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Biomedical subjects

Paolo Rossi

Publications and source records attributed to Paolo Rossi.

At least 19 recordsLinked to original sources
PubMed2007

Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity.

Natural killer (NK) cells are a major component of the host innate immune defence against various pathogens. Several viruses, including Human immunodeficiency virus 1 (HIV-1), have developed strategies to evade the NK-cell response. This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG2D, an activating receptor expressed by all NK cells. Results show that the HIV-1 Nef protein downmodulates cell-surface expression of MICA, ULBP1 and ULBP2, with a stronger effect on the latter molecule. The activity on MICA and ULBP2 is well conserved in Nef protein variants derived from HIV-1-infected patients. In HIV-1-infected cells, cell-surface expression of NKG2D ligands increased to a higher extent with a Nef-deficient virus compared with wild-type virus. Mutational analysis of Nef showed that NKG2D ligand downmodulation has structural requirements that differ from those of other reported Nef activities, including HLA-I downmodulation. Finally, data demonstrate that Nef expression has functional consequences on NK-cell recognition, causing a decreased susceptibility to NK cell-mediated lysis. These findings provide a novel insight into the mechanisms evolved by HIV-1 to escape from the NK-cell response.

Cell Line↗
PubMed2006

Interleukin-4 inhibits cyclo-oxygenase-2 expression and prostaglandin E production by human mature dendritic cells.

Interleukin-4 (IL-4) is considered the key cytokine for inducing T helper type 2 (Th2) cell differentiation, while interferon-gamma and IL-12 are pivotal cytokines for Th1 immune responses. Paradoxically, IL-4 has also been demonstrated to enhance IL-12 production by dendritic cells, suggesting an IL-4-dependent regulatory feedback of the Th1/Th2 system. In addition, prostaglandin E(2) (PGE(2)), a lipid mediator of inflammation, has been implicated in the enhancement of Th2-type responses acting directly on T and B lymphocytes. PGE(2) synthesis is dependent on the serial engagement of various enzymes, among which the inducible cyclo-oxygenase-2 (COX-2) exerts a critical role in monocytes and dendritic cells. In this study we demonstrate that IL-4 inhibits COX-2 gene expression and consequently prevents secretion of PGE(2) by mature human dendritic cells. We also show that PGE(2) does not regulate IL-12 and IL-10 production by dendritic cells in an autocrine fashion. Hence, we suggest that IL-4 may exploit an IL-12-independent regulatory feedback of the Th1/Th2 system through PGE(2) inhibition.

Cells, Cultured↗
PubMed2006

Switching from protease inhibitor-based-HAART to a protease inhibitor-sparing regimen is associated with improved specific HIV-immune responses in HIV-infected children.

To evaluate the effects of switching from successful long-term protease inhibitor (PI)-based HAART to a three nucleoside reverse transcriptase inhibitor PI-sparing regimen, viral load quantification, HIV-specific lymphoproliferative assay and T-cell receptor (TCR) spectratyping were performed during 96 weeks of simplification follow-up in 19 HIV-infected children. Our data showed that simplification of therapeutic strategies acts positively on immune competence in HIV paediatric patients. Our children maintained viral suppression, increased lymphoproliferative responses and normalized TCRBV repertoire on the CD8 subset.

Adolescent↗
PubMed2006

Co-localization of susceptibility loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human chromosome 1q21.

Psoriasis (PS) is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and altered differentiation. Atopic dermatitis (ATOD) is a chronic inflammatory, pruritic and eczematous disease frequently associated with respiratory atopy. These diseases are associated with distinct immunologic abnormalities and represent typical examples of complex diseases triggered by both genetic and environmental factors, as demonstrated by independent twin studies. Genome wide linkage studies have mapped susceptibility loci on several chromosomes (PSORS1-9; ATOD1-5). Four of them overlap on chromosomes 1q21, 3q21, 17q25 and 20p although ATOD is quite distinct from PS and these two diseases rarely occur together in the same patient. An association fine-mapping study has been performed to refine PSORS4 and ATOD2 susceptibility loci on chromosome 1q21 analyzing two independently collected cohorts of 128 PS and 120 ATOD trios. Genotype and haplotype analysis of PSORS4 and ATOD2 led us to detect significant p value for haplotypes defined by MIDDLE and ENDAL16 markers in both PS (p = 0.0000036) and ATOD (p = 0.0276), suggesting a strict co-localization within an interval of 42 kb. This genomic interval contains a single gene, LOR, encoding for loricrin. Polymorphic markers mapping in regulatory and coding regions did not show evidence of association in neither of the two diseases. However, expression profiles of LOR in skin biopsies have shown reduced levels in PS and increased levels in ATOD, suggesting the existence of a specific misregulation in LOR mRNA production.

Chromosome Mapping↗
PubMed2006

Can individual repair kinetics of UVC-induced DNA damage in human lymphocytes be assessed through the comet assay?

The suitability of the comet assay for quantifying DNA repair capacity at individual level was studied following the kinetics of nucleotide excision repair (NER) in human lymphocytes from four healthy donors, at various time steps after a single dose of UVC. A significant increase of DNA migration was seen as soon as 20 min after UV exposure, reaching the peak within 60-90 min. Afterwards, a rapid decline was observed, approaching the basal level at 180-240 min. The increase could be ascribed to excision activity, while the reduction to gap filling and rejoining, as demonstrated by the effects of phase-specific inhibitors, novobiocin and aphidicolin. Therefore, the comet assay should allow following the biphasic kinetics of NER. Wide inter-individual differences were observed, although repeated tests on the same donor cells revealed a large experimental variation. To quantitatively compare the individual patterns, a mathematical model was developed that adequately fitted the experimental results and estimated appropriate descriptors for each phase and for each donor. A second approach was also used to directly compare the distributions of damaged cells and to assess the differences between donors and between experiments visualizing them as reciprocal distances on a two-dimensional space computed with a principal component analysis (PCA). The results confirmed the inter-individual differences, but also the strong influence of experimental factors of the comet assay. The two approaches provided the means of accurately comparing DNA repair kinetics at individual level, taking also into account the experimental variability which poses serious doubts on the suitability of the comet assay. Nevertheless, since this methodology allows a detailed analysis of repair kinetics and it is potentially very useful for identifying individual with reduced repair capacity, further efforts have to be addressed to improve the reproducibility of the comet assay.

Adult↗
PubMed2006

Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency.

Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor kappaB essential modulator (NEMO)/IkappaB kinase complex and a hypermorphic mutation in inhibitor alpha of nuclear factor kappaB (IkappaBalpha) both result in impaired nuclear factor kappaB activation and are associated with X-recessive and autosomal-dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploidentical T-cell-depleted bone marrow after myeloablative conditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical outcome is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and persisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ectodermal dysplasia with immunodeficiency. Hematopoietic stem cell transplantation is well tolerated and efficiently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency.

Chimerism↗
PubMed2006

Humeral head impression fracture in acute posterior shoulder dislocation: new surgical technique.

Posterior shoulder dislocation with humeral head impression fracture is rare and its early diagnosis and treatment remain a challenge for the orthopaedic surgeon. Although literature describes several surgical options, most are based on the detachment of the subscapularis or on more complex techniques that change the humeral joint anatomy even more. This report describes a new operative technique that is only slightly invasive, where the depressed chondral surface is raised to regain a normal articular contour. The chondral surface is supported by an interference biabsorbable screw and the insertion of the subscapularis tendon is left intact. Two male patients with an acute shoulder posterior dislocation associated with anteromedial impression fracture of about 40 and 50%, respectively, of the articular humeral shape were treated in our department. The average follow-up was 26 months where plain X-ray and CT scan showed an anatomical humeral surface free from signs of arthritis or necrosis. Functional results were excellent in both cases. This new technique is easy, less invasive than others and ensures a stable cartilage and subchondral support without the use of grafts.

Absorbable Implants↗
PubMed2006

Analysis of implantable cardioverter defibrillator signals for non conventional cardiac electrical activity characterization.

Implantable cardioverter defibrillators (ICDs) can store intracardiac electrograms (EGMs) in sinus rhythm (SR), at the onset of spontaneous ventricular tachyarrhythmias (VT) or during their course. This allows the investigation of unknown features of the heart electrical activity associated with different cardiac rhythms. In this study we propose a non conventional cardiac electrical activity characterization (CEAC) that extracts quantitative information about the power spectrum wideness and variability of the beat-by-beat morphology. We analyze 293 EGMs from 40 patients who underwent implantation of St Jude Medical-Ventritex ICDs that allow the storage of EGMs with two different modes of recording: bipolar (BIP) and unipolar or far-field (FF). The EGMs are studied with this CEAC by (1) exploring differences between the CEAC measured from FF and BIP EGMs during similar cardiac rhythms, and (2) investigating the mode of recording that allows a better separation between SR and VT rhythms. Results show that, with similar cardiac rhythm, the CEACs from FF or BIP recordings are different (for SR rhythm: sensitivity 81.5%, specificity 93.6%; for VT rhythm: sensitivity and specificity 100%); thus FF and BIP EGMs analyze different aspects of cardiac activity. The CEAC applied to FF EGMs distinguishes better EGMs obtained during SR from VT rhythms (VT vs SR with sensitivity 92.7% and specificity 79.7%) than when it is applied to BIP signals (VT vs SR with sensitivity 60% and specificity 73.3%).

Defibrillators, Implantable↗
PubMed2006

A novel form of non-X-linked hyperigm associated with growth and pubertal disturbances and with lymphoma development.

HyperIgM syndrome is a heterogenous immunodeficiency characterized by impaired class-switch recombination due to different molecular abnormalities. We report on two female patients affected by a novel syndrome associating HIGM, growth and pubertal disturbances, and severe lymphoid hyperplasia with eventual development into lymphomas, suggesting a DNA repair defect.

Adolescent↗
PubMed2006

Electromagnetic fields: principles of exposure mitigation.

Basic principles of reducing exposure to electromagnetic fields are reviewed in this article. Measures to reduce exposure can be divided into organisational/administrative and technical/engineering actions. Both strategies are briefly analysed and the basic principles of the theory of shielding are presented. A definition of shielding effectiveness (SE) is given, and the results from the general Transmission Lines Theory are presented. Practical situations of shielding static and time-varying electric and magnetic fields are discussed on the basis of the physical properties of the fields and of the shield.

Electric Conductivity↗
PubMed2006

Rapid T-cell receptor CD4+ repertoire reconstitution and immune recovery in unrelated umbilical cord blood transplanted pediatric leukemia patients.

Umbilical cord blood transplantation has been successfully employed for treatment of many immune and hematologic disorders. The aim of this study was to evaluate the quality of immune reconstitution after umbilical cord blood transplantation in 6 leukemia children. T-cell receptor Vbeta third complementary region spectratyping was used for monitoring the contribution of the thymic pathway in patients' immune reconstitution. Absolute numbers of lymphocyte subsets (T, B, and natural killer), and lymphoproliferative in vitro response to mitogens, recovered within 12 months after transplantation. Furthermore, an overall diversification of T-cell receptor complexity in the repopulating T cells, with a polyclonal Gaussian profiles in most (74%) of total families was observed. Noteworthy, we showed a wider and more rapid reconstitution of T-cell receptor CD4+ T cell families compared with T-cell receptor CD8+ T ones still exhibiting some perturbations at 24 months. These data show that umbilical cord blood transplantation allows immune reconstitution already within 12 months with generation of newly diversified CD4+ T lymphocyte subsets.

Adolescent↗
PubMed2006

The Pro78 residue regulates the capacity of the human immunodeficiency virus type 1 Nef protein to inhibit recycling of major histocompatibility complex class I molecules in an SH3-independent manner.

The Nef protein is a crucial pathogenicity factor of human immunodeficiency virus type 1 (HIV-1) that contains a proline-rich motif consisting of four conserved prolines: Pro69 (P69), P72, P75 and P78. P72 and P75 were shown to bind Src homology domains 3 (SH3) and have been implicated in many biological functions of Nef, including downmodulation of cell-surface major histocompatibility complex class I (MHC-I). P78 is involved together with P69 in positioning of the Nef-SH3 complex and it has been shown to be essential for Nef activity of MHC-I downmodulation. It is shown here that alteration of P78 affects recycling of MHC-I molecules to the cell surface, but does not interfere with SH3 binding. In addition, it is demonstrated that P72 and P75, and thus the SH3-binding capacity, are fully dispensable for Nef activity on MHC-I.

Amino Acid Substitution↗
PubMed2006

Use of complementary and alternative medicine by patients with chronic tension-type headache: results of a headache clinic survey.

OBJECTIVES: This study was undertaken to evaluate the rates, pattern, and presence of predictors of complementary and alternative medicine use in a clinical population of patients with chronic tension-type headache. BACKGROUND: The use of complementary and alternative medicine in the treatment of headaches is a growing phenomenon about which little is known. METHODS: A total of 110 chronic tension-type headache patients attending a headache clinic participated in a physician-administered structured interview designed to gather information on complementary and alternative medicine use. RESULTS: Past use of complementary and alternative therapies was reported by 40% of the patients surveyed (22.7% in the previous year). Chronic tension-type headache patients prefer complementary and alternative practitioner-administered physical treatments to self-treatments, the most frequently used being chiropractic (21.9%), acupuncture (17.8%), and massage (17.8%). Only 41.1% of the patients perceived complementary and alternative therapies to be beneficial. The most common source of recommendation of complementary and alternative medicine was a friend or relative (41.1%). Most of the chronic tension-type headache patients used complementary and alternative treatment as a specific intervention for their headache (77.3%). Almost 60% of complementary and alternative medicine users had not informed their medical doctors of their use of complementary and alternative medicine. The most common reasons given for choosing to use a complementary or alternative therapy was the "potential improvement of headache" it offered (45.4%). The patients who had used more complementary and alternative treatments were found to be those recording a higher lifetime number of visits to conventional medical doctors, those with a comorbid psychiatric disorder, those enjoying a higher (household) income, and those who had never tried a preventive pharmacological treatment. CONCLUSIONS: Our findings suggest that headache-clinic chronic tension-type headache patients, in their need of and quest for care, seek and explore both conventional and complementary and alternative therapies, even if only 41.1% of them perceived complementary treatments as effective. Physicians should be made aware of this patient-driven change in the medical climate in order to prevent misuse of health care resources and to be better equipped to meet patients' care requirements.

Adolescent↗
PubMed2006

Lack of improvement of clinical outcomes by a low-cost, hospital-based heart failure management programme.

OBJECTIVE: Heart failure (HF) is a major health problem resulting in a high financial burden for the healthcare system. Many previous HF management programmes reduced adverse clinical outcomes and costs, but they usually involved several professional figures as well as huge investments, requiring resources and budgets not often available in our healthcare system. We evaluated the effects of our HF management programme, which included patient education and regular outpatient contact with the HF team, on re-hospitalisation and death, optimising the few resources already available at our hospital. METHODS: Two hundred consecutive patients admitted to the internal medicine department with a diagnosis of HF were randomised to the intervention group (nurse-led education programme, facilitated telephone communication and follow-up visits with an internist at 15 days, 1 and 6 months) or to the usual care group (follow-up by their primary care physician). The primary endpoints were all-cause readmissions and all-cause deaths during the 6-month post-discharge period. RESULTS: There were 81 all-cause hospital readmissions in the intervention group and 82 in the control group (P = NS). Fourteen patients (14%) in the intervention group and eight patients (8%) in the control group died during the study period (P = NS). Unplanned outpatient visits were less frequent in the intervention group than in the control group (39 [28%] versus 99 [72%], P < 0.001). CONCLUSIONS: The present low-cost HF management programme reduced unplanned outpatient visits but proved ineffective in reducing subsequent readmissions and in improving clinical status. More intense follow-up monitoring and more resources are needed to achieve better results.

Aged↗
PubMed2005

The lower limb flexion reflex in humans.

The flexion or flexor reflex (FR) recorded in the lower limbs in humans (LLFR) is a widely investigated neurophysiological tool. It is a polysynaptic and multisegmental spinal response that produces a withdrawal of the stimulated limb and resembles (having several features in common) the hind-paw FR in animals. The FR, in both animals and humans, is mediated by a complex circuitry modulated at spinal and supraspinal level. At rest, the LLFR (usually obtained by stimulating the sural/tibial nerve and by recording from the biceps femoris/tibial anterior muscle) appears as a double burst composed of an early, inconstantly present component, called the RII reflex, and a late, larger and stable component, called the RIII reflex. Numerous studies have shown that the afferents mediating the RII reflex are conveyed by large-diameter, low-threshold, non-nociceptive A-beta fibers, and those mediating the RIII reflex by small-diameter, high-threshold nociceptive A-delta fibers. However, several afferents, including nociceptive and non-nociceptive fibers from skin and muscles, have been found to contribute to LLFR activation. Since the threshold of the RIII reflex has been shown to correspond to the pain threshold and the size of the reflex to be related to the level of pain perception, it has been suggested that the RIII reflex might constitute a useful tool to investigate pain processing at spinal and supraspinal level, pharmacological modulation and pathological pain conditions. As stated in EFNS guidelines, the RIII reflex is the most widely used of all the nociceptive reflexes, and appears to be the most reliable in the assessment of treatment efficacy. However, the RIII reflex use in the clinical evaluation of neuropathic pain is still limited. In addition to its nocifensive function, the LLFR seems to be linked to posture and locomotion. This may be explained by the fact that its neuronal circuitry, made up of a complex pool of interneurons, is interposed in motor control and, during movements, receives both peripheral afferents (flexion reflex afferents, FRAs) and descending commands, forming a multisensorial feedback mechanism and projecting the output to motoneurons. LLFR excitability, mediated by this complex circuitry, is finely modulated in a state- and phase-dependent manner, rather as we observe in the FR in animal models. Several studies have demonstrated that LLFR excitability may be influenced by numerous physiological conditions (menstrual cycle, stress, attention, sleep and so on) and pathological states (spinal lesions, spasticity, Wallenberg's syndrome, fibromyalgia, headaches and so on). Finally, the LLFR is modulated by several drugs and neurotransmitters. In summary, study of the LLFR in humans has proved to be an interesting functional window onto the spinal and supraspinal mechanisms of pain processing and onto the spinal neural control mechanisms operating during posture and locomotion.

Electric Stimulation↗
PubMed2005

Comparisons of NMR spectral quality and success in crystallization demonstrate that NMR and X-ray crystallography are complementary methods for small protein structure determination.

X-ray crystallography and NMR spectroscopy provide the only sources of experimental data from which protein structures can be analyzed at high or even atomic resolution. The degree to which these methods complement each other as sources of structural knowledge is a matter of debate; it is often proposed that small proteins yielding high quality, readily analyzed NMR spectra are a subset of those that readily yield strongly diffracting crystals. We have examined the correlation between NMR spectral quality and success in structure determination by X-ray crystallography for 159 prokaryotic and eukaryotic proteins, prescreened to avoid proteins providing polydisperse and/or aggregated samples. This study demonstrates that, across this protein sample set, the quality of a protein's [15N-1H]-heteronuclear correlation (HSQC) spectrum recorded under conditions generally suitable for 3D structure determination by NMR, a key predictor of the ability to determine a structure by NMR, is not correlated with successful crystallization and structure determination by X-ray crystallography. These results, together with similar results of an independent study presented in the accompanying paper (Yee, et al., J. Am. Chem. Soc., accompanying paper), demonstrate that X-ray crystallography and NMR often provide complementary sources of structural data and that both methods are required in order to optimize success for as many targets as possible in large-scale structural proteomics efforts.

Animals↗