Myelodysplastic syndromes--coping with ineffective hematopoiesis.
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Angiogenesis Inhibitors↗
Biomedical subjects
Mario Cazzola
Publications and source records attributed to Mario Cazzola.
Treatment of acute exacerbation of severe-to-very severe COPD with azithromycin in patients vaccinated against Streptococcus pneumoniae.
Sixty-five consecutive eligible adult patients, who were treated as outpatients for stable severe-to-very severe COPD, were enrolled in the study. All of them received 23-valent pneumococcal capsular polysaccharide vaccine intramuscularly. Patients were seen monthly, as well as whenever they had symptoms suggestive of an exacerbation, at our outpatient clinic. Eighteen out of 65 patients suffered from acute exacerbation (AECOPD). Three of these patients presented two episodes of AECOPD. Patients with an acute exacerbation of COPD received azithromycin 500 mg/day once daily for 3 days and a short course of oral prednisolone 25 mg/die. In 16 cases, a single species was isolated, while in the remaining 5 cases at least two species were recovered. Clinical cure or improvement at the end of therapy (3-5 days post-therapy) was reported in 17 episodes of AECOPD with no relapse at the late post-therapy (10-14 days after the completion of treatment). Bacteriologic eradication or presumptive eradication rates at the end of therapy were 86% (24 out of 28 isolates). Azithromycin eradicated all isolates of Haemophilus influenzae, Moraxella catarrhalis, H. parainfluenzae, Klebsiella pneumoniae, and Klebsiella spp. isolated at baseline. Eradication of Sta aureus occurred in 1 of 3 isolates whereas azithromycin was unable to eradicate Pseudomonas aeruginosa isolates. Our data seem to indicate that pneumococcal vaccination reduces the possibility that an AECOPD is caused by Streptococcus pneumoniae. This finding allows the use of antibiotics such as azithromycin, which, otherwise, should be avoided because of resistances.
Acute Disease↗
Role of ferritin and ferroportin genes in unexplained hyperferritinaemia.
A large body of evidence indicates that the level of serum ferritin parallels the concentration of storage iron within the body, regardless of the cell type in which it is stored. Elevated serum ferritin levels, in the absence of inflammation and liver disease, are currently taken to indicate increased iron stores and require further investigation to determine the site of iron overload. Until recently, the only genetic disorder with elevated serum ferritin levels known in Western countries was hereditary HLA-related HFE-related genetic haemochromatosis in Caucasians (HFE, OMIM 235200), and a high serum ferritin in apparently healthy persons was considered suggestive of this disease. In the last few years, at least two novel genetic disorders of iron metabolism presenting as unexplained hyperferritinaemia have been recognized. The first one is hereditary hyperferritinaemia/cataract syndrome (HHCS, OMIM 600886). HHCS arises from various point mutations or deletions within a protein binding sequence in the 5'-UTR of the L-ferritin mRNA that results in increased efficiency of L-ferritin translation. The second one is haemochromatosis type 4, or HFE4 (OMIM 606069), or ferroportin disease. In this latter condition, reticuloendothelial iron overload and hyperferritinaemia are caused by loss-of-function mutations in the SLC11A3 gene that mainly impair macrophage iron recycling. These genetic disorders should be taken into account in the differential diagnosis of unexplained hyperferritinaemia.
Anemia↗
The effect of pet ownership on the risk of allergic sensitisation and bronchial asthma.
An increasing volume of evidence suggests that early contact of children with the allergens of furred pets (especially those produced by cats) may determine a lower risk of developing allergic sensitisation to these materials. A possible explanation of this data is that an early inhalation of high levels of the major cat allergen Fel d 1 induces the production of IgG and IgG4 antibodies with a "protective" effect. Other authors have shown that the prevalence of allergic sensitisation to cats, in adults, is reduced in those patients exposed to the lowest and highest levels of the allergens. On the contrary, the risk of developing sensitisation to cats is significantly higher when the patients were exposed to intermediate levels of Fel d 1. Moreover, epidemiological studies have demonstrated a relatively low prevalence of cat allergy (about 10%) in some countries where rates of cat ownership are high. This data confirms the role of indirect exposure to pet allergens in inducing allergic sensitisation. Clothes of pet owners have been indicated as the carriers for the dispersal of these allergens in pet-free environments. However, it is important to point out that exposure of highly sensitised patients to relevant amounts of pet allergens (such as in a pet shows/shops) may determine a dramatic exacerbation of nasal and/or bronchial symptoms.
Adult↗
New insights in allergen avoidance measures for mite and pet sensitized patients. A critical appraisal.
It is widely acknowledged that avoidance of allergens such as those derived from foods, drugs, latex and stinging insects results in a complete disappearance of symptoms. By contrast, although it has been clearly shown that allergens are an important risk factor for the development of respiratory symptoms and that several avoidance measures reduce allergen levels, whether this gives clinical improvement in symptoms is debatable. Many reasons could be invoked to justify this evident discrepancy. Apart from the intrinsic methodological aspects (e.g. single or combined interventions measure, population studied, severity of respiratory symptoms, outcomes, evaluated parameters, etc.), it is important to outline that a successful approach requires that the avoided allergen is the only and real factor responsible for symptoms, the patient's education and the use of a comprehensive protocol to reduce allergen exposure. Other important factors include the involvement of the patient, the relevance of other allergens/non-specific agents, and exposure to sensitizing agents also outside patient's home. It is likely that the clinical phase of allergic airway disease and the degree of bronchial (and also nasal) remodelling, in each individual, represent relevant factors for the clinical outcome of allergen avoidance procedures. Since the management of respiratory allergy is a complex strategy (including drugs, allergen avoidance, immunological and educational interventions), it is difficult in real life to distinguish the efficacy of a single intervention in comparison to the others. A combined strategy is likely to produce better clinical results.
Adult↗
Genetic and clinical heterogeneity of ferroportin disease.
Ferroportin is encoded by the SLC40A1 gene and mediates iron export from cells by interacting with hepcidin. SLC40A1 gene mutations are associated with an autosomal type of genetic iron overload described as haemochromatosis type 4, or HFE4 (Online Mendelian Inheritance in Man number 606069), or ferroportin disease. We report three families with this condition caused by novel SLC40A1 mutations. Denaturing high-performance liquid chromatography was employed to scan for the SLC40A1 gene. A D181V (A846T) mutation in exon 6 of the ferroportin gene was detected in the affected members of an Italian family and shown to have a de novo origin in a maternal germinal line. This mutation was associated with both parenchymal and reticuloendothelial iron overload in the liver, and with reduced urinary hepcidin excretion. A G80V (G543T) mutation in exon 3 was found in the affected members of an Italian family with autosomal hyperferritinaemia,. Finally, a G267D (G1104A) mutation was identified in exon 7 in a family of Chinese descent whose members presented with isolated hyperferritinaemia. Ferroportin disease represents a protean genetic condition in which the different SLC40A1 mutations appear to be responsible for phenotypic variability. This condition should be considered not only in families with autosomal iron overload or hyperferritinaemia, but also in cases of unexplained hyperferritinaemia.
Adolescent↗
Pharmacodynamics of levofloxacin in patients with acute exacerbation of chronic bronchitis.
STUDY OBJECTIVES: Levofloxacin is a fluoroquinolone antimicrobial agent for which pharmacodynamic relationships between the maximum serum antibiotic concentration (Cmax)/minimum inhibitory concentration (MIC) ratio and/or the area under the serum concentration-time curve during a 24-h dosing period (AUC(0-24))/MIC ratio and clinical and/or microbiological outcomes have been developed. In this study we examined the relationship between the in vitro bacterial susceptibility to levofloxacin, the achieved levofloxacin serum and sputum concentrations, and the in vivo bacterial eradication in patients with acute exacerbations of chronic bronchitis. PATIENTS AND INTERVENTIONS: Thirty patients received levofloxacin, 500 mg/d po for 7 days. Samples of venous blood and sputum for the determination of levofloxacin concentrations were collected on day 1 immediately prior to dosing, and then at 1, 4, 8, 12, and 24 h. RESULTS: The mean peak concentration in serum (6.5 mg/L) was found 1 h after administration, and at 4 h after administration in sputum (5.1 mg/L). Levofloxacin was always detectable 24 h after administration from both samples. Successful treatment occurred in 90% (27 of 30 patients) when assessed both clinically and bacteriologically. Treatment was successful in eight patients when the AUC(0-24)/MIC ratio was > 40 for serum, and in nine patients when it was > 30 for sputum. Treatment was also successful in seven patients when the Cmax/MIC ratio was > 5.01 for serum, and in nine patients when the Cmax/MIC ratio was > 4.01 for sputum. Treatment was successful in 90% (27 of 30 patients) when the AUC(0-24)/MIC ratio was > 125 for serum and > 100 for sputum, and when Cmax/MIC was > 10.01 for serum and > 8.01 for sputum following the first dose. CONCLUSIONS: The pharmacodynamics values that we have obtained in sputum with levofloxacin may be used as predictors of therapy outcomes.
Acute Disease↗
Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease.
After the discovery of formoterol and salmeterol, new candidates for long-acting beta2-adrenoceptor agonists (LABAs) have emerged from various companies. In particular, once-daily beta2-adrenoceptor agonists such as arformoterol, carmoterol, indacaterol, GSK-159797, GSK-597901, 159802, 642444 and 678007 are under development for the treatment of asthma and chronic obstructive pulmonary disease. The majority of these compounds are (R,R)-isomers in order to control desensitisation and accumulation. Several options for combination products are currently being evaluated in parallel with the development of these ultra LABAs. Once-daily dosing of an ultra LABA would be a significant convenience and probably a compliance-enhancing advantage leading to improved overall clinical outcomes in patients with asthma and chronic obstructive pulmonary disease. The only limits set for the development of a LABA with a new product profile are medical needs and marketing opportunities.
Adrenergic beta-2 Receptor Agonists↗
Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease.
Although large surveys have documented the favourable safety profile of beta(2)-adrenoceptor agonists (beta(2)-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of beta(1)- and beta(2)-adrenoceptors in the heart clearly indicates that beta(2)-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the beta(2)-agonists utilised in clinical practice have differing selectivities and potencies. beta(2)-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of beta(2)-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, beta(2)-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease.
Administration, Inhalation↗
Pyruvate kinase deficiency.
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Adenosine Diphosphate↗
Gain of function, loss of control - a molecular basis for chronic myeloproliferative disorders.
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Chromosome Aberrations↗
Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma.
Ten patients with moderate to severe asthma (mean FEV1+/-SD: 57.3+/-5.8% of predicted) participated in this 4-day single-blind, placebo-controlled, crossover study, aimed to comparatively evaluate the bronchodilating effects of a single dose of inhaled salmeterol (50 microg) and oral slow-release theophylline (Theo-Dur, 600 mg tablets), used either alone or in combination. In particular, FEV1 was recorded at baseline and 2, 4, 6, 8, 10, and 12 h after drug administration; at the same times, with the exception of the 12 th h, theophylline plasma concentrations were also measured. When compared to theophylline, bronchodilation induced by salmeterol was characterized by an earlier onset, a greater magnitude, and a longer duration. Given in combination with salmeterol, theophylline elicited a further slight increase in airway calibre with respect to the bronchodilator action of the beta2-agonist alone, with FEV1 changes which resulted to be statistically significant at the 4th, 6th and 8th h after administration (p<0.05, p<0.03 and p<0.05, respectively). At the 4th h theophylline reached serum levels included within the therapeutic range, which were persistently maintained at least until the the 10th h. Therefore, our findings suggest that inhaled salmeterol and oral slow-release theophylline, the latter acting within the range of therapeutic plasma concentrations, exert additive bronchodilating effects in asthmatic patients with moderate to severe airflow limitation.
Administration, Oral↗
Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients.
We conducted a randomized, crossover trial with tiotropium 18 microg once daily (group A), and formoterol 12 microg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 microg+formoterol 12 microg; group B: formoterol 12 microg+tiotropium 18 microg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154-0.298) after tiotropium+formoterol and 0.228 L (0.165-0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029-0.133) after tiotropium+formoterol and 0.054 L (0.016-0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361-0.676) after tiotropium+formoterol and 0.495 L (0.307-0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048-0.270) after tiotropium+formoterol and 0.175 L (0.083-0.266) after formoterol+tiotropium. The FEV1 AUCs(0-360 min) were 62.70 (45.67-79.74) after tiotropium+formoterol and 69.20 (50.84-87.57) after formoterol+tiotropium, the FEV1 AUCs(0-180 min) were 24.70 (18.19-31.21) after tiotropium+formoterol and 29.74 (21.02-38.46) after formoterol+tiotropium, whereas the FEV1 AUCs(180-360 min) were 15.70 (10.88-20.52) after tiotropium+formoterol and 11.71 (7.21-16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P>0.05). The addition of second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient's advantage.
Administration, Inhalation↗
Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.
PURPOSE: To assess life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. METHODS: The study sample consisted of 831 consecutive patients with polycythemia vera (n = 396; 4184 person-years of follow-up) or essential thrombocythemia (n = 435; 4304 person-years of follow-up). Mortality in each group was compared with the Italian population using the standardized mortality ratio (SMR) based on life expectancy data obtained from the Italian Institute of Statistics. RESULTS: The 15-year survival was 65% in patients with polycythemia and 73% in those with thrombocythemia. By Cox regression analysis, the independent predictors of death were a history of thrombosis for polycythemia (hazard ratio [HR] = 2.2; P = 0.0002) and thrombocythemia (HR = 2; P = 0.01), and male sex (HR = 1.8; P = 0.03) for thrombocythemia. Mortality compared with the general population was 1.6-fold higher (P <0.001) in patients with polycythemia but was not increased in those with thrombocythemia (SMR = 1; P = 0.8). CONCLUSION: Life expectancy of patients with polycythemia vera (especially if younger than 50 years) was reduced compared with the general population, whereas life expectancy of patients with essential thrombocythemia was not affected significantly by the disease, reflecting the more indolent nature of the proliferation. History of thrombosis was the main predictor of death in both diseases.
Female↗
Cutaneous and serological responses to cat allergen in adults exposed or not to cats.
BACKGROUND: The relationship between pet ownership and the risk of developing respiratory allergic sensitization to pet allergens is still controversial. OBJECTIVE: To determine the degree of cutaneous immediate hypersensitivity and the levels of specific IgE and IgG4 antibodies to cat allergen in cat sensitized patients directly or indirectly exposed to this animal. METHODS: We studied 112 adolescents and adults sensitized to cat allergens (43 with and 69 without a cat at home). There were also 52 control subjects, 27 atopic non-sensitized to cat and 25 non-atopic. The degree of immediate hypersensitivity was assessed by using, in duplicate, skin prick test with four five-fold dilutions of cat hair allergen extract with the content of its major allergen Fel d 1 quantified in micrograms plus positive (10 mg/ml histamine chlorhydrate) and negative (saline solution) controls. The resulting wheal areas were analysed by means of Parallel Line Assay. A blood sample was collected from every patient and control subjects for the evaluation of serological cat specific IgE and IgG4 antibodies. RESULTS: Patients with cat at home had a lower cutaneous response than patients without this pet. The difference in the skin sensitivity was estimated in 3.4 times (P<0.01). There was no statistical difference between the levels of cat specific IgE antibodies in the two groups of patients (P=0.065). The levels of Fel d 1 specific IgG4 antibodies showed a statistically significant association with the presence of cat at home, with higher levels in patients owing cat at home than in patients without this pet (P<0.001). CONCLUSION: The results of this study demonstrate that direct cat exposure in adolescents and adults with respiratory allergy is associated with a lower cutaneous response to cat allergenic extract, assessed by SPT and compared with indirect exposure. In patients with cat at home mean levels of specific IgE are statistically comparable whereas the levels of IgG4 are higher in comparison with subjects not exposed to cats. The role of indirect exposure to cat allergens in airways sensitization also in adults is emphasized. Moreover, patients with cat at home show a cutaneous and serological sensitization to cat allergen not higher in comparison with subjects not exposed to cats.
Adolescent↗
Long-term follow-up of young patients with essential thrombocythemia treated with pipobroman.
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Adult↗
Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis.
Juvenile or type 2 hemochromatosis (JH) is transmitted as a recessive trait that leads to severe iron overload and organ damage typically before age 30 years. Linkage to a locus on chromosome 1q has been found in most patients with JH. The recently identified causal gene encodes hemojuvelin, a protein with a proposed crucial role in iron metabolism. A second, rare type of JH, with clinical expression identical to the 1q-linked form, is due to inactivation of hepcidin, the key regulator of iron homeostasis. Here we report the spectrum of mutations of the hemojuvelin gene (HJV) in 34 patients who did not show hepcidin mutations. This represents the largest cohort of patients with JH collected worldwide. We identified 17 different (16 novel) mutations of HJV, both at the homozygous and at the compound heterozygous state. Mutations either generate premature termination codons or were missense substitutions, affecting highly conserved residues, relevant to the protein structure and/or function.
Adolescent↗
The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD.
The aim of this double-blind, double-dummy, cross-over, randomized, pilot study was to compare the acute bronchodilator efficacy of a single dose of formoterol with that of tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). Because the potential of tiotropium for additive effects is yet unknown, the acute effects of adding this anticholinergic agent to formoterol were also explored. A total of 20 outpatients with stable COPD were enrolled. Single doses of 12 microg formoterol, 18 microg tiotropium, and 12 microg formoterol+18 microg tiotropium were given. Serial measurements of FEV1 were performed over 24 h. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action and showed a trend for a greater maximum bronchodilation than tiotropium alone. At 24 h, mean FEV1 continued to be significantly higher than pre-dosing value following tiotropium and formoterol+tiotropium. These findings indicate that formoterol and tiotropium have different profiles that make both agents attractive alternatives in the treatment of stable COPD. Since tiotropium ensures prolonged bronchodilation, whereas formoterol adds fast onset and a greater peak effect, the two drugs appear complementary.
Administration, Inhalation↗