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Biomedical subjects

S Grasso

Publications and source records attributed to S Grasso.

At least 55 records · Page 3Linked to original sources

Liver is not the unique site of synthesis of beta 2-glycoprotein I (apolipoprotein H): evidence for an intestinal localization.

Apolipoprotein H is a protein of about 50 kilodaltons, structurally related to the regulators of the complement activation family. Its physiological function is poorly understood but it has been implicated in lipid metabolism and coagulative pathways. The major site of synthesis is thought to be the liver. Several reports indicate that apolipoprotein H is the antigen of the antiphospholipid antibodies and also behaves as an acute-phase reactant. Moreover, 40% of plasma apolipoprotein H is associated with very low-density lipoprotein, high-density lipoprotein, and postprandial chylomicrons. In this study we investigated other sites of synthesis by reverse transcription/polymerase chain reaction and we found apolipoprotein H mRNA expression in intestinal cell lines and tissues. Immunohistochemistry was performed on various fresh and paraffin-embedded tissues and apolipoprotein H was immunolocalized in the cytoplasm of hepatocytes and epithelial cells from colon and jejunum. This study indicates that apolipoprotein H is expressed at both mRNA and protein levels in enterocytes.

Apolipoproteins↗

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats.

The behavioural and electrocorticographic (ECoG) convulsant effects of several xanthine derivatives injected intraperitoneally (i.p.) were studied in genetically-epilepsy prone rats. The aim of the study was to evaluate the relationship among convulsant potency, molecular structure and lipophilicity of some xanthines. Animals were injected i.p. with various doses (250-1000 micromol/kg) and a different convulsant potency was observed among the various xanthines tested. IBMX (3-isobutyl-1-methylxanthine), theophylline (1,3-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) induced an epileptogenic pattern that consisted in an initial phase characterized by wet-dog shakes followed by head tremor, nodding, clonic convulsion and they appeared to be the most potent xanthines among those studied. During seizures, the electrocortical activity was usually characterized by single or multiple sharp- or spike-wave episodes followed by polyspike discharges. After the highest doses of IBMX, theophylline and caffeine, the animals react with falling down, transient tonic clonic seizures, escape response and generalized seizures followed by post-ictal period. Equimolar doses of 8-chlorotheophylline and theobromine (3,7-dimethylxanthine) produced less evident epileptic responses in comparison to previous compounds, whereas no epileptic signs were observed following the administration of enprofylline (3-propylxanthine), etofylline [7-(2-hydroxyethyl)theophylline], diprophylline [7-(2,3-dihydroxy-propyl)theophylline] and doxofylline [7-(1,3-dioxolan-2-ylmethyl) theophylline]. Lipophylicity of the compounds was determined, but no convincing correlations were found between the rank order of lipophilicities and the convulsant potencies of the compounds studied. On the other hand, structure-activity relationship was also investigated. We suggest that the substitution pattern on the xanthine nucleus may explain, in part, the different convulsant potency of the compounds studied. Furthermore, a selective antagonism of adenosine subtype receptors should be considered.

1-Methyl-3-isobutylxanthine↗

Immunohistochemical identification and comparison of glial cell lineage in foetal, neonatal, adult and neoplastic human adrenal medulla.

The differentiation of glial cells in developing, neonatal, adult and neoplastic human adrenal medulla has studied immunohistochemically. From 8 to 28 weeks' gestational age, S-100 protein and its beta-subunit revealed two different glial cell populations in adrenal glands, namely Schwann-like and sustentacular cells. Schwann-like cells were spindle-shaped cells forming a continuous layer around groups of sympathetic neuroblasts, often in contact with Schwann cells of nerve fibres entering neuroblastic groups. Sustentacular cells were round or oval cells with dendritic cytoplasmic processes; they were not associated with nerve fibres and mingled both with sympathetic neuroblasts and differentiating chromaffin cells. The developmental fate of Schwann-like cells was different from that of sustentacular cells. Schwann-like cells disappeared from the 28th week of gestational age, in association with the disappearance of sympathetic neuroblastic groups, and they were rarely found in neonatal and adult adrenal medulla. In contrast, sustentacular cells persisted between medullary chromaffin cells, and their number and dendritic cytoplasmic processes progressively increased from foetus to adult. In eight cases of primitive adrenal neuroblastic tumours of neonatal age (five undifferentiated neuroblastomas and three ganglioneuroblastomas), Schwann-like cells were found at the periphery of tumoral nests with a lobular growth pattern, while rare sustentacular cells were associated with neuroblasts. In two cases of adult phaeochromocytomas, only sustentacular cells were detected between chromaffin tumoral cells. Our findings suggest that the glial cell types and their distribution in primitive adrenal medulla tumours closely resemble those observed during development in the groups of adrenal sympathetic neuroblasts and in the clusters of chromaffin cells.

Adrenal Gland Neoplasms↗

Protection from concanavalin A (Con A)-induced T cell-dependent hepatic lesions and modulation of cytokine release in mice by sodium fusidate.

The immunomodulatory effects of the antibiotic sodium fusidate (SF) were tested in a model of T cell-dependent hepatic injury that can be induced in normal mice by a single i.v. injection of Con A. Signs of hepatitis with elevated transaminase activities in plasma, severe infiltration of the liver by neutrophil granulocytes, lymphocytes and monocytes, and necrotic areas were observed in control mice treated intraperitoneally with PBS 24 h and 1 h before Con A challenge. T cell- and macrophage-derived cytokines (IL-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha, IL-1beta, IL-6) were released with different kinetics in the circulation of these mice. SF, 20, 40 or 80 mg/kg, administered 24 h and 1 h before Con A challenge, protected the mice against the hepatitic effects of Con A. The protective effects of SF were dose-dependent and accompanied by profound modifications of blood levels of cytokines induced by Con A, so that, relative to control mice, SF (80 mg/kg)-treated animals showed markedly diminished plasma levels of IL-2, IFN-gamma and TNF-alpha, along with augmented levels of IL-6. These results suggest that SF might be useful in the treatment of immunoinflammatory liver diseases in humans.

Animals↗

Effects of proportional assist ventilation on inspiratory muscle effort in patients with chronic obstructive pulmonary disease and acute respiratory failure.

BACKGROUND: Acute respiratory failure may develop in patients with chronic obstructive pulmonary disease because of intrinsic positive end-expiratory pressure (PEEPi) and increased resistive and elastic loads. Proportional assist ventilation is an experimental mode of partial ventilatory support in which the ventilator generates flow to unload the resistive burden (flow assistance: FA) and volume to unload the elastic burden (volume assistance: VA) proportionally to inspiratory muscle effort, and PEEPi can be counterbalanced by application of external PEEP. The authors assessed effects of proportional assist ventilation and optimal ventilatory settings in patients with chronic obstructive pulmonary disease and acute respiratory failure. METHODS: Inspiratory muscles and diaphragmatic efforts were evaluated by measurements of esophageal, gastric, and transdiaphragmatic pressures. Minute ventilation and breathing patterns were evaluated by measuring airway pressure and flow. Measurements were performed during spontaneous breathing, continuous positive airway pressure, FA, FA+PEEP, VA, VA+PEEP, FA+VA, and FA+VA+PEEP. RESULTS: FA+PEEP provided the greatest improvement in minute ventilation (89 +/- 3%) and dyspnea (62 +/- 2%). The largest reduction in pressure time product per breath of the respiratory muscles and diaphragm (44 +/- 3% and 33 +/- 2%, respectively) also was observed during FA+PEEP condition. When VA was added to this setting, a reduction in respiratory rate (50 +/- 3%), an increase in inspiratory time (102 +/- 6%), and a further reduction in pressure time product per minute (65 +/- 2% and 64% for the respiratory muscles and diaphragm, respectively) was observed. However, values of pressure time product per liter of minute ventilation during FA+VA+PEEP did not differ with those observed during FA+PEEP condition. Worsening of patient-ventilator interaction and breathing asynchrony occurred when VA was implemented. CONCLUSIONS: Application of PEEP to counterbalance PEEPi and FA to unload the resistive burden provided the optimal conditions in such patients. Ventilator over-assistance and patient-ventilator asynchrony was observed when VA was added to this setting. The clinical use of proportional assist ventilation should be based on continuous measurements of respiratory mechanics.

Acute Disease↗

HCV-RNA levels play an important role independently of genotype in predicting response to interferon therapy.

OBJECTIVE: To evaluate the relationship between hepatitis C virus (HCV)-RNA levels and genotypes in order to establish their potentially predictive role in interferon (IFN) response. DESIGN: To detect HCV genotype at baseline and HCV viraemia levels before and during IFN treatment in three groups of patients with different IFN response. METHODS: Our study included 85 patients with biopsy-proven chronic hepatitis C who underwent IFN therapy at standard schedule (3 MU thrice weekly for 6 months). On the basis of IFN response they were subdivided into three groups as follows: non responders (NR: 27 cases) when alanine aminotransferase (ALT) values (normal value: 0-40 IU) at the end of treatment were abnormal (101.7 +/- 10.4); responders relapsing (RR: 29 cases) when normal ALT values at the end of therapy (28.14 +/- 1.7) increased during follow-up; sustained (long-term) responders (LTR: 29 cases) when ALT values remained normal for at least 12 months of follow-up (ALT values at the end of therapy: 21.8 +/- 1.4). ALT activity was monitored monthly during therapy and each month during 12 months of follow-up. HCV genotype was evaluated before starting treatment whereas HCV-RNA viraemia was checked at baseline and at the 1st and 6th months of therapy. RESULTS: The baseline viral load was higher in the NR group than in the RR and LTR groups independently of genotype; HCV-RNA levels progressively decreased during therapy independently of response but the levels remained significantly higher in the NR group. Genotype 1b was prevalent in the NR group. However, levels of viraemia in genotype 1b LTR patients are significantly lower than in genotype 1b NR patients. CONCLUSION: These results suggest that among viral-related parameters viraemia alone seems to play an important role in predicting response to IFN independently of genotype.

Adult↗

Tuberous sclerosis complex: neonatal deaths in three of four children of consanguineous, non-expressing parents.

We describe here four sibs, born to consanguineous, healthy, asymptomatic parents. Three of these infants had a rapidly fatal course in the neonatal period; death was attributed to congestive heart failure with radiographic evidence of cardiomegaly in all of them. Necropsy was done in only one of them and showed the typical findings of tuberous sclerosis complex (TSC) in the central nervous system (CNS), kidneys, heart, and liver. The fourth sib, currently 2 years old, also has typical signs of TSC, namely hypomelanotic skin macules and calcified subependymal nodules. Both parents and a living maternal grandmother had appropriate examination, which included skin inspection under Wood's lamp, dental examination, fundoscopy, echocardiography, abdominal and renal ultrasound, and head CT and MRI scans, and no signs of TSC were found in either parent or in the only living grandmother. By history alone there is no other relative with signs or symptoms suggestive of TSC. Linkage analysis and loss of heterozygosity (LOH) investigations on a variety of lesions obtained from postmortem and tissue or blood specimens from all available family members studied failed to identify a microdeletion in the chromosomal regions where TSC genes are located. It is very unusual that in a single TSC family there were three consecutive neonatal deaths, and very likely that all had cardiac rhabdomyomas. Moreover, to the best of our knowledge, there are no previous reports of TSC families with more than one affected sib, unusually severe manifestations of the disease, and completely normal, consanguineous parents.

Child, Preschool↗

Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-gamma antibody.

The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different, experimental conditions with a purified polyclonal antibody (Ab), antirat IFN gamma. The results show that when administered at doses of 100 or 200 micrograms/week from the 30/33th until the 105th day of age, the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFN gamma Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFN gamma Ab (500 micrograms or 1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 micrograms/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BB rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.

Animals↗

Encapsulated uninodular dermatofibrosarcoma protuberans of the dermis: a case report.

We report an unusual case of dermatofibrosarcoma protuberans presenting as a small encapsulated uninodular mass, located exclusively in the dermis. Differential diagnostic problems with nodular spindle-shaped cell lesions of the dermis are discussed. A distinct histologic finding was the presence of a myofibroblast-rich fibrous pseudocapsule surrounding the tumor. The possible origin and role of this pseudocapsule are proposed.

Actins↗

Marine fungi in Terra Nova Bay (Ross Sea, Antarctica).

The occurrence of lignicolous marine fungi in Antarctic marine water far from the coast is reported. Thirty-six wooden baits (beech and poplar), hung in a metallic structure were immersed in Penguin Bay (Adelie Cove) at a depth of 50 m for a year. Fourteen species belonging to Deuteromycotina and six Ascomycotina were observed on the baits examined in Italy. Phoma sp., Trichocladium achrasporum, Trichocladium constrictum and Trichocladium lignincola were the predominant species. Phoma sp., the first species, are not typically marine, but rather of terrestrial origin. Penguin dung proximity can explain this occurrence.

Acremonium↗

Angiomyomatous hamartoma of the lymph node: case report with adipose tissue component.

We report the first case of an angiomyomatous hamartoma of the inguinal lymph node with a significant adipose tissue component. The presence of a mixture of smooth muscle cells, blood vessels and adipose tissue, haphazardly arranged within a fibrous background, extending from the hilar region to the lymph node cortex, provides morphologic evidence of the hamartomatous nature of the lesion. We think that the term "angiomyolipomatous hamartoma" is more appropriate for such a lymph node lesion.

Actins↗

Anti-HIV agents. V. Synthesis, structure and in vitro anti-HIV activity of novel 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles.

A series of 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles, TBZ analogues, was prepared in order to explore the influence on anti-HIV activity of the spatial requirements of the hydrophobic moiety fused to imidazothiazole system. In spite of a butterfly-like conformation evidenced by X-ray analysis of compound 4g, the results of in vitro screening suggest that the replacement of the benzene fused ring by the naphthyl moiety negatively influences the activity of analogous thiazolobenzimidazole derivatives, some of which are potent non-nucleoside HIV-1 RT inhibitors.

Anti-HIV Agents↗

Immunohistochemical distribution of type VI collagen in developing human kidney.

The distribution of type VI collagen was investigated immunohistochemically in the developing human kidney from 15 to 32 weeks gestational age and it was compared with that observed in the normal infantile and adult human kidney. In fetal kidney, type VI collagen was widely distributed as a fibrillar network in the subcapsularly undifferentiated mesenchyme and intertubular interstitium, and as a basement membrane-like structure around the ureteral bud branches, tubules, and collecting ducts. During nephrogenesis, type VI collagen disappeared from the induced mesenchyme close to the tips of ureteral branches, while it formed a distinct basement membrane-like structure around the early stages of nephron differentiation (comma-shaped and S-shaped bodies) and later along Bowman's capsule of capillary loop and maturing glomeruli A strong immureactivity for type VI collagen was also found in the glomerular basement membrane and mesangial areas of capillary loop and maturing glomeruli. In infantile kidney, type VI collagen showed a distribution pattern similar to that observed during the fetal period. In adult human kidney, glomerular basement membrane showed a weak positivity for type VI collagen and the basement membrane-like staining around Bowman's capsule, tubules, and collecting ducts was less evident than in fetal and infantile kidney. Our immunohistochemical findings suggest that type VI collagen is a normal component of the glomerular and extraglomerular extracellular matrix of developing human kidney and that it undergoes changes in the expression during maturation.

Adult↗

Auto-positive end-expiratory pressure and dynamic hyperinflation.

PEEP is indicated in patients with COPD only to unload the respiratory muscles from the auto-PEEP resulting from expiratory flow limitation. If auto-PEEP is not caused by flow limitation, application of PEEP will cause further hyperinflation, worsening respiratory mechanics, muscle activity, and hemodynamics. To assess the presence of expiratory flow limitation correctly, to measure auto-PEEP correctly, and to identify the maximal PEEP level to be used, measurements of flow and opening pressure must be obtained during a brief period of suspended respiratory muscle activity (obtained by sedation) with the patient's own breathing pattern reproduced accurately.

Humans↗

Synergistic effect of deoxyspergualin (DSP) and cyclosporin A (CsA) in the prevention of spontaneous autoimmune diabetes in BB rats.

Dose-dependent side effects are frequently observed with immunosuppressive drugs of potential relevance for the immunotherapy of insulin-dependent diabetes mellitus (IDDM), such as CsA and DSP. If CsA and DSP acted synergistically in vivo, their combined use would allow using each compound at lower doses than those required when each drug is given in monotherapy. Consequently, dose-dependent side effects could be reduced and the therapeutic activity maintained or even enforced. Toward this end we studied the effects of combined treatment with CsA and DSP on the course of IDDM in the diabetes-prone (DP)-BB rat. The results show that two 'low' doses of CsA (2 mg/kg) and DSP (1 mg/kg) that are clinically ineffective in suppressing IDDM development in BB rats when administered alone under a prolonged prophylactic regimen (30-105 days old), may successfully prevent, but not cure, the disease when given contemporaneously under the same experimental conditions. The combined treatment was well tolerated, and no side effects were noticed. These data suggest that the combined use of CsA and DSP may deserve consideration for its possible application in the prevention/treatment of human IDDM and other autoimmune diseases.

Animals↗

Patient-ventilator interaction during acute hypercapnia: pressure-support vs. proportional-assist ventilation.

The objective of this study was to compare patient-ventilator interaction during pressure-support ventilation (PSV) and proportional-assist ventilation (PAV) in the course of increased ventilatory requirement obtained by adding a dead space in 12 patients on weaning from mechanical ventilation. With PSV, the level of unloading was provided by setting the inspiratory pressure at 20 and 10 cmH2O, whereas with PAV the level of unloading was at 80 and 40% of the elastic and resistive load. Hypercapnia increased (P < 0.001) tidal swing of esophageal pressure and pressure-time product per breath at both levels of PSV and PAV. During PSV, application of dead space increased ventilation (VE) during PSV (67 +/- 4 and 145 +/- 5% during 20 and 10 cmH2O PSV, respectively, P < 0.001). This was due to a relevant increase in respiratory rate (48 +/- 4 and 103 +/- 5% during 20 and 10 cmH2O PSV, respectively, P < 0.001), whereas the increase in tidal volume (VT) played a small role (13 +/- 1 and 21 +/- 2% during 20 and 10 cmH2O PSV, respectively, P < 0.001). With PAV, the increase in VE consequent to hypercapnia (27 +/- 3 and 64 +/- 4% during 80 and 40% PAV, respectively, P < 0.001) was related to the increase in VT (32 +/- 1 and 66 +/- 2% during 80 and 40% PAV, respectively, P < 0.001), respiratory rate remaining unchanged. The increase in pressure-time product per minute and per liter consequent to acute hypercapnia and the sense of breathlessness were significantly (P < 0.001) higher during PSV than during PAV. Our data show that, after hypercapnic stimulation of the respiratory drive, the capability to increase VE through changes in VT modulated by variations in inspiratory muscle effort is preserved only during PAV; the compensatory strategy used to increase VE during PSV requires greater muscle effort and causes more pronounced patient discomfort than during PAV.

Adult↗

Chest wall and lung contribution to the elastic properties of the respiratory system in patients with chronic obstructive pulmonary disease.

Conflicting data are available on the relative contribution of the chest wall (cw) to the intrinsic positive end-expiratory pressure of the total respiratory system (PEEPi,rs) in patients with chronic obstructive pulmonary disease (COPD). In order to assess the chest wall and lung contribution to the elastic properties of the respiratory system in COPD patients during acute ventilatory failure, using the "interrupter technique", static inflation volume-pressure (V-P) curves of the total respiratory system (rs), lung (L) and cw were obtained in seven mechanically-ventilated COPD patients during application of zero end-expiratory pressure (ZEEP) and different levels (0-15 cmH2O) of PEEP. On ZEEP, PEEPi,rs was present in all patients (range 10.5-13.1 cmH2O), to which PEEPi,cw and PEEPi,L contributed 17 +/- 2 and 83 +/- 1%, respectively. The static V-P curves of the rs, L, and cw on ZEEP were concave toward the horizontal axis, indicating that elastance increased with inflating volume. Application of PEEP did not affect lung and chest wall mechanics until PEEP levels exceeding 90% of PEEPi,cw on ZEEP (critical value of PEEP (Pcrit)). At PEEP levels higher than Pcrit, and relative to the V-P curves on ZEEP, we observed that: 1) the V-P curve of the rs showed an initial shift along the curve on ZEEP followed by a downward displacement with inflating volume; 2) the V-P curve of the L was shifted along the curve on ZEEP throughout inflating volume; and 3) the V-P curve of the cw was initially displaced along the curve on ZEEP, whilst a downward displacement appeared at higher lung volume. In conclusion, our data show that, in chronic obstructive pulmonary disease patients with flow limitation, the increase in pleural pressure does not make a significant contribution to the intrinsic positive end-expiratory pressure of the total respiratory system. However, during tidal ventilation, a substantial increase in elastance of the chest wall is present. The critical values of positive end-expiratory pressure below which there are no changes in chest wall and lung mechanics amount to 90% of the total PEEPi,rs on ZEEP. Positive end-expiratory pressure levels higher than such critical value cause important alterations of the elastic properties of the lung and chest wall.

Aged↗

The effects of a nonimmunogenic form of murine soluble interferon-gamma receptor on the development of autoimmune diabetes in the NOD mouse.

Previous studies have shown that in vivo treatment with antiinterferon-gamma (anti-IFNgamma) monoclonal antibodies (mAbs) prevents the development of autoimmune diabetes in NOD mice. Although these findings anticipate that specific anti-IFNgamma therapies may be useful for the prevention/treatment of human insulin-dependent diabetes mellitus, there are several reasons why the use of anti-IFNgamma mAb may be difficult in the clinical setting. With the aim to develop alternative forms of specific anti-IFNgamma therapies, we recently produced a nonimmunogenic form of the soluble IFNgamma receptor (sIFNgammaR) that binds and neutralizes murine IFNgamma with an affinity higher than that of anti-IFNgamma mAb. In this study we compared the efficacy of sIFNgammaR to that of two anti-IFNgamma mAbs (XMG 1.2 and AN-18) in the prevention of spontaneous and accelerated (cyclophosphamide-induced) forms of autoimmune diabetes in NOD mice. The results show that in the spontaneous model, sIFNgammaR could prevent histological and clinical signs of autoimmune diabetes as efficiently as the two mAbs. Under ex vivo conditions, sIFNgammaR exhibited a more powerful modulatory effect than XMG 1.2 mAb on cytokine secretion from splenic lymphoid cells, which resulted in a significant reduction of Concanavalin A-induced IL-2 secretion and an augmented release of both unstimulated and lipopolysaccharide-induced IL-6. Moreover, although both mAbs were immunogenic and elicited formation of high titers of anti-rat IgG, sIFNgammaR did not induce antibody formation. Unexpectedly, in the cyclophosphamide-induced model, sIFNgammaR turned out to be less effective than either of the two anti-IFNgamma mAbs. Taken together, these data support the role of IFNgamma in the pathogenesis of NOD mice, but, more importantly, suggest that a nonimmunogenic approach is possible to the diminution of the effects of IFNgamma in this model.

Animals↗