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Biomedical subjects

A Castellano

Publications and source records attributed to A Castellano.

At least 19 recordsLinked to original sources
PubMed2006

Temozolomide in resistant or relapsed pediatric solid tumors.

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

Adolescent↗
PubMed2006

[Diarrhoea in the traveller].

Diarrhoeic diseases caused by water and food contaminated by enteropathogens continue to be an important cause of morbidity in countries with a low level of development. Some 50,000 cases of diarrhoea in travellers are estimated in the world every day, and this is the main cause of consultation by travellers who return from undeveloped zones. The principal determinant of risk is the place of destination; there are significant differences between different regions with respect to risk and to the aetiology of the diarrhoea. The most frequent cause of diarrhoeas is of bacterial origin, which represents between 60 and 85% of the cases, while parasites represent 10% and some 5% are produced by viruses. Although it normally follows a benign course, complications can arise, with mortality being only exceptionally associated to this disease. Prevention is essentially based on strictly following elemental hygienic measures and avoiding the ingestion of foodstuffs and drinks with a risk of contamination. Prophylaxis with antibiotics is only advisable in journeys of short duration, in which the risk and/or seriousness of diarrhoeas, above all in immunosuppressed patients, are higher than the possible collateral effects. The treatment of diarrhoea in the traveller is based on adequate hydration, and the use of microbians is reserved for moderate and serious situations, with quinolones being the drug of choice. Rifaximine is a new drug approved for the treatment of diarrhoeas in the traveller, above all in areas with enteropathogens that are resistant to quinolones.

Diarrhea↗
PubMed2005

The inflammatory reaction in human traumatic oedematous cerebral cortex.

The inflammatory reaction surrounding hemorrhagic and perihematomal brain parenchyma has been studied by means of light and transmission electron microscopy in 12 patients with severe traumatic head injuries complicated with subdural or extradural hematoma or hygroma. Perivascular cells, ameboid phagocytic microglial cells, and infiltrated macrophage/monocyte system were observed surrounding perivascular and intraparenchymal hemorrhagic foci. They showed phagocytic activity of degenerated nerve cell processes, and organized proteinaceous edema fluid present in the enlarged extracellular space. Endocytosis by means of clathrin coated vesicles also was observed. Facultative and professional phagocytes exhibited a full repertoire of lysosomes, phagosomes containing nerve cell debris, lipid droplets, and lipofucsin granules. Phagocytic pericytes remaining within the capillary basement membrane were also observed around perivascular hemorrhages. The inflammatory reaction was examined in young and old patients with an evolution time of brain injury ranging from 1 day to 2 years. The inflammatory process developed according to the intensity of traumatic insult, patient age, associated hematoma or hygroma, severity of vasogenic and cytotoxic oedema, and anoxic-ischemic conditions of brain parenchyma.

Adolescent↗
PubMed2004

Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age.

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

Adolescent↗
PubMed2004

Correlative microscopy of Purkinje dendritic spines: a field emission scanning and transmission electron microscopic study.

Purkinje dendritic spines (Pds) of mouse cerebellar cortex were examined by field emission scanning electron microscopy (FESEM) and by transmission electron microscopy (TEM) using ultrathin sections and freeze-etching replicas, to study their three-dimensional features and intramembrane morphology. FESEM showed unattached mushroom-type, elongated and lanceolate Pds separated by 100-500 nm on the dendritic shaft surface. High resolution FESEM showed 25-50 nm globular subunits at the spine postsynaptic density corresponding to the localization of postsynaptic proteins and/or postsynaptic receptors. TEM images of ultrathin sections showed gem-like, mushroom-shaped, lanceolate and neckless or stubby spines. Freeze etching replicas exposed postsynaptic intramembrane particles that can be correlated with the globular subunits observed at high resolution FESEM. Parallel and climbing fiber endings were observed making asymmetric synaptic contacts with the Pds heads. Simultaneous contacts with the necks and heads were also found. The variety of Pds shapes were interpreted as spine conformational changes related with spine dynamic, and spine plasticity.

Animals↗
PubMed2004

Transmission electron microscopy of cortical dendritic spines in the human oedematous cerebral cortex.

The cortical biopsies of 31 patients with clinical diagnosis of congenital hydrocephalus, vascular anomalies, brain tumours and brain trauma were examined with the transmission electron microscope. A variety of swollen spine shapes were found: mushroom shaped, filopodic, lanceolated spines, and megaspines. The spines appeared axonless or making asymmetric synaptic contacts with swollen presynaptic axons. They exhibited a disrupted actin-like network, dilated endoplasmic reticulum profiles, oedematous clear or dense mitochondria, and clusters of free ribosomes. Some spines contained a hypertrophic cytoskeleton. The spine apparatus appeared generally swollen with clear and dilated cisterns. In severe brain trauma and tumours some spine apparatus appeared disorganised or atrophic. In complicated brain trauma with subdural haematoma or hygroma some degenerated spines displayed a high electron density. The ultrastructural findings suggest that alterations of the spines are responsible for the neurological symptoms exhibited by some patients, which imply a disturbance of cortical nerve circuits. The presence of axonless spines is symptomatic of a loss of nerve connectivity, and are expected to have a significant input on neurological and mental functions.

Adolescent↗
PubMed2002

Electron microscopy of umbilical cord endothelial cells in preeclampsia.

We have studied by means of transmission electron microscopy the umbilical cord endothelial cells in 11 preeclamptic women. Endothelial cells exhibited oval, round, elongated, flattened, triangular or polygonal shapes. The nuclei displayed shallow and deep invaginations of nuclear envelope. The endoplasmic reticulum appeared highly dilated and vacuolated. The swollen mitochondria showed cristae fragmentation. Areas of focal necrosis were appreciated throughout the cytoplasm. A marked enlargement of subendothelial space and the presence of an electron dense granular material were also found. The findings reveal activation and injury of endothelial cells and disruption of endothelial cell layer.

Adult↗
PubMed2001

Consecutive light microscopy, scanning-transmission electron microscopy and transmission electron microscopy of traumatic human brain oedema and ischaemic brain damage.

Cortical biopsies of 11 patients with traumatic brain oedema were consecutively studied by light microscopy (LM) using thick plastic sections, scanning-transmission electron microscopy ((S)TEM) using semithin plastic sections and transmission electron microscopy (TEM) using ultrathin sections. Samples were glutaraldehyde-osmium fixed and embedded in Araldite or Epon. Thick sections were stained with toluidine-blue for light microscopy. Semithin sections were examined unstained and uncoated for (S)TEM. Ultrathin sections were stained with uranyl and lead. Perivascular haemorrhages and perivascular extravasation of proteinaceous oedema fluid were observed in both moderate and severe oedema. Ischaemic pyramidal and non-pyramidal nerve cells appeared shrunken, electron dense and with enlargement of intracytoplasmic membrane compartment. Notably swollen astrocytes were observed in all samples examined. Glycogen-rich and glycogen-depleted astrocytes were identified in anoxic-ischaemic regions. Dark and hydropic satellite, interfascicular and perivascular oligodendrocytes were also found. The status spongiosus of severely oedematous brain parenchyma observed by LM and (S)TEM was correlated with the enlarged extracellular space and disrupted neuropil observed by TEM. The (S)TEM is recommended as a suitable technique for studying pathological processes in the central nervous system and as an informative adjunct to LM and TEM.

Adolescent↗
PubMed2000

Collapse of conductance is prevented by a glutamate residue conserved in voltage-dependent K(+) channels.

Voltage-dependent K(+) channel gating is influenced by the permeating ions. Extracellular K(+) determines the occupation of sites in the channels where the cation interferes with the motion of the gates. When external [K(+)] decreases, some K(+) channels open too briefly to allow the conduction of measurable current. Given that extracellular K(+) is normally low, we have studied if negatively charged amino acids in the extracellular loops of Shaker K(+) channels contribute to increase the local [K(+)]. Surprisingly, neutralization of the charge of most acidic residues has minor effects on gating. However, a glutamate residue (E418) located at the external end of the membrane spanning segment S5 is absolutely required for keeping channels active at the normal external [K(+)]. E418 is conserved in all families of voltage-dependent K(+) channels. Although the channel mutant E418Q has kinetic properties resembling those produced by removal of K(+) from the pore, it seems that E418 is not simply concentrating cations near the channel mouth, but has a direct and critical role in gating. Our data suggest that E418 contributes to stabilize the S4 voltage sensor in the depolarized position, thus permitting maintenance of the channel open conformation.

Amino Acid Sequence↗
PubMed2000

Predicting the result of noninvasive ventilation in severe acute exacerbations of patients with chronic airflow limitation.

OBJECTIVE: To analyze prospectively the factors related to the success of noninvasive ventilation (NIV) in the treatment of acute exacerbations of chronic airflow limitation (CAFL) and to generate a multiple regression model in order to detect which patients can be successfully treated by this method. SETTING: A respiratory medicine ward of a referral hospital. METHODS AND PRINCIPAL RESULTS: Initially, we examined 44 episodes of acute respiratory failure in 36 patients with CAFL in whom mechanical ventilation was advisable. In 34 of 44 episodes (77%), NIV was used successfully. Patients in whom NIV succeeded had a lower FEV(1) prior to admission, a higher level of consciousness (LC), and significant improvements in PaCO(2), pH, and LC after 1 h of NIV. A logistic regression model consisting of baseline FEV(1) and PaCO(2) values, initial PaCO(2), pH, and LC values on admission, and PaCO(2) values after 1 h of NIV allowed us to correctly classify > 95% of the 44 episodes in which the outcome was successful. In the second part of the study, we prospectively validated the equation in another 15 consecutive CAFL patients with acute hypercapnic respiratory failure. NIV successfully treated 12 patients (80%), and the model correctly classified 14 patients (93%). CONCLUSION: Good LC at the beginning of NIV and improvements in pH, PaCO(2), and LC values after 1 h of NIV are associated with successful responses to NIV in COPD patients with acute hypercapnic respiratory failure. Our validated multiple regression model confirms that these variables predict the result of NIV in acute hypercapnic failure in CAFL patients.

APACHE↗
PubMed1999

A small domain in the N terminus of the regulatory alpha-subunit Kv2. 3 modulates Kv2.1 potassium channel gating.

Recent work has demonstrated the existence of regulatory K(+) channel alpha-subunits that are electrically silent but capable of forming heterotetramers with other pore-forming subunits to modify their function. We have investigated the molecular determinant of the modulatory effects of Kv2.3, a silent K(+) channel alpha-subunit specific of brain. This subunit induces on Kv2.1 channels a marked deceleration of activation, inactivation, and closing kinetics. We constructed chimeras of the Kv2.1 and Kv2.3 proteins and analyzed the K(+) currents resulting from the coexpression of the chimeras with Kv2.1. The data indicate that a region of 59 amino acids in the N terminus, adjacent to the first transmembrane segment, is the major structural element responsible for the regulatory function of Kv2.3. The sequence of this domain of Kv2.3 is highly divergent compared with the same region in the other channels of the Kv2 family. Replacement of the regulatory fragment of Kv2.3 by the equivalent of Kv2.1 leads to loss of modulatory function, whereas gain of modulatory function is observed when the Kv2.3 fragment is transferred to Kv2.1. Thus, this study identifies a N-terminus domain involved in Kv2.1 channel gating and in the modulation of this channel by a regulatory alpha-subunit.

Amino Acid Sequence↗
PubMed1998

Proximal and distal gastric distension in normal subjects and H. pylori-positive and -negative dyspeptic patients and correlation with symptoms.

Aim of the study was to analyze gastric distension with water in H. pylori-positive and -negative dyspeptic patients and normal subjects and the correlation with symptoms. Twenty dyspeptic patients and 19 normal subjects were studied. H. pylori was determined in each dyspeptic patient with the rapid urea test at endoscopy. Gastric distension was evaluated by real-time ultrasonography with the ingestion of stepwise-increasing amounts of water up to a total of 600 ml. During distension, the symptom score was evaluated as well. The proximal stomach was significantly smaller in dyspeptic patients than in healthy controls, at 100-600 ml water (P<0.01). A larger distal stomach was observed at 500 and 600 ml of water (P<0.01). The score of bloating and fullness was greater in dyspeptics than in controls at 300 and 600 ml of water distension. The symptoms score was linearly correlated with proximal and distal gastric measurements in dyspeptic patients and in controls. No significant difference was found in dyspeptic patients regarding the H. pylori status. In conclusion, dyspeptic patients show a defective adaptation of the whole stomach to water distension and an increased symptom perception score as compared to controls. H. pylori infection does not seem to be a determining factor in these observed findings.

Adult↗
PubMed1997

Identification and functional characterization of a K+ channel alpha-subunit with regulatory properties specific to brain.

The physiological diversity of K+ channels mainly depends on the expression of several genes encoding different alpha-subunits. We have cloned a new K+ channel alpha-subunit (Kv2.3r) that is unable to form functional channels on its own but that has a major regulatory function. Kv2.3r can coassemble selectively with other alpha-subunits to form functional heteromultimeric K+ channels with kinetic properties that differ from those of the parent channels. Kv2.3r is expressed exclusively in the brain, being concentrated particularly in neocortical neurons. The functional expression of this regulatory alpha-subunit represents a novel mechanism without precedents in voltage-gated channels, which might contribute to further increase the functional diversity of K+ channels necessary to specify the intrinsic electrical properties of individual neurons.

Amino Acid Sequence↗
PubMed1996

Role of deferoxamine in tumor therapy.

Several studies are consistent with the hypothesis that available iron may have some role in promoting tumor cell growth with different biological mechanisms. For this reason, several studies have been carried out to demonstrate the antitumor activity of deferoxamine (DFO), an iron chelator with a high affinity for ferritin-bound iron. In particular, the effects of DFO have been studied in patients with neuroblastoma, where ferritin is in part tumor derived and high concentrations correlate with poor outcome. To date, in vitro and in vivo studies demonstrating the antitumor effects of DFO are very promising, but further investigations are required to establish an exact role for DFO in the treatment of cancer.

Antineoplastic Agents↗
PubMed1995

Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients.

BACKGROUND: A clinical pilot study performed by our group showed that dacarbazine can induce a marked reduction of blast cells in patients with acute myelogenous leukaemia (AML). Leukaemic blasts (LB) from responsive patients showed low levels of O6-alkylguanine-DNA alkyltransferase (OGAT). DESIGN: An in vitro study was performed to evaluate OGAT levels and sensitivity to temozolomide (a triazene compound that spontaneously decomposes into the active metabolite of dacarbazine) in a relatively large number of LB samples. RESULTS: OGAT levels varied widely among the LB of different patients, with a mean value higher in acute lymphoblastic leukaemias than in AML. About 25% of LB obtained from patients with AML showed low OGAT activity, in the range corresponding to that observed in leukaemic patients responsive to dacarbazine in vivo. A reasonable inverse correlation was found between OGAT levels and LB sensitivity to temozolomide. CONCLUSIONS: Triazenes could have a therapeutic potential in human leukaemias. Moreover, OGAT determination could provide rapid and reliable information about a patient's susceptibility to these antitumor agents.

Adolescent↗
PubMed1995

Stabilizing effect of water/alcohol solvents towards autoxidation of glutaraldehyde-modified haemoglobin.

Glutaraldehyde-cross-linked haemoglobin is potentially very attractive as a useful oxygen carrier for biomedical and technological purposes. However, its oxygen-binding ability is restricted by the autoxidation of the iron which is faster than for native haemoglobin. We have studied the stabilization effect of ethanol, butan-1-ol, ethylene glycol and glycerol on the autoxidation of glutaraldehyde-cross-linked oxyhaemoglobin. We have shown that, in the presence of water/alcohol mixtures, cross-linked haemoglobin became more stable towards autoxidation than native oxyhaemoglobin in an aqueous environment. From a structural point of view, an e.p.r. study showed that alcohols and cross-linking had opposite effects on the haem environment. In contrast with the cross-linking, alcohols stabilize oxyhaemoglobin by decreasing the charge transfer from the iron to the oxygen, decreasing the O-O length and increasing the total distance (F8 His)-N-F-O2.

Alcohols↗