapid and reliable identification of the target peptides and a number of associated side products. In solid-phase synthesis of peptides and small proteins such side products are inevitable, therefore the use of CZE and/or high-performance liquid chromatography combined with mass spectrometry is gaining a central role in such synthesis procedures.

Augmentation of the affinity of HLA class I-binding peptides lacking primary anchor residues by manipulation of the secondary anchor residues.

A direct binding assay has been used to investigate the effect of the secondary anchor residues on peptide binding to class I proteins of the major histocompatibility complex. Based on predictions from a previous chemometric approach, synthetic peptide analogues containing unnatural amino acids were synthesized and tested for B*2705 binding. Hydrophobic unnatural amino acids such as alpha-naphthyl- and cyclohexyl-alanine were found to be excellent substituents in the P3 secondary anchor position giving peptides with very high B*2705-binding affinity. The binding to B*2705 of peptides optimized for their secondary anchor residues, but lacking one of the P2 or P9 primary anchor residues was also investigated. Most such peptides did not bind, but one peptide, lacking the P2 Arg residue generally considered essential for binding to all B27 subtypes, was found to bind quite strongly. These findings demonstrate that peptide binding to class I proteins is due to a combination of all the anchor residues, which may be occupied also by unnatural amino acids-a necessary step towards the development of peptidic or non-peptidic antagonists for immunomodulation.

Isolation of Borrelia burgdorferi in Tuscany (Italy).

To evaluate the diffusion of Borrelia burgdorferi in Tuscani (Italy) 720 ticks were collected and subsequently cultured for Borrelia burgdorferi. A strain of Borrelia burgdoferi was isolated from one tick; this being the first such reported identification in Central-Southern Italy.

The importance of secondary anchor residue motifs of HLA class I proteins: a chemometric approach.

In this paper we report a chemometric approach to Quantitative Structure-Activity Relationship (QSAR) analysis applied to a study of the binding of peptides to Major Histocompatibility Complex (MHC) class I proteins. Peptides which possess the known primary anchor residue motif for HLA-B27 binding do not necessarily bind to HLA-B27 proteins. Secondary anchor residues are also involved, but it is not yet clear which amino acids are required or in which positions. A classic approach to this problem would be to synthesize multiple peptides each varying by a single amino acid from a starting peptide, and test them for their binding properties. Not only is this approach inefficient, but it is essentially unable to provide information about possible mutual interactions of amino acid residues in different positions. Using a statistical design to select the most informative compounds to use in the QSAR study, it was possible to analyse the effects on HLA-B27 peptide binding of different amino acids in four positions by means of only nine peptides. The relative binding activity of these peptides could then be modeled mathematically to provide information about the relative contribution of each of the four positions and to suggest a new peptide with high binding affinity. Our results demonstrate the usefulness of the chemometric strategy for studying peptides of interest in molecular immunology.

[Isosporiasis and sarcocystosis. The current findings]. / Isosporiasi e sarcocistosi. Acquisizioni attuali.

A review on infections by Isospora belli and Sarcocystis spp. both in healthy and in AIDS patients is done on the basis of literature and personal data. In this view a special focus is made on isospora belli infection in AIDS because of its high recurrence after successful attack therapy. Consequently the most recent protocols for maintenance and attack therapy in these patients are reported. At the end, concerning ultrastructural pathology, the features of some Isospora belli developing stages are described by means of electron microscopy on duodenal biopsy specimens from a patient.

High-performance liquid chromatographic method with fluorescence detection for the determination of total homocyst(e)ine in plasma.

A high-performance liquid chromatographic method for the determination of total plasma homocyst(e)ine [H(e)] after reduction with sodium tetrahydroborate and precolumn derivatization with o-phthaldialdehyde is described. The analyses, carried out on a reversed-phase C18 column, were based on spectrofluorimetric detection. The sensitivity was 1 pmol per injection and the intra- and inter-assay relative standard deviations were 1.8% and 5%, respectively. The plasma H(e) concentration determined in 40 healthy volunteers (20-60 years old) was 12.4 +/- 2.9 microM (mean +/- S.D.), in good agreement with reference values.