Biomedical subjects

Domenico Gambi

Publications and source records attributed to Domenico Gambi.

12 recordsLinked to original sources

PubMed2007

Cleavage of cystatin C is not associated with multiple sclerosis.

Recently, Irani and colleagues proposed a C-terminal cleaved isoform cystatin C (12.5 kDa) in cerebrospinal fluid as a marker of multiple sclerosis. In this study, we demonstrate that the 12.5 kDa product of cystatin C is formed by degradation of the first eight N-terminal residues. Moreover, such a degradation is not specific in the cerebrospinal fluid of multiple sclerosis, but rather is given by an inappropriate sample storage at -20 degrees C. We conclude that the use of the 12.5 kDa product of cystatin C in cerebrospinal fluid might lead to a fallacious diagnosis of multiple sclerosis. Preanalytical validation procedure is mandatory for proteomics investigations.

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PubMed2006

The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer's disease patients.

The increased pro-inflammatory cytokine production was previously observed in Alzheimer's disease (AD). We sought to explore whether acetylcholinesterase inhibitor (AChEI) therapy ameliorates clinical symptoms in AD through down-regulation of inflammation. Expression and release of monocyte chemotactic protein-1 (MCP-1), a positive regulator of Th2 differentiation, and interleukin (IL)-4, an anti-inflammatory cytokine from peripheral blood mononuclear cells (PBMC) in AD patients, were investigated. PBMC were purified from AD patients at time of enrollment (T0) and after 1 month of treatment with AChEI (T1) and from healthy controls (HC). Supernatants were analyzed for cytokine levels by ELISA methods. mRNA expression were determined by RT-PCR. Expression and production of MCP-1 and IL-4 were significantly increased in AD subjects under therapy with the AChEI Donepezil, compared to the same AD patients at time of enrollment (P < 0.001). Our data suggest another possible explanation for the ability of Donepezil [diethyl(3,5-di-ter-butyl-4-hydroxybenzyl)phosphonate] to delay the progression of AD; in fact, Donepezil may modulate MCP-1 and IL-4 production, which may reflect a general shift towards type Th0/Th2 cytokines which could be protective in AD disease. The different amounts of MCP-1 and IL-4 observed might reflect the different states of activation and/or responsiveness of PBMC, that in AD patients could be kept in an activated state by pro-inflammatory cytokines.

Aged↗

PubMed2006

Differential post-translational modifications of transthyretin in Alzheimer's disease: a study of the cerebral spinal fluid.

Transthyretin (TTR) is a 55 kDa homotetrameric protein. TTR in the cerebral spinal fluid (CSF) is primarily synthesized by the choroid plexus. TTR can bind to the beta-amyloid peptide and a number of familial amyloidosis diseases (familial amyloid polyneuropathy) have been associated with its allele variants. In a transgenic mice model overexpression of TTR was positively correlated with a neuroprotective effect from the pathogenic APPsw mutation. TTR has a free reactive sulphydryl moiety located on the Cys(10) residue which has been implicated to undergo a variety of oxidation reactions. To examine the neuroprotective role of TTR, we investigated the conjugated forms of TTR with cysteine (Cys) and cysteinglycine (CsyGly) in the CSF of 39 probable Alzheimer's disease (AD)-affected subjects and in a cohort of subjects without cognitive impairment (27 subjects). Linear MALDI-TOF MS experiments were employed to obtain high-resolution protein profiling of TTR isoforms. Nano-LC-TANDEM MS combined with reflectron MALDI-TOF-MS was used to unequivocally assign the investigated TTR-conjugate signals. Our results indicate a differential distribution of TTR-Cys and TTR-CysGly adducts. Both oxidized forms of TTR are significantly less abundant in the AD group (p = 0.0001). The investigated population (66 subjects) was then diagnosed using the ratio of conjugated TTR to free TTR in each subject. A sensitivity >90% and a specificity >70% were derived from a receiver operating characteristic curve when the overall cohort is analysed by the TTR-Cys signals. This manuscript is the first report describing the presence of differential post-translational oxidations of TTR in the CSF of AD patients.

Adult↗

PubMed2005

Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer's disease patients.

Many factors are involved in the pathogenesis of Alzheimer's disease (AD), and inflammatory-immunologic activation seems to play a major role. One strategy for treatment of AD has been to use acetylcholinesterase (AChE) inhibitors to increase the levels of acetylcholine and enhancing cholinergic activity in the affected regions of the brain. Cholinergic compounds modulate the immune system, therefore secretion, by peripheral blood mononuclear cells (PBMC), of cytokines was investigated in age-matched controls and in AD patients. Cytokines released by PBMC from AD patients enrolled as pre-treatment patients (T0) and as post-treatment with AchEI (T1), were detected by ELISA assay. The result showed an increase in oncostatin M, interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) secretion in AD patients compared to healthy controls, and a decrease of cytokine levels in each AD patients treated for 1 month with an acetylcholinesterase inhibitor (AchEI). In conclusion, the results of this study show that the complex pathology in AD may be reflected in a pattern of altered cytokine secretion from PBMC.

Aged↗

PubMed2005

Expression and production of two selected beta-chemokines in peripheral blood mononuclear cells from patients with Alzheimer's disease.

MCP-1 and RANTES are molecules that regulate monocyte and T-lymphocyte recruitment towards sites of inflammation. We sought to evaluate the role of these chemokines in Alzheimer's disease (AD), and the effect of acetylcholinesterase inhibitor (AchEI) therapy on their release from peripheral blood mononuclear cells (PBMC). MCP-1 and RANTES mRNA expressions were determined by RT-PCR and the amount of secreted chemokines was assayed using specific ELISA methods from purified PBMC from each AD patients (n = 40) at the time of enrolment (T0) and after 1 month of treatment with AchEI (T1) and from 20 healthy age and sex-matched subjects (HC). We found that expression and production of MCP-1 in AD patients was significantly lower than in HC subjects. After 1 month of therapy with AchEI (Donepezil), MCP-1 levels increased in each patient. However, higher levels were detected for RANTES in AD patients compared to control subjects and in AD patients treated with Donepezil. MCP-1 and RANTES have a compensatory role in balancing the impaired mechanisms involved in immune response during ageing. Our present findings suggest that these two chemokines are both involved in AD pathogenesis and might reflect different states of activation and/or responsiveness of PBMC from AD patients, contributing to the impaired of the peripheral immune system in these patients.

Aged↗

PubMed2004

Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.

We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.

Adult↗

PubMed2004

IL-4 in vitro production is upregulated in Alzheimer's disease patients treated with acetylcholinesterase inhibitors.

Cytokines appear to be involved in the pathogenesis of Alzheimer's Disease (AD). Their modulation by treatment has been investigated only in a few studies. The aim of our study was to evaluate the effect of acetylcholinesterase inhibitors (AChEI) on Interleukin-4 (IL-4) production in AD patients. IL-4 levels were measured by ELISA on peripheral blood mononuclear cell cultures in the presence or absence of Concanavalin A or Phytohaemagglutinin. Linear regression analysis shows that patients who have been treated, have higher levels of IL-4 independently from age, gender and comorbidity. The increased production of IL-4 in AChEI treated patients might represent an additional mechanism through which AChEI act on AD progression.

Aged↗

PubMed2004

Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines.

Elevated levels of cytokines have been detected in brains of Alzheimer's disease (AD) patients, and altered peripheral levels of IL-1beta, TNFalpha and IL-6 have been reported in these patients. We studied the ability of PBMC from patients with AD, matched with a control group, to release pro- and anti-inflammatory cytokines, and the effect of AChEI treatment on cytokine release. Our data indicates that AChEI treatment down-regulates IL-1, IL-6 and TNF, and up-regulates the expression and production of IL-4 in PBMC in AD patients, and that AChEI leads to the remodelling of the cytokine network, probably acting on the lymphocytic cholinergic system.

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PubMed2004

Alzheimer patients treated with an AchE inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells.

The study evaluates the expression and production of cytokines in peripheral blood mononuclear cells of patients with Alzheimer disease treated or not treated with acetylcholinesterase inhibitor, which enhances neuronal transmission. Cytokines associated with brain inflammation such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha have been implicated in the regulation of amyloid peptide protein synthesis. The anti-inflammatory cytokine, IL-4, may suppress the activity of IL-1beta. Patients were assessed for clinical and immunologic features at baseline and after 1 month of treatment with Donepezil, an acetylcholinesterase inhibitor. Peripheral blood mononuclear cells were cultured with and without phytohemagglutinin stimulation. IL-1beta and IL-4 levels were measured by enzyme-linked immunosorbent assay. Reverse transcriptase-polymerase chain reaction was used to determine the expression of cytokines in peripheral mononuclear cells. Compared with untreated patients and healthy control subjects, IL-1beta levels and expression decreased in Alzheimer disease patients treated with Donepezil (P < 0.001). In contrast, IL-4 levels and expression were significantly higher in Alzheimer patients treated with the acetylcholinesterase inhibitor. This increment was observed in both unstimulated and phytohemagglutinin-stimulated peripheral blood mononuclear cells.

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PubMed2002

Interferon beta-1b modulates MCP-1 expression and production in relapsing-remitting multiple sclerosis.

Monocyte chemoattractant protein-1 (MCP-1) seems to be involved in the pathogenesis of multiple sclerosis (MS). We found that in unstimulated (PHA(-)) and PHA-stimulated (PHA(+)) peripheral blood mononuclear cells (PBMC), MCP-1 and TNFalpha levels are higher in stable untreated MS patients. Interferon gamma (IFNgamma) is higher in relapsing patients in PHA(-) cultures and in stable patients in PHA(+) cultures. Chronic IFNbeta-1b treatment down-regulates TNFalpha, IFNgamma and MCP-1 production except for TNFalpha in relapsing patients. IFNbeta-1b, in vitro, increases MCP-1, TNFalpha and IFNgamma spontaneous production in all patients. Multivariate analysis suggests that MCP-1 production is dependent from clinical status and not from TNFalpha and IFNgamma production. Logistic regression analysis shows that MCP-1 production is significantly modified by treatment. Further studies are needed to clarify the role of MCP-1 in MS.

Adult↗

PubMed1998

Interferon beta normalizes suppressor cell function in dysimmune neuropathies.

We found a defective suppressor cell function in vitro both in idiopathic chronic inflammatory demyelinating polyneuropathy and in paraproteinemic neuropathy with antibodies to sulfated glucuronyl paragloboside. In the presence of interferon beta, suppressor cell function was normalized. Our results suggest that a decreased suppressor cell function plays a pathogenetic role in dysimmune neuropathies. Interferon beta might represent an adjunctive therapy in CIDP both acting on a defective blood-nerve barrier and normalizing an otherwise defective suppressor cell function.

Adolescent↗

PubMedDate not supplied

Drug-induced cutaneous lupus erythematosus after 5 years of treatment with carbamazepine.

Drug-induced lupus is a disease, inducible by several drugs, that shares symptoms and laboratory characteristics with idiopathic lupus erythematosus. We report a case of carbamazepine-induced cutaneous lupus erythematosus which developed after 5 years of treatment in a patient who was on this medication because of an epileptic crisis after cranial trauma. Carbamazepine is a medication rarely implicated in drug-induced cutaneous lupus, moreover there are very few reports of such long periods between the start of therapy and the presentation of the clinical symptoms. We describe this case to emphasize the possibility of cutaneous lupus induction by carbamazepine even after many years of therapy.

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