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M Cazzola

Publications and source records attributed to M Cazzola.

At least 55 records · Page 3Linked to original sources
PubMed2000

Translational pathophysiology: a novel molecular mechanism of human disease.

In higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at the level of messenger RNA (mRNA) translation into protein. Negative regulatory effects are often mediated by the 5'-untranslated region (5'-UTR) and rely on the fact that the 40S ribosomal subunit first binds to the cap structure at the 5'-end of mRNA and then scans for the first AUG codon. Self-complementary sequences can form stable stem-loop structures that interfere with the assembly of the preinitiation complex and/or ribosomal scanning. These stem loops can be further stabilized by the interaction with RNA-binding proteins, as in the case of ferritin. The presence of AUG codons located upstream of the physiological start site can inhibit translation by causing premature initiation and thereby preventing the ribosome from reaching the physiological start codon, as in the case of thrombopoietin (TPO). Recently, mutations that cause disease through increased or decreased efficiency of mRNA translation have been discovered, defining translational pathophysiology as a novel mechanism of human disease. Hereditary hyperferritinemia/cataract syndrome arises from various point mutations or deletions within a protein-binding sequence in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinemia and severity of cataract in affected individuals. Hereditary thrombocythemia (sometimes called familial essential thrombocythemia or familial thrombocytosis) can be caused by mutations in upstream AUG codons in the 5'-UTR of the TPO mRNA that normally function as translational repressors. Their inactivation leads to excessive production of TPO and elevated platelet counts. Finally, predisposition to melanoma may originate from mutations that create translational repressors in the 5'-UTR of the cyclin-dependent kinase inhibitor-2A gene.

5' Untranslated Regions↗
PubMed2000

Exclusion of ZIRTL as candidate gene of juvenile hemochromatosis and refinement of the critical interval on 1q21.

Hemochromatosis type 2 (HFE2) or juvenile hemochromatosis (JH) is a rare recessive disorder that causes iron overload, characterized by early onset and severe clinical course. The JH locus maps to chromosome 1q, in a 4-cM region encompassing markers D1S442 and D1S2347. Recently a gene named ZIRTL has been characterized and mapped to 1q21. This gene belongs to a family of divalent metal ion-transporting genes that encode for proteins involved in transport of different metals, including iron. Thus, the ZIRTL gene represents a positional and functional candidate for JH. Here we further restrict the candidate region through segregation analysis of two new polymorphic markers and haplotype analysis in JH families. Furthermore, we exclude ZIRTL as a JH candidate gene showing that it maps outside the critical interval and that its genomic sequence is normal in three patients.

Carrier Proteins↗
PubMed2000

Parenteral antibiotic therapy in the treatment of lower respiratory tract infections. Strategies to minimize the development of antibiotic resistance.

Antibiotic use is often imputed for increases in the prevalence of infections due to antibiotic-resistant bacteria. Resistance depends on the variety of genotypes in the large bacterial population and also on the selective pressures that are produced along the antibiotic concentration gradients in the body. In effect, at certain selective concentrations the antibiotic eliminates the susceptible majority, leaving a selected remainder intact. Therefore, the choice of antibiotics for the treatment of lower respiratory tract infections should take into consideration not only their effectiveness but also the pharmacokinetics of each agent and its delivery schedule. In fact, the potential therapeutic efficacy of an antibiotic depends not only on its spectrum of action, but also on the concentration it reaches at the site of infection. Most infections occur in the tissues of the body rather than in the blood and that it is accepted that appropriate antibiotic therapy requires the maintenance of significant concentrations of antibiotics at the site of infection in the lung long enough to eliminate the invading pathogen. Thus, the development of dosing schedules for most antimicrobials has been based on the postulate that drug levels need to be above the minimal inhibitory concentration (MIC) at this site for most or all the dosing interval. The selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUIC(0-24)/MIC ratio of less than 100O125. Antimicrobial regimens that do not achieve these values cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations. It has been suggested that resistance can be avoided with attention to dosing, since dosing which provides an AUIC(0-24)/MIC ratio of at least 100 appears to reduce the rate of the development of bacterial resistance. Unfortunately, very different serum or lung concentration profiles can result in the same AUIC(0-24)/MIC. High doses administered sufficiently may often completely prevent any possibility of attaining a selective concentration. Alternatively, an antibiotic which has good bactericidal potency and maintains tissue and/or serum concentrations greater than the MIC or, better, minimal bactericidal concentration (MBC) throughout the dosing interval is equally effective in minimizing the development of antibiotic resistance.

Anti-Bacterial Agents↗
PubMed2000

Lung function improvement in smokers suffering from COPD with zafirlukast, a CysLT(1)-receptor antagonist.

The present study was designed to evaluate the bronchodilating role of zafirlukast, a CysLT(1)receptor antagonist, at the standard dosage currently recommended in the marketing of this agent in smokers with COPD. The study was performed using a double-blind, cross-over, randomized design and was conducted on 2 non-consecutive days. Sixteen outpatients suffering from stable COPD received 40 mg oral zafirlukast, or placebo. Lung function was controlled before drug administration and 30, 60, 120, 180, 240 min thereafter. At the end of the 4-h period, each patient received 400 microg inhaled salbutamol and spirometric testing was performed 30 min later. Zafirlukast, but not placebo, produced a significant (P<0.05) bronchodilation between 30 min and 4 h following administration, with a maximum mean increase in FEV(1)of 0.134 l (11.2%) above baseline after 2 h. Nine of 16 patients showed an increase in FEV(1)of at least 15% above baseline after zafirlukast. The maximum mean increase in FEV(1)after zafirlukast in these subjects, who were considered responders, observed after 2 h, was 0.221 (19.4%). The mean difference of post-salbutamol FEV(1)values after zafirlukast and placebo (-0.036 l) was not significant (P<0.05). In responders, the mean of differences in pre- and post-salbutamol FEV(1)values after zafirlukast was 0.077 l, whereas the mean of differences between post-salbutamol values after zafirlukast and those after placebo was -0.064 l. The mean AUC(0-4 h)for all patients was 0.121 l for placebo and 0.385 l for zafirlukast. The difference between the placebo and zafirlukast AUC(0-4 h)was significant (P<0.05). The individual FEV(1)AUC(0-4 h)after zafirlukast were higher than those after placebo in 12 out of 16 patients. These findings suggest that cysteinyl leukotrienes might be one of the causes of persistent bronchoconstriction in COPD, at least in several smokers, but do not confirm the hypothesis that the effects of zafirlukast and salbutamol are independent and additive.

Aged↗
PubMed2000

Autografting with Ph-negative progenitors in patients at diagnosis of chronic myeloid leukemia induces a prolonged prevalence of Ph-negative hemopoiesis.

OBJECTIVE: In many patients with chronic myeloid leukemia (CML), a residual population of primitive normal (Ph-negative) progenitors persists despite the marked expansion of the leukemic (Ph-positive) clone. These cells may be found in the blood of patients studied soon after diagnosis or during the period of endogenous hematopoietic recovery that follows myeloreductive therapy. Based on those observations, we have developed a clinical protocol that allows collection of Ph-negative peripheral blood progenitor cells (PBPC) with transplantable hematopoietic regenerative potential. The aim of this study is to examine changes that occur in the percentage of Ph-negative- and Ph-positive-committed progenitor cells and to determine the relationship between changes and clinical outcome. MATERIALS AND METHODS: We followed 15 patients with CML, mobilized and autografted soon after diagnosis with 85%-100% Ph-negative PBPC for a median time of 28 months (range 18-50) after transplant. At 6 months, 1 year, 2 years, and last follow-up, cytogenetic analyses were performed on fresh bone marrow cells and on colony-forming cells (CFC). RESULTS: Autologous transplantation induces a reduction in the proportion of Ph-positive CFC, from 70%-100% to 0%-25% in the majority of patients (78%). After autografting, 8 of 15 patients achieved a long-lasting cytogenetic remission (median, 24 months; range, 21-43) with a Ph-positivity ranging between 0% and 20% at the level of mature mononuclear cells and colony-forming cells (CFC). In some patients, the majority of CFC remained Ph-negative, whereas the majority of the mature cells were Ph-positive. Other patients (5/15) developed cytogenetic relapse (100% Ph-positive), although they were in hematological remission. We found that detection of Ph-positive long-term-culture initiating cells (LTC-IC) in the marrow at diagnosis was the only factor significantly associated with recurrence of the disease (p < 0.01); on the other hand, the number of Ph-negative LTC-IC infused showed a significant correlation with a better outcome (p < 0.03). CONCLUSION: We have shown that a prolonged period of complete or almost complete Ph-negative hemopoiesis can be achieved in patients with CML who undergo autografting with Ph-negative progenitors. Longer follow-up study will be needed to assess whether these changes are associated with improved survival.

Adult↗
PubMed2000

Biochemical and genetic defects underlying human congenital hypotransferrinemia.

INTRODUCTION: Human congenital hypotransferrinemia is a rare disorder characterized by the virtual absence of transferrin in the serum. No information on the causes of the disease is known. MATERIALS AND METHODS: Here we describe the identification of a new case, its treatment and the biochemical and genetic defects underlying the disorder. RESULTS: At diagnosis the patient had serum Tf levels equal to about 1% of the normal values. The treatment with plasma infusions each month allowed a good erythropoiesis and the prevention of iron overload with no need of red blood cell transfusions or iron chelators. In order to define the genetic basis of the disease, we performed a haplotype analysis of the Tf gene region in the 26 individuals forming the proband's family, and demonstrated that the genetic defect is located in the Tf gene and that it is inherited as a recessive trait. Protein analyses indicate that the proband serum contains two transferrin forms: one of 80 kD analogous to the normal one, and a smaller one of 50 kD, which may arise from a specific degradation or be the gene product of a modified allele. CONCLUSION: These data suggest the presence of two Tf alleles carrying genetic defects that cause two distinct abnormalities. One allele causes low expression of an apparently normal protein that probably allowed the survival of the patient in the first years of age. The other allele produces a modified Tf with different biochemical characteristics compared to the normal one.

Abnormalities, Multiple↗
PubMed2000

Cell cycle distribution of cord blood-derived haematopoietic progenitor cells and their recruitment into the S-phase of the cell cycle.

The objective of this study was to evaluate the cycling status of cord blood (CB)-derived colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC), and their recruitment into the S-phase of the cell cycle. By using the cytosine arabinoside (Ara-C) suicide approach, we found that only small proportions of both CFC and LTC-IC were in the S-phase of the cell cycle. These estimates were confirmed by flow cytometric DNA analysis, which showed that 96 +/- 2% of CB-derived CD34+ cells were in G0/G1 and only 1.6 +/- 0.4% in the S-phase. Staining of CD34+ cells with an antistatin monoclonal antibody, a marker of the G0 phase, indicated that among CD34+ cells with a flow cytometric DNA content typical of the G0/G1 phase 68 +/- 7% of cells were in the G0 phase of the cell cycle. Incubation (24 h) with interleukin 3 (IL-3), recombinant human stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) significantly increased the proportion of cells in the S-phase for both CFC and LTC-IC without inducing any loss in numbers. Flow cytometric DNA analysis also showed an increase in CD34+ cells in the S-phase upon continuous exposure to these cytokines. Our findings indicate that: (i) very few CB-derived CFC or LTC-IC were in the S-phase of the cell cycle; (ii) a substantial amount of CD34+ cells with a flow cytometric DNA content typical of the G0/G1 fraction was cycling, as found in the G1 phase of the cell cycle; and (iii) 24-h incubation with IL-3, SCF and G-CSF could drive a proportion of progenitor cells into the S-phase without reducing their number. These data might be useful for gene transfer protocols and the ex vivo expansion of CB-derived progenitor cells.

Antigens, CD34↗
PubMed2000

Pets and cockroaches: two increasing causes of respiratory allergy in indoor environments. Characteristics of airways sensitization and prevention strategies.

The increasing prevalence of allergic sensitization to indoor allergens such as dust mites, pets and cockroaches is the result of the changes in indoor environments induced by human activities. The Westernized lifestyle and the increasing time spent indoors determine a reduction in natural air ventilation and, consequently, higher levels of allergen concentrations and longer exposure to allergens. The major cat allergen Fel d 1 is carried by small-dimension particles (< 5 microm diameter) that readily become airborne and persist immodified for a long time. Fel d 1 must be considered a ubiquitous allergen because it has been found in indoor environments and even in public places where a cat has never been kept. Recent research has demonstrated that clothing of cat owners may contribute to the dispersal of Fel d 1 in cat-free environments. Therefore, washing Fel d 1-contaminated clothes should be considered a simple and effective method for removing this allergen from clothing and, consequently, reducing the risk of Fel d 1 dispersion. Cockroach allergens constitute another important cause of environment-related respiratory allergy and may trigger asthma exacerbations in sensitized individuals. In the prevention of cockroach allergy, the use of chemical agents associated with an intensive vacuum cleaning of indoor environments is an important tool in removing cockroach material containing allergenic proteins. Early recognition of allergy-predisposed babies, monitoring indoor allergens and adequate strategies of allergen avoidance are likely to be important means for reducing the prevalence of bronchial asthma.

Allergens↗
PubMed2000

Non-pulmonary effects induced by the addition of formoterol to budesonide therapy in patients with mild or moderate persistent asthma.

OBJECTIVE: The present study was designed to assess the non-pulmonary effects of a 2-week treatment with the addition of formoterol to budesonide therapy in 10 patients with mild or moderate asthma. METHODS: Each patient was invited to perform a screening visit which included spirometry before and after inhalation of 12 microg formoterol with a metered dose inhaler (MDI), measurement of arterial blood pressure, baseline electrocardiography and 24-hour Holter monitoring, and a test for evaluating upper limb tremor. Patients then began bronchodilating therapy with 12 microg formoterol MDI and 400 microg budesonide Turbuhaler b.i.d. Each patient was also given a peak flowmeter and a diary in which he had to record the morning and evening values measured before taking inhaled drugs. Two weeks later, the patients repeated the same examinations; the diary card was returned 2 months after the beginning of the study. RESULTS: Adding formoterol to budesonide therapy caused a significant improvement in lung function, but neither induced any statistically significant effect on mean heart rate, nor altered the circadian rhythm of autonomic regulation nor elicited significant alterations in cardiac morphology. However, the evaluation of upper limb tremor revealed a statistically significant increase (p = 0.02). CONCLUSIONS: This study shows that adding the recommended dose of formoterol to an inhaled corticosteroid therapy does not induce significant cardiac undesirable effects, although tremor, surely due to stimulation of beta(2) receptors of the skeletal muscles, may sometimes be a limiting effect.

Adrenergic beta-Agonists↗
PubMed2000

Lamotrigine-induced lupus.

A 57-year-old woman was under treatment for epilepsy with lamotrigine 2 mg/kg/d since 1996. In April 1998 she was admitted to the Rheumatology Unit for arthralgias affecting the small joints of the hands, wrists and knees, erythematosus skin rash and myalgias. She referred a vascular abnormality at the hands exposed to cold, compatible with Raynaud's phenomenon. Serum antinuclear antibodies (ANA) were positive (1:320, speckled pattern); moreover, a positivity for anti-Ro/SSA was observed. Rheumatoid factor was negative, serum complement was normal. LAC and anticardiolipin antibodies were negative. Drug-related lupus diagnosis was made with resolution of symptoms and gradual normalisation of positivity of ANA and anti-Ro/SSA upon lamotrigine withdrawal. To our knowledge, this is the first case report of an association between lamotrigine and the onset of SLE (systemic lupus erythematosus).

Antibodies, Antinuclear↗
PubMed2000

Interrelationship between the pharmacokinetics and pharmacodynamics of cefaclor advanced formulation in patients with acute exacerbation of chronic bronchitis.

Cefaclor advanced formulation (cefaclor AF) is an extended-release form of the oral cephalosporin cefaclor. When cefaclor AF 750 mg twice-daily and cefaclor immediate release 500 mg three-times-a-day are compared there is a skew to the right of the pharmacokinetic profile and higher levels are achieved. Based on this pharmacokinetic finding, we examined the relationship between the bacterial susceptibility to cefaclor (MIC), the achieved cefaclor AF serum and sputum concentrations, and in vivo eradication of the bacteria in 36 patients with acute exacerbations of chronic bronchitis. The mean peak concentrations in serum and sputum 5 h after administration were 8.6 microg/ml (95% CI: 8.1 microg/ml - 9.1 microg/ml) and 1.5 microg/ml (95% CI: 1.4 microg/ml - 1.7 microg/ml), respectively. Cefaclor was always detectable 8 h after administration. At post therapy, treatment was successful in 31 (86.1%) patients. Cefaclor concentrations in serum persisted above the MIC for more than 40% of dosing interval in 31 subjects, and those in sputum in 24 patients. Treatment was successful in all subjects with percent of time above the MIC in serum of >40%, whereas the time that levels in sputum stayed above the MIC was not the pharmacodynamic parameter that correlated best with therapeutic efficacy for cefaclor. Our data demonstrate that when cefaclor AF is dosed twice-daily, the in vivo pharmacodynamic susceptibility breakpoint is 8 microg/ml. The good activity and pharmacokinetics of cefaclor AF provide serum concentrations higher than the MIC of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for more than 40% of the validated dosing interval. Therefore, it might be considered for first choice treatment of acute exacerbations of chronic bronchitis.

Acute Disease↗
PubMed2000

Comparison of the effects of single oral doses of nebivolol and celiprolol on airways in patients with mild asthma.

OBJECTIVE: The respiratory effects of nebivolol, a new selective ss(1)-adrenergic blocking agent, and celiprolol, a ss-blocker possessing strong ss(1)-adrenoceptor antagonist and mild ss(2)-agonist properties, were investigated in 12 patients with mild asthma. DESIGN: Changes in several spirometric indexes (FVC, FEV(1), and forced expiratory flow rate at 50% of FVC) were measured. The interaction with the bronchodilator effect of the ss(2)-adrenoceptor-selective agonist albuterol also was investigated. RESULTS: The effect of both nebivolol and celiprolol on FEV(1) was considered to be significant (p < 0.05). The administration of nebivolol and celiprolol, but not of placebo, elicited a decrease in FEV(1): mean maximum difference for nebivolol, -0.272 L (95% confidence interval [CI], -0.402 to -0.142); mean maximum difference for celiprolol, -0.193 L (95% CI, -0.316 to -0.071); mean maximum difference for placebo, -0.0001 L (95% CI, -0.087 to 0.085). The inhalation of albuterol, up to a dose of 800 microg, significantly (p < 0.05) improved FEV(1), but the values after nebivolol and celiprolol administration were lower than the initial values. Both ss-blockers caused equal changes in heart rate, systolic BP, and diastolic BP. CONCLUSIONS: There were no significant differences between the respiratory actions of the two active drugs.

Administration, Oral↗
PubMed2000

Additive effects of salmeterol and fluticasone or theophylline in COPD.

BACKGROUND: ss(2)-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma, but this has not been established in COPD. METHODS: Eighty patients with well-controlled COPD were randomized to receive 3 months of treatment in one of four treatment groups: (1) salmeterol, 50 microg bid; (2) salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid; (3) salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid; and (4) salmeterol, 50 microg, plus titrated theophylline bid. At each visit, a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 microg. RESULTS: A gradual increase in FEV(1) was observed with each of the four treatments. Maximum significant increases in FEV(1) over baseline values that were observed after 3 months of treatment were as follows: salmeterol, 50 microg bid, 0.163 L (95% confidence interval [CI], 0.080 to 0.245 L); salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid, 0.188 L (95% CI, 0.089 to 0. 287 L); salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, 0.239 L (95% CI, 0.183 to 0.296 L); and salmeterol, 50 microg, plus titrated theophylline bid, 0.157 L (95% CI, 0.027 to 0. 288 L). Salbutamol always caused a significant dose-dependent increase in FEV(1) (p < 0.001), although the 800-microg dose never induced further significant benefit when compared with the 400-microg dose. The mean differences between the highest salbutamol FEV(1) after salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, and that after salmeterol, 50 microg, plus titrated theophylline bid or salmeterol, 50 microg bid, were statistically significant (p < 0.05). CONCLUSION: These data show that both long-acting ss(2)-agonists and inhaled corticosteroids have a role in COPD. The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone. Moreover, it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol, although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect. In any case, patients must be treated for at least 3 months before a real improvement in lung function is achieved.

Administration, Inhalation↗
PubMed2000

Novel oral cephalosporins.

The therapeutic use of oral cephalosporins to treat infectious diseases continues to challenge clinicians; many attempts have been made over recent years to improve the efficacy and spectrum of these anti-infectives. Many oral cephalosporins are in development and include cefdinir, cefprozil, cefetamet pivoxil, cefcapene pivoxil, cefcanel daloxate hydrochloride in Phase II trials, S-1090 in Phase III trials and the novel compounds E1100, E1101 and BRL-57347. Differences between these drugs are sometimes subtle and the improvement over existing compounds modest, although recent cephalosporins have shown greater activity against Gram-negative bacterial infections. A better knowledge of the pharmacodynamic and pharmacokinetic interrelationships of existing oral cephalosporins is demanded for a more rational use of these compounds and to avoid the subsequent development of resistance. Perhaps with such an approach, the perceived need for new cephalosporins will diminish.

Administration, Oral↗
PubMed2000

Long-acting beta2 agonists in the management of stable chronic obstructive pulmonary disease.

Long-acting beta2 agonist bronchodilators (e.g. formoterol, salmeterol) are a new interesting therapeutic option for patients with chronic obstructive pulmonary disease (COPD). In the short term, both salmeterol and formoterol appear to be more effective than short-acting beta2 agonists, and in patients with stable COPD they are more effective than anticholinergic agents and theophylline. Regular treatment of patients with COPD with long-acting beta2 agonists can induce an improvement in the respiratory function and certain aspects of quality of life. Moreover, salmeterol seems to be better than ipratropium and theophylline in improving lung function at the recommended doses after a long term treatment. Use of combination therapy of a long-acting inhaled beta2 agonist and an anticholinergic agent or theophylline in patients with COPD has not been sufficiently studied. Combination of usual doses of ipratropium or oxitropium with usual doses of salmeterol or formoterol does not appear to improve pulmonary function, but this lack of improvement with the combination should not, in itself, prevent implementation of further therapeutic steps in patients responsive to an anticholinergic agent and/or salmeterol or formoterol administered singly. Neither formoterol nor salmeterol elicit significant cardiovascular effects in healthy individuals and patients with reversible airway obstruction. However, adverse cardiac events might occur in patients with COPD with pre-existing cardiac arrhythmias and hypoxaemia if they use long-acting 12 agonists, although the recommended single dose of salmeterol 50 microg or formoterol 12 microg ensures a relatively higher safety margin than formoterol 24 microg. The bronchodilatory effect of long-acting beta2 agonists seems to be fairly stable after regular treatment with these bronchodilators. Moreover, pre-treatment with a conventional dose of formoterol or salmeterol does not preclude the possibility of inducing further bronchodilation with salbutamol in patients with partially reversible COPD. All these findings support the use of long-acting beta2 agonist bronchodilators as first-line bronchodilator therapy for the long term treatment of airflow obstruction in patients with COPD. However, since physicians must always choose a drug that is highly efficacious, well tolerated and inexpensive, the cost-effectiveness analysis in relation to other bronchodilators will determine the proper place of long-acting beta2 agonists in the long term therapy of stable COPD.

Adrenergic beta-2 Receptor Agonists↗