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Biomedical subjects

M Altieri

Publications and source records attributed to M Altieri.

At least 19 recordsLinked to original sources
PubMed2000

In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes.

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8(+)/mII(-)). They did not develop insulitis or spontaneous diabetes. However, when DQ8(+)/mII(-) mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on beta cells (which normally do not develop diabetes), 81% of the DQ8(+)/mII(-)/B7-1(+) mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4(+) and CD8(+)) and B cells. T cells from the diabetic mice secreted large amounts of interferon gamma, but not interleukin 4, in response to DQ8(+) islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8(+)/mII(-)/B7-1(+) mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic beta cells (DQ6(+)/mII(-)/B7-1(+)) developed diabetes. Only 7% of DQ(-)/mII(-)/B7-1(+) mice developed diabetes at an older age, and none of the DQ(-)/mII(+)/B7-1(+) mice or DQ8(+)/mII(+)/B7-1(+) mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non-diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique "humanized" animal model of spontaneous diabetes.

Animals↗
PubMed1999

Multiple brain infarcts: clinical and neuroimaging patterns using diffusion-weighted magnetic resonance.

The capability of diffusion-weighted (DW) magnetic resonance imaging (MRI) to identify very early ischemic brain injury better than conventional MRI is well known. This technique, which successfully discriminates acute from old infarcts, is particularly useful in patients with multiple brain infarcts (MBI). Among 142 patients with acute stroke consecutively admitted to our primary care center, we selected 43 patients with two or more brain infarcts on conventional MRI. All patients presented with clinical deficits consistent with acute cerebral ischemia and underwent conventional spin echo for T(1) (T1-WI) and T(2)-weighted images (T2-WI), T(1)-W gadolinium-enhanced images, and echo-planar technique for DW MRI sequences. Patients underwent DW MRI examinations within 15 days of stroke onset (mean +/- SD: 3 +/- 3 days). In all but 1 case, the infarcts detected on DW MRI were also visible on T2-WI. The different signal pattern on DW MRI, compared with T2-WI, facilitated the detection of acute infarcts in all patients. T1-WI with gadolinium enhancement was only helpful in 5 (11.6%) patients. DW MRI enabled precise clinicotopographic correlations in 79% of our patients and provided additional clinically relevant findings in 72% of the patients. Based on the neuroradiological findings, patients were divided into three clinicotopographic types of MBI as follows: 13 patients (30.2%) presented with multiple acute infarcts, 24 patients (55.8%) with a single acute infarct and multiple old infarcts, and 6 patients (13.9%) with multiple acute and old infarcts. In conclusion, DW MRI can easily be added to conventional MRI in order to be able to distinguish acute from old infarcts, and to identify acute multiple lesions. Therefore, a better correlation between clinical symptoms and the site of lesions can be obtained, considerably improving patient care.

Adolescent↗
PubMed1998

Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.

Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.

Animals↗
PubMed1998

GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice.

Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.

Adoptive Transfer↗
PubMed1998

Large-scale identification of virulence genes from Streptococcus pneumoniae.

Streptococcus pneumoniae is the major cause of bacterial pneumonia, and it is also responsible for otitis media and meningitis in children. Apart from the capsule, the virulence factors of this pathogen are not completely understood. Recent technical advances in the field of bacterial pathogenesis (in vivo expression technology and signature-tagged mutagenesis [STM]) have allowed a large-scale identification of virulence genes. We have adapted to S. pneumoniae the STM technique, originally used for the discovery of Salmonella genes involved in pathogenicity. A library of pneumococcal chromosomal fragments (400 to 600 bp) was constructed in a suicide plasmid vector carrying unique DNA sequence tags and a chloramphenicol resistance marker. The recent clinical isolate G54 was transformed with this library. Chloramphenicol-resistant mutants were obtained by homologous recombination, resulting in genes inactivated by insertion of the suicide vector carrying a unique tag. In a mouse pneumonia model, 1.250 candidate clones were screened; 200 of these were not recovered from the lungs were therefore considered virulence-attenuated mutants. The regions flanking the chloramphenicol gene of the attenuated mutants were amplified by inverse PCR and sequenced. The sequence analysis showed that the 200 mutants had insertions in 126 different genes that could be grouped in six classes: (i) known pneumococcal virulence genes; (ii) genes involved in metabolic pathways; (iii) genes encoding proteases; (iv) genes coding for ATP binding cassette transporters; (v) genes encoding proteins involved in DNA recombination/repair; and (vi) DNA sequences that showed similarity to hypothetical genes with unknown function. To evaluate the virulence attenuation for each mutant, all 126 clones were individually analyzed in a mouse septicemia model. Not all mutants selected in the pneumonia model were confirmed in septicemia, thus indicating the existence of virulence factors specific for pneumonia.

Animals↗
PubMed1998

RA/DA cumulative curve analysis of local and diffuse neuroretinal rim area damage in glaucoma patients.

AIM: To evaluate the validity of cumulative rim/disc area (RA/DA) curve analysis as a clinical tool for the identification of glaucoma induced optic disc pathology. METHODS: 71 normal and 83 glaucomatous eyes were evaluated from a series of 154 subjects recruited for this study. For each eye, the cumulative distribution of RA/DA was calculated from 36 equally spaced rim sectors of each optic disc obtained by the automatic evaluation of simultaneous videographics (Image-net X Rev.3/51b). To increase the sensitivity of this analysis in early glaucoma and in normal eyes, these cumulative curves were subsequently divided into two equal segments and the slopes of their respective regression lines compared. RESULTS: The median RA/DA value obtained from the 36 sectors was significantly different in glaucomatous eyes compared with normals (p < 0.001). Nevertheless, the curves (5th-95th percentile of the cumulative curves distribution) of early glaucomatous eyes fell within the normal range. When the cumulative curve of these marginal cases was then divided into two equal segments, the comparison of the slopes of the regression lines showed a significant difference (p < 0.05) in 100% of early glaucomatous eyes. Furthermore, normal eyes were shown to be true negatives in 93% of the cases in which no significant difference between the two slopes was observed. CONCLUSION: Analysis of the RA/DA cumulative curve from 36 sectors of the optic disc was a valid method for the identification of glaucomatous disc pathology; however, a further calculation of the slopes of the two RA/DA regression lines was needed to identify early glaucomatous damage.

Female↗
PubMed1997

[Brain dysfunction in climacteric and prevention].

The risk of cardiovascular disease in women is relatively small before menopause but increases considerably afterwards. Postmenopausal women have on average a total cholesterol, LDL and VLDL cholesterol levels higher than premenopausal women; at the same time, HDL cholesterol serum level is lower. Postmenopausal estrogen replacement therapy (ERT) has been repeatedly proven to reduce the incidence of coronary heart disease as well as the mortality from cardiovascular disease. Furthermore, little is known about the potential risk of developing a stroke associated to hormonal changes involved in the menopause. Likewise the benefit of the ERT on reduction in stroke-legated mortality and morbidity is still debated. On the other hand, preliminary trials suggest a beneficial role of ERT in women with Alzheimer's disease (AD), probably due to the estrogen's cholinergic neurotrophic and neuroprotective effects. Moreover, recent reports suggest a possible additive beneficial effect of ERT to cholinergic treatments for AD In normal postmenopausal women the ERT not only improve cognitive and emotional functions but also increase verbal memory.

Aged↗
PubMed1997

Anticipation of onset age in hereditary essential tremor.

The genetic anticipation phenomenon has been described in several neurological disorders, often associated with unstable trinucleotide repeats in the affected genes. The occurrence of this phenomenon in hereditary essential tremor is still debated. We describe a family in which three male members with essential tremor showed a progressive anticipation in onset age and an increased severity of clinical symptomatology.

Adult↗
PubMed1997

Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse.

A cloned Th1 cell line was isolated from pancreatic lymph nodes of NOD mice that carries a T-cell receptor encoding Vbeta14 and proliferates in response to NOD islets, islet supernatant, and crystalline bovine and rat insulin, specifically to a B-chain peptide bound to IA(g7). The response to islet supernatant was reduced by 75% by anti-insulin antibody treatment. The insulin-reactive clone reduced insulitis and totally blocked the development of spontaneous diabetes in NOD mice (n = 8) as well as the adoptive transfer of diabetes into irradiated NOD mice following the injection of splenocytes from diabetic mice (n = 13). Trafficking of the adoptively transferred cells was assessed by labeling the clone or diabetic splenocytes with a fluorescent marker (DiI). The labeled clone was detected in the islet periphery, whereas labeled splenocytes alone invaded the islets by 3 days. In contrast, the protective clone dramatically delayed and reduced the number of labeled diabetic splenocytes infiltrating the islet, although their appearance in the spleen was unaffected. In vitro, the clone as well as supernatant derived from the clone blocked the proliferation of diabetic NOD splenocytes to islets. This inhibitory effect was diminished by anti-transforming growth factor-beta. In conclusion, an insulin-specific Th1 cell was isolated from NOD mice that traffics to the islet and prevents the spontaneous development and the adoptive transfer of diabetes. It appears to act locally by releasing transforming growth factor-beta and/or other factors that inhibit homing to and/or proliferation of diabetic splenocytes within the islet. These findings may provide insights into and suggest mechanisms for the protective effects of insulin therapy against diabetes.

Adoptive Transfer↗
PubMed1997

[An original case of simultaneous cardiac, pancreatic and renal transplantation. Results over 6 years].

Combined transplantation is actually performed on specific and rare indications. We are presenting here the results of a combined heart-kidney and pancreatic graft. It was performed in a patient presenting an idiopathic cardiomyopathy in end-stage failure and a post-diabetic nephropathy on dialysis. Today, organs function is quite satisfactory with a 6 year follow-up. Only one isolated heart rejection episode was observed at the 15th post-operative day. The patient has recovered a full-time professional activity at one year. This successful graft was obtained by an "homogeneous multiorgan approach" during all the pre-peri and postoperative time.

Adult↗
PubMed1996

Longitudinal study of human herpesvirus 6 infection in organ transplant recipients.

Human herpesvirus 6 (HHV-6) has been frequently isolated from immunocompromised patients. To determine if a routine survey of HHV-6 infection is needed after organ transplantation, as is the case for human cytomegalovirus infection, we observed patients who had received kidney, liver, and kidney-liver transplants; these patients were followed up for the first 3 months after transplantation. HHV-6 infection was diagnosed by isolation of the virus and by the results of serological tests. Antibodies to HHV-6 were detected in 28 (87.5%) of the 32 recipients, before the transplant, whereas only 4 (12.5%) of the 32 recipients were seronegative for HHV-6. After engraftment, HHV-6 infection occurred in 10 (31%) of the 32 recipients; infection was diagnosed by isolation of the virus (6 of 32 recipients) or by the results of serological tests (4 of 32 recipients). Regardless of whether they had HHV-6 primary infection or reactivation, severe clinical manifestations were observed only in patients who had concomitant cytomegalovirus infection, and no correlation could be found between graft rejection and HHV-6 infection. These results suggest that HHV-6 infection occurs frequently in organ transplant recipients and that it is usually not associated with severe clinical manifestations unless accompanied by a concomitant CMV infection.

Adult↗
PubMed1992

Rat alpha 1-microglobulin: co-expression in liver with the light chain of inter-alpha-trypsin inhibitor.

A 1162 bp rat liver cDNA clone encoding the immunoregulatory plasma protein alpha 1-microglobulin was isolated and sequenced. The open reading frame encoded a 349 amino acid polyprotein, including alpha 1-microglobulin, 182 amino acids, and bikunin, the light chain of the plasma protein inter-alpha-trypsin inhibitor, 145 amino acids. The alpha 1-microglobulin/bikunin mRNA was found only in the liver when different tissues were examined. Free alpha 1-microglobulin and a polyprotein, containing both alpha 1-microglobulin and inter-alpha-trypsin inhibitor epitopes, were found in the microsomal fraction from rat liver homogenates.

Alpha-Globulins↗
PubMed1991

Patient flow in the emergency department: the chest pain patient.

Prompt treatment of the chest pain patient in the emergency department (ED) is crucial. To ensure prompt treatment, identification of factors that delay flow of these patients through the department is essential. To identify factors that delay patient flow through the ED, the authors conducted a prospective study of all chest pain patients, using a time-flow analysis. Eighty-eight (36%) of 245 patients required critical unit admissions and had an average department stay of 3 1/2 hours. Flow differences were seen between critical and noncritical care patients. Three primary sources of delay were identified: critical unit bed availability, the registration process, and the role of the unit admitting resident. Additional findings confirmed the efficacy and role of the triage nurse in patient flow. Nursing and medical education and staffing needs were addressed. The use of the community's emergency medical services was examined by analyzing the disposition of patients arriving at the ED by ambulance.

Bed Occupancy↗
PubMed1990

TAC topical anesthesia produces positive urine tests for cocaine.

The combination of tetracaine, adrenalin, and cocaine (TAC) has become increasingly popular as a topical anesthetic for the suturing of simple skin lacerations. The purpose of this study was to determine the effects of TAC on a urine drug test for cocaine. On the morning after the use of TAC, 14 of 18 patients (78%) studied had positive screening tests for benzoylecgonine (cocaine metabolite) by the enzyme multiplied immunoassay test (EMIT) method. All specimens also were analyzed by gas chromatography and mass spectrometry, the reference standard for analysis of drugs of abuse in urine, and 15 of the specimens (83%) were positive. Four of 18 positive specimens (22%) still had positive EMIT drug screens on the morning of the next day, an average of 36 hours after use of TAC. We recommend that physicians who use TAC solution as a local anesthetic caution their patients that they may fail a urine drug screen for cocaine if they are tested within 36 to 48 hours of the administration of the use of TAC.

Administration, Topical↗